17.9: Extension of the EM Approach - Biology

17.9: Extension of the EM Approach - Biology

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The approach presented before (OOPS) relies on the assumption that every sequence is characterized by only one motif (e.g., there is exactly one motif occurrence in a given sequence). The ZOOPS model takes into consideration the possibility of sequences not containing motifs.

In this case let i be a sequence that does not contain a motif. This extra information is added to our previous model using another parameter λ to denote the prior probability that any position in a sequence is the start of a motif. Next, the probability of the entire sequence to contain a motif is λ = (L − W + 1) ∗ λ

The E-Step

The E-step of the ZOOPS model calculates the expected value of the missing information–the probability that a motif occurrence starts in position j of sequence Xi. The formulas used for the three types of model are given below.

where λt is the probablity that sequence i has a motif, Prt(Xi|Qi = 0) is the probablity that Xi is generated from a sequence i that does not contain a motif

The M-Step

The M-step of EM in MEME re-estimates the values for λ using the preceding formulas. The math remains the same as for OOPS, we just update the values for λ and γ

The model above takes into consideration sequences that do not have any motifs. The challenge is to also take into consideration the situation in which there is more than one motif per sequence. This can be accomplished with the more general model TCM. TCM (two-component mixture model) is based on the assumption that there can be zero, one, or even two motif occurrences per sequence.

Finding Multiple Motifs

All the above sequence model types model sequences containing a single motif (notice that TCM model can describe sequences with multiple occurences of the same motif). To find multiple, non-overlapping, different motifs in a single dataset, one incorporates information about the motifs already discovered into the current model to avoid rediscovering the same motif. The three sequence model types assume that motif occurrences are equally likely at each position j in sequences xi. This translates into a uniform prior probability distribution on the missing data variables Zij. A new prior on each Zij had to be used during the E-step that takes into account the probability that a new width-W motif occurrence starting at position Xij might overlap occurrences of the motifs previously found. To help compute the new prior on Zij we introduce variables Vij where Vij = 1 if a width-W motif occurrence could start at position j in the sequence Xi without overlapping an occurrence of a motif found on a previous pass. Otherwise Vij = 0.

N-terminal Transmembrane-Helix Epitope Tag for X-ray Crystallography and Electron Microscopy of Small Membrane Proteins

Structural studies of membrane proteins, especially small membrane proteins, are associated with well-known experimental challenges. Complexation with monoclonal antibody fragments is a common strategy to augment such proteins however, generating antibody fragments that specifically bind a target protein is not trivial. Here we identify a helical epitope, from the membrane-proximal external region (MPER) of the gp41-transmembrane subunit of the HIV envelope protein, that is recognized by several well-characterized antibodies and that can be fused as a contiguous extension of the N-terminal transmembrane helix of a broad range of membrane proteins. To analyze whether this MPER-epitope tag might aid structural studies of small membrane proteins, we determined an X-ray crystal structure of a membrane protein target that does not crystallize without the aid of crystallization chaperones, the Fluc fluoride channel, fused to the MPER epitope and in complex with antibody. We also demonstrate the utility of this approach for single particle electron microscopy with Fluc and two additional small membrane proteins that represent different membrane protein folds, AdiC and GlpF. These studies show that the MPER epitope provides a structurally defined, rigid docking site for antibody fragments that is transferable among diverse membrane proteins and can be engineered without prior structural information. Antibodies that bind to the MPER epitope serve as effective crystallization chaperones and electron microscopy fiducial markers, enabling structural studies of challenging small membrane proteins.

Keywords: cryo-EM crystallization chaperone electron microscopy fiducial marker membrane protein transporter.

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

17.9: Extension of the EM Approach - Biology

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All group 4 subjects (except computer science and environmental systems and societies see below) follow roughly the same format. Each subject has its Subject Specific Core (SSC), i.e., material taught at both the standard and higher levels. Students sitting the Higher Level examination study the Additional Higher Level (AHL) material. Lastly, there is a list of options for each subject from which two are chosen. Higher Level students are sometimes unable to choose certain options that are available to Standard Level students because the AHL already covers it. Ideally, students choose the options based on their own abilities and preferences, but in practice the options are usually chosen by the school (based on the school's scientific facilities as well as the discretion of the instructor). Students spend one-quarter of the 150 hours of SL instruction (240 hours for HL however, both numbers are merely recommendations and are not enforced) doing practical work in the laboratory. Group 4 subjects at the Standard Level are tailored for students who do not see themselves in further science instruction after leaving the programme. [6]

Assessment of a Group 4 subject comprises the following:

  • Internal assessment of the practical work (24%)
  • Paper 1 – multiple choice questions on the SSC (20%)
  • Paper 2 – free response questions on the SSC (32% at SL, 36% at HL)
  • Paper 3 – free response questions on the options (24% at SL, 20% at HL)

At the Standard Level, the examinations are respectively 45 minutes, 1 hour and 15 minutes, and 1 hour long. At the Higher Level, they are 1 hour, 2 hours and 15 minutes, and 1 hour and 15 minutes long. Calculators are not permitted for Paper 1, but they (as well as a provided formula booklet and periodic table) are permitted for papers 2 and 3.

Physics (2009–2015) Edit

Standard level Edit

80 hours of instruction on 8 topics

  • Physics and physical measurement and waves
  • Fields and forces
  • Atomic and nuclear physics
  • Energy, power and climate change

with 30 hours of instruction on two optional subjects:

and 40 hours of practical work. [7]

Higher level Edit

80 hours on Physics SL core subjects, with 55 hours on 6 additional topics:

  • Motion in fields
  • Wave phenomena
  • Electromagnetic induction and nuclear physics
  • Digital technology

and 45 hours of instruction on two optional subjects:

and 60 hours of practical work. [8]

Physics (2016–2022) Edit

Topics Edit

SL/HL core Edit
  • Topic 1: Measurements and uncertainties (5 hours)
  • Topic 2: Mechanics (22 hours)
  • Topic 3: Thermal physics (11 hours)
  • Topic 4: Waves (15 hours)
  • Topic 5: Electricity and magnetism (15 hours)
  • Topic 6: Circular motion and gravitation (5 hours)
  • Topic 7: Atomic, nuclear and particle physics (14 hours)
  • Topic 8: Energy production (8 hours)
HL extension Edit
  • Topic 9: Wave phenomena (17 hours)
  • Topic 10: Fields (11 hours)
  • Topic 11: Electromagnetic induction (16 hours)
  • Topic 12: Quantum and nuclear physics (16 hours)
Options Edit
  • Option A: Relativity (15/25 hours)
  • Option B: Engineering physics (15/25 hours)
  • Option C: Imaging (15/25 hours)
  • Option D: Astrophysics (15/25 hours)

Chemistry (2009–2015) Edit

Standard level Edit

80 hours of instruction on the topics:

  • Quantitative Chemistry
  • Atomic structure
  • Periodicity
  • Bonding
  • Energetics
  • Kinetics
  • Equilibrium
  • Measurement and data processing

and 30 hours on two options from the topics:

  • Modern analytical chemistry
  • Human Biochemistry
  • Chemistry in industry and technology
  • Medicines and drugs
  • Environmental Chemistry
  • Food chemistry
  • Further Organic Chemistry

together with 40 hours of practical work. [10]

Higher level Edit

80 hours on the core subjects of the Standard level course with 55 hours of instruction on these topics:

and 45 hours on two of the options in the standard course, and 60 hours of practical work. [11]

Chemistry (2016–2022) Edit

Topics Edit

SL/HL core and HL extension Edit
  • Topic 1: Stoichiometric relationships (13.5 hours)
  • Topic 2 + 12: Atomic structure (6/8 hours)
  • Topic 3 + 13: Periodicity (6/10 hours)
  • Topic 4 + 14: Chemical bonding and structure (13.5/20.5 hours)
  • Topic 5 + 15: Energetics/thermochemistry (9/16 hours)
  • Topic 6 + 16: Chemical kinetics (7/13 hours)
  • Topic 7 + 17: Equilibrium (4.5/8.5 hours)
  • Topic 8 + 18: Acids and bases (6.5/16.5 hours)
  • Topic 9 + 19: Redox processes (8/14 hours)
  • Topic 10 + 20: Organic chemistry (11/23 hours)
  • Topic 11 + 21: Measurement and data processing (10/12 hours)
Options Edit
  • Option A: Materials (15/25 hours)
  • Option B: Biochemistry (15/25 hours)
  • Option C: Energy (15/25 hours)
  • Option D: Medicinal chemistry (15/25 hours)

Biology (2009–2015) Edit

Biology is the science of life and living organisms. Aside from instruction relevant to this, students are given the chance to learn complex laboratory techniques (e.g., DNA extraction) as well as develop mindful opinions about controversial topics in biology (e.g., stem-cell research and genetic modification). The syllabus lists thirteen topics, to be covered in an order varying from school to school:

Standard level Edit

80 hours of instruction on 6 topics

with 30 hours of instruction on two options from:

    and health
  • Physiology of exercise
  • Cells and energy and behavior
  • Microbes and Biotechnology and conservation[13]

Higher level Edit

80 hours of instruction on 6 topics in the standard course and 55 hours on a further 5 topics:

with 45 hours of instruction on addition topics in the SL course plus:

Biology (2016–2022) Edit

Topics Edit

SL/HL core Edit
  • Topic 1: Cell biology (15 hours)
  • Topic 2: Molecular biology (21 hours)
  • Topic 3: Genetics (15 hours)
  • Topic 4: Ecology (12 hours)
  • Topic 5: Evolution and biodiversity (12 hours)
  • Topic 6: Human physiology (20 hours)
HL extension Edit
  • Topic 7: Nucleic acids (9 hours)
  • Topic 8: Metabolism, cell respiration and photosynthesis (14 hours)
  • Topic 9: Plant biology (13 hours)
  • Topic 10: Genetics and evolution (8 hours)
  • Topic 11: Animal physiology (16 hours)
Options Edit
  • Option A: Neurology and behaviour (15/25 hours)
  • Option B: Biotechnology and bioinformatics (15/25 hours)
  • Option C: Ecology and conservation (15/25 hours)
  • Option D: Human physiology (15/25 hours)

Design technology (2009–2015) Edit

Topics addressed in this course include:

  • Design process
  • Product innovation
  • Green design
  • Materials
  • Product development
  • Product design
  • Evaluation

with additional topics in the higher level:

  • Energy
  • Structures
  • Mechanical design
  • Advanced manufacturing techniques
  • Sustainable development. [16]

Design technology (2016–2022) Edit

Topics Edit

SL/HL core Edit
  • Topic 1: Human factors and ergonomics (12 hours)
  • Topic 2: Resource management and sustainable production (22 hours)
  • Topic 3: Modelling (12 hours)
  • Topic 4: Raw material to final product (23 hours)
  • Topic 5: Innovation and design (13 hours)
  • Topic 6: Classic design (8 hours)
HL extension Edit
  • Topic 7: User-centred design (UCD) (12 hours)
  • Topic 8: Sustainability (14 hours)
  • Topic 9: Innovation and markets (13 hours)
  • Topic 10: Commercial production (15 hours)

Sport, exercise and health science (2014–2020) Edit

Topics Edit

Core Edit

All candidates study the 6 core topics (80 hours):

  • Topic 1: Anatomy (7 hours)
  • Topic 2: Exercise physiology (17 hours)
  • Topic 3: Energy systems (13 hours)
  • Topic 4: Movement analysis (15 hours)
  • Topic 5: Skill in sport (15 hours)
  • Topic 6: Measurement and evaluation of human performance (13 hours)
Options Edit

In addition, they also study two of the following four options (30 hours):

  • Option A: Optimizing physiological performance (15 hours)
  • Option B: Psychology of sport (15 hours)
  • Option C: Physical activity and health (15 hours)
  • Option D: Nutrition for sport, exercise and health (15 hours)

Environmental systems and societies (2010–2016) Edit

Topics Edit

All topics are compulsory (i.e. there are no options).

  • Topic 1: Systems and models (5 hours)
  • Topic 2: The ecosystem (31 hours)
  • Topic 3: Human population, carrying capacity and resource use (39 hours)
  • Topic 4: Conservation and biodiversity (15 hours)
  • Topic 5: Pollution management (18 hours)
  • Topic 6: The issue of global warming (6 hours)
  • Topic 7: Environmental value systems (6 hours)

The remaining 30 hours are derived from the internal assessment (practical work), making a total of 150 teaching hours.

Assessment Edit

There are two external assessment components and one internal assessment component.

External assessment Edit

Calculators are required for both papers.

  • Paper 1 (45 raw marks contributing 30% of the course, 1 hour) consists of short-answer and data-based questions.
  • Paper 2 (65 raw marks contributing 50% of the course, 2 hours) consists of:
    • Section A: Candidates are required to analyse and make reasoned and balanced judgements relating to a range of data on a specific unseen case study.
    • Section B: Candidates are required to answer two structured essay questions from a choice of four.
    Internal assessment Edit

    Candidates will need to complete 30 hours of practical work throughout the course. Each of the three criteria - planning (Pl), data collection and processing (DCP) and discussion, evaluation and conclusion (DEC) - are assessed twice, while the fourth criterion - personal skills (PS) - is assessed summatively throughout the course. The maximum raw mark is 42, which contributes 20% of the course.

    Computer science (2014–2020) Edit

    [20] The computer science course was recently updated and moved from Group 5 (as an elective course) to Group 4, becoming a full course, from first examinations in 2014. The structure and assessment of the course has changed to greater emphasize problem solving rather than Java program construction. [21] The curriculum model for the course still differs from other Group 4 subjects however.

    Topics Edit

    Standard Level candidates study the SL/HL core (80 hours) and the core of one option (30 hours), while Higher Level candidates study the SL/HL core (80 hours), HL extension (45 hours), an annually-issued case study (30 hours) and the whole of one option (30 + 15 hours). The remaining 40 hours for both Standard and Higher Level comes from the internal assessment component, for a total of 150 teaching hours at SL and 240 hours at HL.

    SL/HL core Edit
    • Topic 1: System fundamentals (20 hours)
    • Topic 2: Computer organization (6 hours)
    • Topic 3: Networks (9 hours)
    • Topic 4: Computational thinking, problem-solving and programming (45 hours)
    HL extension Edit
    • Topic 5: Abstract data structures (23 hours)
    • Topic 6: Resource management (8 hours)
    • Topic 7: Control (14 hours)
    Options Edit
    • Option A: Databases (30/45 hours)
    • Option B: Modelling and simulation (30/45 hours)
    • Option C: Web science (30/45 hours)
    • Option D: Object-oriented programming (30/45 hours)

    Assessment Edit

    There are three external assessment components and two internal assessment components.

    External assessment Edit

    Unlike other Group 4 subjects, calculators are not permitted in any computer science examination.

    • Paper 1 (SL: 70 raw marks contributing 45% of the course, 1 hour 30 minutes HL: 100 raw marks contributing 40% of the course, 2 hours 10 minutes) consists of:
      • Section A (about 30 minutes): Compulsory short answer questions on the SL/HL core and (for HL) the HL extension. Some questions are common to HL and SL. The maximum raw mark for this section is 25.
      • Section B (60 minutes for SL, 100 minutes for HL): 3 (SL) or 5 (HL) compulsory structured questions on the SL/HL core and the HL extension. Some questions may be common to HL and SL. The maximum raw marks for this section is 45 (SL) or 75 (HL).
      Internal assessment Edit

      Both SL and HL candidates must complete the following:

      • A computational solution (30 hours, 34 raw marks). Candidates will need to develop a solution for a client to a problem or an unanswered question. This can be in the form of an entirely new system, or an addition of functionality to an existing system. Candidates will need to select, identify and work closely with an adviser, a third-party that can assist the candidate throughout the creation of the product. Candidates will need to complete an electronic HTML cover sheet (not assessed), the product and the documentation of the product (maximum 2000 words in total), including a 2 to 7-minute video showing the functionality of the product. The entire solution and documentation is marked against 5 criteria and is digitally compressed in a ZIP file and submitted for moderation.
      • The group 4 project (10 hours, 6 raw marks). Candidates will need to complete an interdisciplinary project with other science students. This is marked against the personal skills criterion.

      Both components carry a weightage of 30% (SL) or 20% (HL) of the computer science course.

      All students of the Diploma Programme in any of these subjects, with the exception of environmental systems and societies, will compulsorily complete an inter-disciplinary and collaborative investigation called the Group 4 project. The Group 4 project assessment is included in the internal assessment marks. Students undertaking two or more group 4 courses will obtain the same mark for all of the courses.

      Nicotinic Acetylcholine Receptors

      Quaternary Structure

      The overall shape of the ACh receptor is known from cryo-electron microscopy of two-dimensionally ordered Torpedo receptors in membrane [ 16 ] and from the X-ray structure of the ACh binding protein [ 14 ]. The receptor is a narrow-waisted cylinder, roughly 120 Å in length, of which 65 Å is extracellular, 30 Å spans the lipid bilayer, and 25 Å is intracellular. The extracellular domain is 80 Å in diameter. The five subunits are arranged like thick barrel staves around an axial channel. The channel lumen is about 30 Å in diameter in the extracellular domain and tapers to less than 10 Å in the membrane domain. It is possible that access to the channel on the cytoplasmic side is through gaps between the cytoplasmic domains of neighboring subunits [ 16 ].

      Gero scientists found a way to break the limit of human longevity

      The research team of Gero, a Singapore-based biotech company in collaboration with Roswell Park Comprehensive Cancer Center in Buffalo NY, announces a publication in Nature Communications, a journal of Nature portfolio, presenting the results of the study on associations between aging and the loss of the ability to recover from stresses.

      Recently, we have witnessed the first promising examples of biological age reversal by experimental interventions. Indeed, many biological clock types properly predict more years of life for those who choose healthy lifestyles or quit unhealthy ones, such as smoking. What has been still unknown is how quickly biological age is changing over time for the same individual. And especially, how one would distinguish between the transient fluctuations and the genuine bioage change trend.

      The emergence of big biomedical data involving multiple measurements from the same subjects brings about a whole range of novel opportunities and practical tools to understand and quantify the aging process in humans. A team of experts in biology and biophysics presented results of a detailed analysis of dynamic properties of the fluctuations of physiological indices along individual aging trajectories.

      Healthy human subjects turned out to be very resilient, whereas the loss of resilience turned out to be related to chronic diseases and elevated all-cause mortality risks. The rate of recovery to the equilibrium baseline level after stresses was found to deteriorate with age. Accordingly, the time needed to recover was getting longer and longer. Being around 2 weeks for 40 y.o. healthy adults the recovery time stretched to 6 weeks for 80 y.o. on average in the population. This finding was confirmed in two different datasets based on two different kinds of biological measurements - blood test parameters on one hand and physical activity levels recorded by wearable devices on the other hand.

      "Calculation of resilience based on physical activity data streams has been implemented in GeroSense iPhone app and made available for the research community via web-based API." - commented the first author of the study, Tim Pyrkov, head of the mHealth project at Gero.

      If the trend holds at later ages, the extrapolation shows a complete loss of human body resilience, that is the ability to recover, at some age around 120-150 y.o. The reduced resilience was observed even in individuals not suffering from major chronic disease and led to the increase in the range of the fluctuations of physiological indices. As we age, more and more time is required to recover after a perturbation, and on average we spend less and less time close to the optimal physiological state.

      The predicted loss of resilience even in the healthiest, most successfully aging individuals, might explain why we do not see an evidential increase of the maximum lifespan, while the average lifespan was steadily growing during the past decades. The divergent fluctuations of physiological indices may mean that no intervention that does not affect the decline in resilience may effectively increase the maximum lifespan and hence may only lead to an incremental increase in human longevity.

      Aging in humans is a complex and multi-stage process. It would, therefore, be difficult to compress the aging process into a single number, such as biological age. Gero's work shows that longitudinal studies open a whole new window on the aging process and produce independent biomarkers of human aging, suitable for applications in geroscience and future clinical trials of anti-aging interventions.

      "Aging in humans exhibits universal features common to complex systems operating on the brink of disintegration. This work is a demonstration of how concepts borrowed from physical sciences can be used in biology to probe different aspects of senescence and frailty to produce strong interventions against aging.", - says Peter Fedichev, co-founder and CEO of Gero.

      Accordingly, no strong life extension is possible by preventing or curing diseases without interception of the aging process, the root cause of the underlying loss of resilience. We do not foresee any laws of nature prohibiting such an intervention. Therefore, the aging model presented in this work may guide the development of life-extending therapies with the strongest possible effects on healthspan.

      "This work by the Gero team shows that longitudinal studies provide novel possibilities for understanding the aging process and systematic identification of biomarkers of human aging in large biomedical data. The research will help to understand the limits of longevity and future anti-aging interventions. What's even more important, the study may help to bridge the rising gap between the health- and life-span, which continues to widen in most developing countries." - says Brian Kennedy, Distinguished Professor of Biochemistry and Physiology at National University Singapore.

      "This work, in my opinion, is a conceptual breakthrough because it determines and separates the roles of fundamental factors in human longevity - the aging, defined as progressive loss of resilience, and age-related diseases, as "executors of death" following the loss of resilience. It explains why even most effective prevention and treatment of age-related diseases could only improve the average but not the maximal lifespan unless true antiaging therapies have been developed" - says prof. Andrei Gudkov, PhD, Sr. Vice President and Chair of Department of Cell Stress Biology at Roswell Park Comprehensive Cancer Center, a co-author of this work and a co-founder of Genome Protection, Inc., a biotech company that is focused on the development of antiaging therapies/.

      "The investigation shows that recovery rate is an important signature of aging that can guide the development of drugs to slow the process and extend healthspan." - commented David Sinclair, Harvard Medical School professor of genetics.

      "The research from Gero surprisingly comes to a similar quantification of human resilience - a proposed biomarker of ageing - based on two very different kinds of data: blood test parameters on one hand and physical activity levels recorded by wearable devices on the other hand. I'm very excited to see how Person-generated Health Data, including data from commercial wearables, can help create individual, longitudinal profiles of health that will be instrumental to shed light on lifetime-scale health phenomena, such as ageing." - commented Luca Foschini, Co-founder & Chief Data Scientist at Evidation Health.

      The authors characterized the dynamics of physiological parameters on time scales of human lifespan by a minimum set of two parameters. The first is an instant value, often referred to as the biological age, and is exemplified in this work by the Dynamic Organism State Index (DOSI). The quantity is associated with stresses, lifestyles and chronic diseases and can be computed from a standard blood test.

      The other parameter - the resilience - is new and reflects the dynamic properties of the organism state fluctuations: it informs how quickly the DOSI value gets back to the norm in response to stresses.

      Age-related changes in physiological parameters start from birth. However, various parameters change in different ways at different stages of life, see, e.g., a previous work by the same authors published in Aging US in 2018).

      The data from the Nature Communications work shows that there is a good differentiation between the growth phase (mostly complete by the age of 30 and following the universal growth theory by Geoffrey West and aging. At 40+ years, aging manifests itself as a slow (linear, sub-exponential) deviation of physiological indices from their reference values.

      How often should one measure biological age?

      Physiological parameters are naturally subject to fluctuations around some equilibrium level. Glucose levels rise and drop after having a meal, the number of sleeping hours is slightly different each day. Yet, one can collect a longitudinal dataset, that is a series of such measurements for the same person, and observe that the average levels are different between individuals. Resilience also requires repeated measurements, since one needs to know exactly when recovery was achieved to calculate the resilience.

      Importantly, resilience also provides a convenient guide on how often repeated measurements should be taken. As a rule of thumb, the period of observation required for the robust bioage determination should comprise multiple stress and recovery events. For the most healthy individuals such an observation period would amount to several months and should increase with age. During that time, a robust bioage determination would require several data points per recovery time, that is ideally one measurement in a few days.

      Wearable technology comes into play

      In 2021, the only practical way to achieve a high (once-per-day or better) sampling rate is to use mobile/wearable sensor data.

      In another paper, the authors have focused on wearable/mobile sensor data. They have built "wearable DOSI", which they called GeroSense and reported its validation tests in Pyrkov et al. Aging (Albany NY) 13.6 (2021): 7900. GeroSense can be used to compute resilience. Population study shows that the number of individuals showing signs of the loss of resilience increases exponentially with age and doubles every 8 years at a rate matching that of the Gompertz mortality law (the observation by B. Gompertz from 1827, who observed for the first time that the all-cause mortality rate doubles every 8 years).

      Gero is a data-driven biotech company applying modern AI/ML tools to big longitudinal biomedical data to understand aging and major diseases.

      Gero AI/ML models are originating from the physics of complex dynamic systems. We have presented our unique approach in Frontiers in Genetics (Fedichev 2018, Frontiers in genetics 9:483). We combine the potential of deep neural networks with the physical models to study human health as a dynamic process. In conjunction with high-quality genetics data, we produce quantitative explanatory models of (aka theory of) aging and complex diseases, as well as actional drug target hypotheses.

      Gero conducts high-quality research in collaborations with Harvard Medical School, Massachusetts Institute of Technology, University of Edinburgh, National University of Singapore, Moscow Institute of Physics and Technology, and Roswell Park Comprehensive Cancer Center. The company is a regular contributor to peer-reviewed journals.

      Gero has developed a unique framework "GeroSense" for continuous day-to-day monitoring of biological age based on data streams of mobile and wearable sensors. "GeroSense" provides biological age monitoring in our free iPhone app.

      Gero encourages using "GeroSense" via web API for monitoring of anti-aging and pro-longevity effects of therapies as well as lifestyle choices, physical activities, diets, food supplements, recommended by health/fitness and wellness apps (see https:/ / techcrunch. com/ 2021/ 05/ 07/ longevity-startup-gero-ai-has-a-mobile-api-for-quantifying-health-changes/ ).

      Gero is funded by AI champions, including AIMATTER founders (recently acquired by Google). In 2019 and 2021, Gero was also named one of the leading companies in artificial intelligence in life extension along with Google and IBM.

      About Roswell Park Comprehensive Cancer Center

      Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer's grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at http://www. roswellpark. org, or contact us at 1-800-ROSWELL (1-800-767-9355) or [email protected]

      Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

      Johannes Lehmann

      Johannes focuses his research and teaching in soil biogeochemistry and soil fertility management. His specialization is in soil organic matter and nutrient studies of managed and natural ecosystems with a focus on soil carbon sequestration, nutrient recycling from wastes, biochar systems, circular economy, and sustainable agriculture in the tropics (especially Africa). His research stretches from ultra-fine scale microscopy to examine carbon stabilization in soils to global-scale carbon and nutrient cycles. Learn more about Johannes' work on the Lehmann Lab website.


      Soil biogeochemistry, fertility management, organic matter, and carbon and nutrient cycling from wastes

      Soil carbon sequestration and biochar systems

      Sustainable agriculture in the tropics

      Recent Research

      I am interested to advance our general understanding of biogeochemical cycles of carbon and nutrient elements in soil, providing important insight into regional and global element cycles such as the carbon or sulfur cycle. This field of research has global and local relevance with implications for climate change and environmental pollution.
      The strong background in the chemistry, biology and physics of soils and its cycles provide the basis for the development of intelligent solutions for sustainable soil and land use management. The most exciting examples include the discovery of stabilization mechanisms of organic matter in soil nano-structures and the development of a biochar soil management technology that improves soil fertility, sequesters carbon and reduces off-site pollution. Recent efforts involve the conversion of wastes to valuable fertilizers and the discovery of novel reactions and pathways of nitrogen in soil organic matter and plant uptake.

      Selected Publications

      Representative review publications for work on soil carbon, biochar, and nutrient cycle science

      • Lehmann J, Hansel CM, Kaiser C, Kleber M, Maher K, Manzoni S, Nunan N, Reichstein M, Schimel JP, Torn MS, Wieder WR and Kögel-Knabner I 2020 Persistence of soil organic carbon caused by functional complexity. Nature Geoscience, in press
      • Bradford MA, Carey CJ, Atwood L, Bossio D, Fenichel EP, Gennet S, Fargione J, Fisher JRB, Fuller E, Kane DA, Lehmann J, Oldfield EE, Ordway EM, Rudek J, Sanderman J and Wood SA 2019 Soil carbon science for policy and practice. Nature Sustainability 2, 1070–1072.
      • Kleber M and Lehmann J 2019 Humic substances extracted by alkali are invalid proxies for the dynamics and functions of organic matter in terrestrial and aquatic ecosystems. Journal of Environmental Quality 48, 207–216.
      • Lehmann J and Gaskins B 2019 Learning scientific creativity from the arts. Palgrave Communications 5, 96.
      • Liang C, Amelung W, Lehmann J and Kästner M 2019 Quantitative assessment of microbial necromass contribution to soil organic matter. Global Change Biology 25, 3578-3590.
      • Rillig M, Bonneval K and Lehmann J 2019 Sounds of soil: a new world of interactions under our feet? Soil Systems 3, 45.
      • Vermeulen S, Bossio D, Lehmann J, Luu P, Paustian K, Webb C, Augé F, Bacudo I, Baedeker T, Havemann T, Jones C, King R, Reddy M, Sunga I, Von Unger M and Warnken M 2019 A global agenda for collective action on soil carbon. Nature Sustainability 2, 2-4.
      • Chabbi A, Lehmann J, Ciais P, Loescher H, Cotrufo MF, Don A, SanClements M, Schipper L, Six J, Smith P, and Rumpel C 2017 Aligning agriculture and climate policy. Nature Climate Change 7, 307-309.
      • Paustian K, Lehmann J, Ogle S, Reay D, Robertson GP and Smith P 2016 Climate-smart soils. Nature 532, 49-57.
      • Lehmann J and Kleber M 2015 The contentious nature of soil organic matter. Nature 528, 60-68.
      • Lehmann J and Rillig M 2014 Distinguishing variability from uncertainty. Nature Climate Change 4, 153.
      • Simons A, Solomon D, Chibssa W, Blalock G and Lehmann J 2014 Filling the phosphorus fertilizer gap in developing countries. Nature Geoscience 7, 3.
      • Lehmann J, Rillig M, Thies J, Masiello CA, Hockaday WC, Crowley D 2011 Biochar effects on soil biota – a review. Soil Biology and Biochemistry 43, 1812–1836.
      • Schmidt MWI, Torn MS, Abiven S, Dittmar T, Guggenberger G, Janssens IA, Kleber M, Kögel-Knabner I, Lehmann J, Manning DAC, Nannipieri P, Rasse DP, Weiner S, and Trumbore SE 2011 Persistence of soil organic matter as an ecosystem property. Nature 478, 49-56.
      • Lehmann J 2007 A handful of carbon. Nature 447: 143-144.
      • Lehmann J 2007 Bio-energy in the black. Frontiers in Ecology and the Environment 5: 381-387.
      • Lehmann J, Kinyangi J and Solomon D 2007 Organic matter stabilization in soil microaggregates: implications from spatial heterogeneity of organic carbon contents and carbon forms. Biogeochemistry 85: 45-57.
      • Glaser G, Lehmann J and Zech W 2002 Ameliorating physical and chemical properties of highly weathered soils in the tropics with charcoal – a review. Biology and Fertility of Soils 35: 219-230.

      Representative publications of our experimental and modeling work

      • Possinger AR, Bailey SW, Inagaki TM, Kögel-Knabner I, Dynes JJ, Arthur ZA and Lehmann J 2020 Organo-mineral interactions and soil carbon mineralizability with variable saturation cycle frequency. Geoderma 375, 114483.
      • Torres-Rojas D, Hestrin R, Solomon D, Gillespie AW, Dynes JJ, Regier TZ and Lehmann J 2020 Nitrogen speciation and transformations in fire-derived organic matter. Geochimica et Cosmochimica Acta 276, 179-185.
      • Fungo B, Lehmann J, Kalbitz K, Thionģo M, Tenywa M, Okeyo I and Neufeldt H 2019 Ammonia and nitrous oxide emissions from a field Ultisol amended with tithonia green manure, urea, and biochar. Biology and Fertility of Soils 55, 135–148.
      • Hestrin R, Torres-Rojas D, Dynes JJ, Hook JM, Regier TM, Gillespie AW, Smernik RS and Lehmann J 2019 Fire-derived organic matter retains ammonia through covalent bond formation. Nature Communications 10, 664.
      • Krounbi L, Enders A, van Es H, Woolf D, van Herzen B and Lehmann J 2019 Biological and thermochemical conversion of human solid waste to soil amendments. Waste Management 89, 366–378.
      • Woolf D and Lehmann J 2019 Microbial models with minimal mineral protection can explain long-term soil organic carbon persistence. Scientific Reports 9, 6522.
      • DeCiucies S, Whitman T, Woolf D, Enders A and Lehmann A 2018 Priming mechanisms with additions of pyrogenic organic matter to soil. Geochimica et Cosmochimica Acta 238, 329-342.
      • Woolf D, Solomon D and Lehmann J 2018 Land restoration in food-security programmes: synergies with climate change mitigation. Climate Policy 18, 1260–1270.
      • Sun T, Levin BDA, Guzman JJL, Enders A, Muller DA, Angenent LT and Lehmann J 2017 Rapid electron transfer by the carbon matrix in natural pyrogenic carbon. Nature Communications 8, 14873.
      • Solomon D, Lehmann D, Fraser JA, Leach M, Amanor K, Frausin V, Kristiansen SM, Millimouno D and Fairhead J 2016 Indigenous African soil enrichment as a climate-smart sustainable agriculture alternative. Frontiers in Ecology and the Environment 14, 71–76.
      • Woolf D, Lehmann J and Lee D 2016 Optimal bioenergy power generation for climate change mitigation with or without carbon sequestration. Nature Communications 7, 13160.
      • Guerena D, Lehmann, Walter T, Enders A, Neufeldt H, Odiwour H, Biwott H, Recha J, Shepherd K, Barrios E and Wurster C 2015 Terrestrial pyrogenic carbon export to fluvial ecosystems: lessons learned from the White Nile watershed of East Africa. Global Biogeochemical Cycles 29, GB005095.
      • Whitman T and Lehmann J 2015 A dual-isotope approach to allow conclusive partitioning between three sources. Nature Communications 6, 8708.
      • Zwetsloot M, Lehmann J and Solomon D 2015 Recycling slaughterhouse waste into fertilizer: how do pyrolysis temperature and biomass additions affect phosphorus availability and chemistry? Journal of the Science of Food and Agriculture 95, 281-288.
      • Cayuela ML, Sánchez-Monedero MA, Roig A, Hanley K, Enders A and Lehmann J 2013 Biochar and denitrification in soils: when, how much and why does biochar reduce N2O emissions? Nature Scientific Reports 3, 1732.
      • Gatere L, Lehmann J, DeGloria S, Hobbs P, Delve R and Travis A 2013 One size does not fit all: conservation farming success in Africa more dependent on management than on location. Agriculture, Ecosystems and Environment 179, 200-207.
      • Recha JW, Lehmann J, Walter MT, Pell A, Verchot L, and Johnson M 2013 Stream water nutrient and organic carbon exports from tropical headwater catchments at a soil degradation gradient. Nutrient Cycling in Agroecosystems 95, 145-158.
      • Enders A, Hanley K, Whitman T, Joseph S, Lehmann J 2012 Characterization of biochars to evaluate recalcitrance and agronomic performance. Bioresource Technology 114, 644-653.
      • Hale SE, Lehmann J, Rutherford D, Zimmerman AR, Bachmann RT, Shitumbanuma V, O’Toole A, Sundqvist KL, Arp HPH and Cornelissen G 2012 Quantifying the total and bioavailable polycyclic aromatic hydrocarbons and dioxins in biochars. Environmental Science and Technology 46, 2830−2838.
      • Mao J-D, Johnson RL, Lehmann J, Olk DC, Neves EG, Thompson ML and Schmidt-Rohr K 2012 Abundant and stable char residues in soils: implications for soil fertility and carbon sequestration. Environmental Science and Technology 46, 9571-9576.
      • Rajkovich S, Enders A, Hanley K, Hyland C, Zimmerman AR, Lehmann J 2012 Corn growth and nitrogen nutrition after additions of biochars with varying properties to a temperate soil. Biology and Fertility of Soils 48, 271–284.
      • Solomon D, Lehmann J, Harden J, Wang J, Kinyangi J, Heymann K, Karunakaran C, Lu Y, Wirick S, and Jacobsen C 2012 Micro- and nano-environments of carbon sequestration: Multi-element STXM-NEXAFS spectromicroscopy assessment of microbial carbon and mineral associations. Chemical Geology 329, 53-73.
      • Roberts K, Gloy B, Joseph S, Scott N and Lehmann J 2010 Life cycle assessment of biochar systems: Estimating the energetic, economic and climate change potential. Environmental Science and Technology 44, 827–833.
      • Woolf D, Amonette JE, Street-Perrott FA , Lehmann J and Joseph S 2010 Sustainable biochar to mitigate global climate change. Nature Communications 1:56.
      • Lehmann J, Skjemstad JO, Sohi S, Carter J, Barson M, Falloon P, Coleman K, Woodbury P and Krull E 2008 Australian climate-carbon cycle feedback reduced by soil black carbon. Nature Geoscience 1: 832–835.
      • Lehmann J, Solomon D, Kinyangi J, Dathe L, Wirick S, and Jacobsen C 2008 Spatial complexity of soil organic matter forms at nanometre scales. Nature Geoscience 1, 238-242.
      • Johnson MS, Weiler M, Couto EG, Riha S and Lehmann J 2007 Storm pulses of dissolved CO2 in a forested headwater Amazonian stream explored using hydrograph separation. Water Resources Research 43, WR11201.
      • Solomon D, Lehmann J, Kinyangi J, Amelung W, Lobe I, Ngoze S, Riha S, Pell A, Verchot L, Mbugua D, Skjemstad J and Schäfer T 2007 Long-term impacts of anthropogenic perturbations on the dynamics and molecular speciation of organic carbon in tropical forest and subtropical grassland ecosystems. Global Change Biology 13: 511-530.
      • Cheng CH, Lehmann J, Thies JE, Burton SD and Engelhard MH 2006 Oxidation of black carbon by biotic and abiotic processes. Organic Geochemistry 37: 1477-1488.
      • Kinyangi J, Solomon D, Liang B, Lerotic M, Wirick S and Lehmann J 2006 Nanoscale biogeocomplexity of the organo-mineral assemblage in soil: application of STXM microscopy and C 1s-NEXAFS spectroscopy. Soil Science Society of America Journal 70: 1708-1718.
      • Liang B, Lehmann J, Solomon D, Kinyangi J, Grossman J, O’Neill B, Skjemstad JO, Thies J, Luizão FJ, Petersen J and Neves EG 2006 Black carbon increases cation exchange capacity in soils. Soil Science Society of America Journal 70: 1719-1730.
      • Lehmann J, Liang B, Solomon D, Lerotic M, Luizão F, Kinyangi J, Schäfer T, Wirick S, and Jacobsen C 2005 Near-edge X-ray absorption fine structure (NEXAFS) spectroscopy for mapping nano-scale distribution of organic carbon forms in soil: application to black carbon particles. Global Biogeochemical Cycles 19: GB1013.
      • Solomon D, Lehmann J and Martinez CE 2003 Sulfur K-edge XANES spectroscopy as a tool for understanding sulfur dynamics in soil organic matter. Soil Science Society of America Journal, 67: 1721-1731.
      • Lehmann J, Peter I, Steglich C, Gebauer G, Huwe B and Zech W 1998 Below-ground interactions in dryland agroforestry. Forest Ecology and Management 111: 157-169.
      • Lehmann J, Schroth G and Zech W 1995 Decomposition and nutrient release from leaves, twigs and roots of three alley-cropped tree legumes in central Togo. Agroforestry Systems 29: 21-36.

      Awards & Honors

      • Hans Fischer Senior Award (2019) Institute for Advanced Studies
      • Fellow 2018 German National Academy of Sciences – Leopoldina
      • Highly Cited Researcher (2017) Thomson Reuter/Clarivate
      • Hans Fischer Senior Award 2016 Institute for Advanced Studies
      • Highly Cited Researcher, Clarivate Analytics
      • Sir Frederick McMaster Award (2007) CSIRO

      Courses Taught

      ENVS/CLASS 2000: Environment and Sustainability Colloquium
      PLSCS 3210: Soil and Crop Management for Sustainability
      PLSCS 4720/6720: Nutrient and Carbon Cycling and Management in Ecosystems

      Nutrient Management in Agroecosystems and Nutrient Cycling in Natural and Managed Ecosystems, Environmental Science Colloquium and support of introductory courses in Environmental Sciences, Traditional Agriculture in Developing Countries and Tropical Cropping Systems.

      The goals of my teaching program is to create enthusiasm in students for the study of soil biogeochemistry, soil fertility and nutrient cycling, as they realize the importance of these topics not only for agricultural production but also for environmental protection. I am particularly interested in the intersection of artistic practice, sustainability and scientific pursuit in general. In the area of environmental sciences, we focus on the pollution of soils and aquifers with inorganic and organic fertilizers, on the effects of atmospheric emissions and on questions regarding soil processes and climate change. The students should get familiar with critical thinking about the impact of land use management on the environment such as soil degradation, climate change or pollution of waterways with agrochemicals. Apart from covering processes and dynamics in temperate agro-ecosystems, particular emphasis is placed on the understanding of constraints and options for nutrient management in tropical environments. The sustainable management of fragile ecosystems under low-input conditions is at the center of such discussions. These three constraints: limited input, environmental protection and sustainability of food production force creative thinking. In order to achieve scientifically sound solutions students need to acquire a profound and integrated understanding of the biological, physical and chemical processes in soil. The students are faced with the challenge to develop previously acquired disciplinary knowledge into more integrated and multidisciplinary thinking.

      Latest news

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      History Edit

      The first steps towards an anthroposophic approach to medicine were made before 1920, when homeopathic physicians and pharmacists began working with Rudolf Steiner, who recommended new medicinal substances as well as specific methods for preparation along with an anthroposophic concept of man. In 1921, Ita Wegman opened the first anthroposophic medical clinic, now known as the Klinik Arlesheim, [16] in Arlesheim, Switzerland. Wegman was soon joined by a number of other doctors. They then began to train the first anthroposophic nurses for the clinic.

      At Wegman's request, Steiner regularly visited the clinic and suggested treatment regimes for particular patients. Between 1920 and 1925, he also gave several series of lectures on medicine. In 1925, Wegman and Steiner wrote the first book on the anthroposophic approach to medicine, Fundamentals of Therapy.

      Wegman later opened a separate clinic and curative home in Ascona. Wegman lectured widely, visiting the Netherlands and England particularly frequently, and an increasing number of doctors began to include the anthroposophic approach in their practices. A cancer clinic, the Lukas Clinic, opened in Arlesheim in 1963. [17]

      In 1976 anthroposophic medicine in Germany got regulated by law as a specific therapeutic system ("Besondere Therapierichtung") by the Medicines Act-Arzneimittelgesetz (AMG) and by the Code of Social Law (Sozialgesetzbuch V) [18]

      In the 1990s the Witten/Herdecke University in Germany established a chair in anthroposophical medicine. The press described the appointment as a "death sentence" and the perception that pseudoscience was being taught damaged the university's reputation, bringing it close to financial collapse. It was ultimately saved by a cash injection from Software AG, a technology corporation with a history of funding anthroposophic projects. [12]

      In 2006, anthroposophical medicine was practised in 80 countries. [19] [20] [ unreliable source? ]

      In 2012 the University of Aberdeen considered establishing a chair in holistic health jointly funded by Software AG, and by the Anthroposophic Health, Education, and Social Care Movement, each of which would provide £1.5 million of endowment. [12] Edzard Ernst commented "that any decent university should even consider an anthroposophical medicine unit seems incomprehensible. The fact that it would be backed by people who have a financial interest in this bogus approach makes it even worse." [12] The University's governance and nominations committee eventually decided not to proceed with the appointment. [11]

      Categorization and conceptual basis Edit

      The categorization of anthroposophical medicine is complex since in part it complements conventional medicine, and in part it substitutes for it. [1] In 2008, Ernst wrote that it was being promoted as an "extension to conventional medicine". [6]

      Ernst writes that Steiner used imagination and insight as a basis for his ideas, drawing mystical knowledge from the occult Akashic Records, a work which is supposedly situated on the astral plane, and which Steiner said was accessible to him via his intuitive powers. [3] On this basis, Steiner proposed "associations between four postulated dimensions of the human body (physical body, etheric body, astral body, and ego), plants, minerals, and the cosmos". [2] Steiner also proposed a connection betweens planets, metals and organs so that, for example, the planet Mercury, the element mercury and the lung were all somehow associated. These propositions form the basis of anthroposophical medicine. [3]

      Ernst has said that anthroposophical medicine "includes some of the least plausible theories one could possibly imagine", [21] categorized it as "pure quackery", [11] and said that it "has no basis in science". [12] According to Quackwatch, anthroposophical medicine practitioners regard illness as a "rite of passage" necessary to purge spiritual impurities carried over from past lives, according to the precepts of "karmic destiny". [8]

      In anthroposophic pharmacy, drugs are prepared according to ancient notions of alchemy and homeopathy which are not related to the science underlying modern pharmacology. [2] During the preparation process, patterns formed by crystallization are interpreted to see which "etheric force" they most closely resemble. [10] Most anthroposophic preparations are highly diluted, like homeopathic remedies. This means that, while they are completely harmless in themselves, using them in place of conventional medicine to treat serious illness carries a risk of severe adverse consequences. [3]

      As well as drug remedies, anthroposophical medicine also includes: [2]

      • Anthroposophic nursing
      • Counselling – claimed to have an effect on "inner life functions" leading to a "re-integration of body, soul, and spirit". [8][22]
      • External applications
      • Rhythmic massages

      Plant-derived treatments Edit

      To select an anthroposophic substance for a particular illness, practitioners consider the source of the substances used. The character of a mineral, plant or animal is hypothesised to have been formed by the substances that are most active within it, in the belief that this character may also influence what the substance will accomplish when given to treat another organism. This is related to Samuel Hahnemann's Doctrine of signatures. Willow, for example, is considered to have an unusual character:

      . plants that grow near water are usually heavy, with big, dark green leaves that wilt and break easily. An exception is . the white willow, a tree that always grows near water and loves light. However, unlike other "watery" plants, the willow has fine, almost dry leaves and looks very light . Its branches are unbelievably tough. They are elastic and cannot be broken. They bend easily and form "joints" rather than break. These few signatures can give us the clue to what salix can be used for therapeutically: arthritis, deformation of joints, swollen joints . [23]

      There is no scientific evidence that the shape of plants has ever caused a new medical property to be discovered. [24]

      Beliefs about human biology Edit

      Steiner described the heart not as a pump, but as a regulator of flow, such that the heartbeat itself can be distinguished from the circulation of blood. [7] [25] Anthroposophic medicine claims the flow in the blood of the circulatory system is, as Marinelli put it, "propelled with its own biological momentum, as can be seen in the embryo, and boosts itself with induced momenta from the heart". [7] [26]

      This view of the heart is not based on any scientific theory and has been characterized as "crank science". [25]

      Steiner believed that the sex of a baby was determined at the moment of conception by the alignment of the stars. [27]

      Steiner's model of anatomy was based on a three-part notion, whereby the head is the thinking part, the abdomen and limbs the "metabolic" part, and the chest and heart a "rhythmic center". [27]

      Reaction to COVID-19 Edit

      During the 2020 COVID-19 pandemic Steiner hospitals in Germany became notorious amongst legitimate medics for forcing quack remedies on sedated hospital patients, some of whom were critically ill. Remedies used included ginger poultices and homeopathic pellets claimed to contain the dust of shooting stars. Stefan Kluge, director of intensive care medicine at Hamburg's University Medical Centre said the claims of anthroposophic doctors during the pandemic were "highly unprofessional" and that they "risk[ed] causing uncertainty among patients". [28]

      Mistletoe treatment for cancer Edit

      Rudolf Steiner hypothesised that mistletoe could cure cancer, on the basis of the observation that the plant was a parasite which eventually killed its host, a process which he claimed paralleled the progression of cancer. [2] Steiner believed the plant's medical potential was influenced by the position of the sun, moon and planets and that it therefore was important to harvest the plant at the right time. [29] Some mistletoe preparations are ultra-diluted others are made from fermented mistletoe. [2] The most commonly used trade names for mistletoe drugs are Iscador and Helixor. [4]

      Although laboratory experiments have suggested that mistletoe extract may affect the immune system and be able to kill some kinds of cancer cells, there is little evidence of its benefit to people with cancer. [5] [30] Most of the clinical research claiming that mistletoe therapy is effective is published in Germany, and it is generally considered unreliable because of major lapses in quality. [30] [31] Edzard Ernst wrote that research by anthroposophic doctors often reached positive conclusions on mistletoe therapy because it drew on unreliable material independent researchers tended instead to find no evidence of benefit. [2] The American Cancer Society says that "available evidence from well-designed clinical trials does not support claims that mistletoe can improve length or quality of life". [4]

      Mistletoe-based cancer drugs are widely used in Europe, especially in German-speaking countries. [31] In 2002 nearly half a million prescriptions were paid for by German health insurance and in 2006 there were reportedly around 30 types of mistletoe extract on the market. [2] [31] Mistletoe extracts have been used as an unconventional treatment for cancer patients in the Netherlands, and in Germany the treatment has been approved as palliative therapy to treat the symptoms of patients with malignant tumors. [4] In Sweden, controversially, mistletoe therapy has been approved for use in the treatment of cancer symptoms. [32]

      In other countries mistletoe therapy is virtually unknown. [31] The United States Food and Drug Administration has not approved mistletoe-based drugs for any purpose mistletoe extracts may not be distributed in or imported into the US except for research purposes. [30] As of 2015 [update] no mistletoe-based drugs are licensed for use in the United Kingdom. [33]

      A 2013 article on mistletoe in Lancet Oncology invoked Ben Goldacre's observation that a geographical preference for certain therapies was a hallmark of quackery, and proposed that the continuing use of this "apparently ineffectual therapy" in a small cluster of countries was based on sociological rather than medical reasons, indicating a need for a more informed consent from patients. [31]

      The risks arising from using anthroposophical medicine as a substitute for evidence-based medicine are exemplified by several cases of low vaccination levels in Waldorf schools, [3] since some anthroposophical doctors oppose immunization. [6] A 1999 study of children in Sweden showed that in Waldorf schools, only 18% had received MMR vaccination, compared to a level of 93% in other schools nationally. [3]

      A 2003 report of a widespread measles outbreak around Coburg, Germany, identified a Waldorf school as the origin. [3] At the time the town's mayor had condemned homeopathic doctors who had discouraged vaccination, saying "Their stronghold is the Waldorf School, which actively encourages people not to have their children vaccinated. Now we have an epidemic." [34]

      Paul Offit wrote that Steiner believed vaccination "interferes with karmic development and the cycles of reincarnation", and that adherence to this belief led to a 2008 pertussis outbreak in a Californian Waldorf school, causing its temporary closure. [9]

      Biophysical and Computational Methods ● Cryo EM

      Rafael Tenga , Ohad Medalia , in Current Opinion in Structural Biology , 2020

      Architecture of lamins at the nuclear lamina

      Cryo-electron tomography (cryo-ET) is a powerful technique to acquire structural insight into single non-repeating structures [ 47–49 ] and therefore became pivotal in cell biology [ 34 , 50 , 51 ]. This method enables structure determination of macromolecular complexes within a cell [ 52–55 ]. Recent technological developments allow to acquire a high-resolution snapshot of molecular processes at a specific point of time [ 56 , 57 ]. Therefore, cryo-ET is the method of choice to decipher the structure of lamin assemblies at close-to-native state.

      Recently, we showed that lamin filaments assemble into 3.5 nm thick filaments ( Figure 1 f) within a ∼14 nm thick meshwork layer beneath the nuclear membrane [ 58 • ]. The filaments are both highly variable in length and exhibit a short persistence length of <200 nm which hints at a large flexibility. This persistence length means that lamin filaments are more bendable than any other components of the cytoskeleton, including other IF proteins. This physical characteristics of lamins represent their unique mechanical properties that are observed when lamin filaments are subjected to external forces [ 59 , 60 • ].

      In the nuclear lamina, the Ig-fold of lamins were seen as globular domains decorating the filaments every 20 nm. The different lamin isoforms could be partially identified using immunogold-labeling. It showed that A-type and B-type lamins form two separate meshworks, confirming previous observations obtained by structural illumination microscopy (3D-SIM) that lamin A, C, B1 and B2 form individual meshworks within the nuclear lamina [ 61 ]. An additional study using stochastic optical reconstruction microscopy (STORM) showed that the lamin meshworks are also spatially distinguished, with the lamin B1 meshwork lying closer to the membrane and the highest concentration of lamin A/C is found further towards the nucleoplasm [ 62 • ].

      The nuclear lamina contains an additional set of proteins and has been shown to tightly bind chromatin [ 63 , 64 ]. Therefore, the nuclear lamina plays a major role in the nuclear architecture and gene expression [ 63 , 65 ]. The heterochromatin domains, which bind to the lamina are referred to as lamina-associated domains (LADs) and are kept in a transcriptionally repressed state to maintain genome stability [ 66 ]. It was recently shown that the interaction of lamin B1 with chromatin is synchronized with the circadian clock [ 67 ]. The interactions between heterochromatin and lamin can be observed by means of cryo-ET ( Figure 2 ). This image reveals that the chromatin is intertwined between nuclear lamins to form a direct interaction which can resist nuclease treatments. However, studying more native and intact nuclear samples is needed to decipher the complicated interactions between chromatin and lamins.

      Figure 2 . Visualizing lamin-chromatin interactions. (a) Applying nuclease treatment to lysed cells, as described in [ 58 • ], retains heterochromatin and lamins, as revealed by visualizing HP1α and LaminA/C. (b) and (c) Segmented cryo-tomogram shows tight interactions between lamin filaments (yellow) and heterochromatin (blue).

      The use of cryo-FIB (focused ion-beam) milling as a sample preparation procedure for cryo-ET allows to study any cellular structures inside the native environment of vitrified cells and multicellular samples [ 68 , 69 ]. By applying recent advances in cryo-FIB milling, in combination with cryo-ET [ 49 , 70 , 71 •• ], it is possible to study structures in the nucleus [ 72–74 ]. FIB milling is used to create thin lamellas of cells or other structures which are too thick (>1 μm) and therefore unsuitable for native cryo-ET. Even subtomogram averaging approaches of nuclear structures like the NPC and nucleosome are feasible [ 73 , 75 ]. Therfore, not only lamins but all lamin-associated proteins, for example, the NPCs, the chromatin and the nuclear membranes can be studied. Thereby, combining cryo-FIB and cryo-ET allows us to study the structural interactions of the nuclear lamina with these cellular structures at high resolution. A typical view into the nuclear lamina as revealed by applying FIB-milling in conjunction with cryo-ET is shown in Figure 1 e.

      Watch the video: Πώς διαβάζω την Ιστορία - 5 Βήματα (September 2022).


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