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Cohen JE, Huillet TE
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Taylor's Law for Some Infinitely Divisible Probability Distributions from Population Models

In a family of random variables, Taylor's law or Taylor's power law of fluctuation scaling is a variance function that gives the variance sigma(2) > 0 of a random variable (rv) X with expectation mu > 0 as a power of mu: sigma(2) = A mu(b) for finite real A > 0, b that are the same for all rvs in the family. Equivalently, TL holds when log sigma(2) = a + b log mu, a = log A, for all rvs in some set. Here we analyze the possible values of the TL exponent b in five families of infinitely divisible two-parameter distributions and show how the values of b depend on the parameters of these distributions. The five families are Tweedie-Bar-Lev-Enis, negative binomial, compound Poisson-geometric, compound geometric-Poisson (or Polya-Aeppli), and gamma distributions. These families arise frequently in empirical data and population models, and they are limit laws of Markov processes that we exhibit in each case.
Haselwandtera CA, Guoc YR, Fuc Z, MacKinnon R
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Quantitative prediction and measurement of Piezo's membrane footprint

Piezo proteins are mechanosensitive ion channels that can locally curve the membrane into a dome shape [Y. R. Guo, R. MacKinnon, eLife 6, e33660 (2017)]. The curved shape of the Piezo dome is expected to deform the surrounding lipid bilayer membrane into a membrane footprint, which may serve to amplify Piezo's sensitivity to applied forces [C. A. Haselwandter, R. MacKinnon, eLife 7, e41968 (2018)]. If Piezo proteins are embedded in lipid bilayer vesicles, the membrane shape deformations induced by the Piezo dome depend on the vesicle size. We employ here membrane elasticity theory to predict, with no free parameters, the shape of such Piezo vesicles outside the Piezo dome, and show that the predicted vesicle shapes agree quantitatively with the corresponding measured vesicle shapes obtained through cryoelectron tomography, for a range of vesicle sizes [W. Helfrich, Z. Naturforsch. C 28, 693-703 (1973)]. On this basis, we explore the coupling between Piezo and membrane shape and demonstrate that the features of the Piezo dome affecting Piezo's membrane footprint approximately follow a spherical cap geometry. Our work puts into place the foundation for deducing key elastic properties of the Piezo dome from membrane shape measurements and provides a general framework for quantifying how proteins deform bilayer membranes.
Richard JC, Frobert E, Destras G, Yonis H, Mezidi M, Dhelft F, Trouillet-Assant S, Bastard P, Gervais A, Danjou W, Aubrun F, Roumieu F, Josset L, Labaune JM, Bal A, Simon B, Casanova JL, Lina B, Picaud JC, Dupont C, Huissoud C, Bitker L
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Virological and clinical features of acute respiratory failure associated with COVID-19 in pregnancy: a case-control study

Objective: Pregnancy is a risk factor for acute respiratory failure (ARF) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We hypothesised that SARS-CoV-2 viral load in the respiratory tract might be higher in pregnant intensive care unit (ICU) patients with ARF than in non-pregnant ICU patients with ARF as a consequence of immunological adaptation during pregnancy. Design: Single-centre, retrospective observational case- control study. Setting: Adult level 3 ICU in a French university hospital. Participants: Eligible participants were adults with ARF associated with coronavirus disease 2019 (COVID-19) pneumonia. Main outcome measure: The primary endpoint of the study was viral load in pregnant and non-pregnant patients. Results: 251 patients were included in the study, including 17 pregnant patients. Median gestational age at ICU admission amounted to 28 + 3/7 weeks (interquartile range [IQR], 26 + 1/7 to 31 + 5/7 weeks). Twelve patients (71%) had an emergency caesarean delivery due to maternal respiratory failure. Pregnancy was independently associated with higher viral load (-4.6 +/- 1.9 cycle threshold; P < 0.05). No clustering or over-represented mutations were noted regarding SARS-CoV-2 sequences of pregnant women. Emergency caesarean delivery was independently associated with a modest but significant improvement in arterial oxygenation, amounting to 32 +/- 12 mmHg in patients needing invasive mechanical ventilation. ICU mortality was significantly lower in pregnant patients (0 v 35%; P < 0.05). Age, Simplified Acute Physiology Score (SAPS) II score, and acute respiratory distress syndrome were independent risk factors for ICU mortality, while pregnancy status and virological variables were not. Conclusions: Viral load was substantially higher in pregnant ICU patients with COVID-19 and ARF compared with non-pregnant ICU patients with COVID-19 and ARF. Pregnancy was not independently associated with ICU mortality after adjustment for age and disease severity.
Wang ZJ, Zhou PC, Muecksch F, Cho ALC, Ben Tanfous T, Canis M, Witte L, Johnson B, Raspe R, Schmidt F, Bednarski E, Da Silva J, Ramos V, Zong S, Turroja M, Millard KG, Yao KH, Shimeliovich I, Dizon J, Kaczynska A, Jankovic M, Gazumyan A, Oliveira TY, Caskey M, Gaebler C, Bieniasz PD, Hatziioannou T, Nussenzweig MC
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Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans

JOURNAL OF EXPERIMENTAL MEDICINE 2022 SEP 23; 219(12):? Article e20221006
Wang et al. analyze memory B cell and antibody responses in SARS-CoV-2 mRNA vaccines to breakthrough infections with Delta or Omicron BA.1 variants. Breakthrough infection after two or three doses of mRNA vaccination was comparable to three doses of vaccination in eliciting broad and potent memory B cells. The findings provide insights on broad and strain-specific memory responses after mRNA vaccination with Wuhan-Hu-1. Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.
Castorani MCN, Bell TW, Walter JA, Reuman DC, Cavanaugh KC, Sheppard LW
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Disturbance and nutrients synchronise kelp forests across scales through interacting Moran effects

ECOLOGY LETTERS 2022 AUG; 25(8):1854-1868
Spatial synchrony is a ubiquitous and important feature of population dynamics, but many aspects of this phenomenon are not well understood. In particular, it is largely unknown how multiple environmental drivers interact to determine synchrony via Moran effects, and how these impacts vary across spatial and temporal scales. Using new wavelet statistical techniques, we characterised synchrony in populations of giant kelp Macrocystis pyrifera, a widely distributed marine foundation species, and related synchrony to variation in oceanographic conditions across 33 years (1987-2019) and >900 km of coastline in California, USA. We discovered that disturbance (storm-driven waves) and resources (seawater nutrients)-underpinned by climatic variability-act individually and interactively to produce synchrony in giant kelp across geography and timescales. Our findings demonstrate that understanding and predicting synchrony, and thus the regional stability of populations, relies on resolving the synergistic and antagonistic Moran effects of multiple environmental drivers acting on different timescales.
Narayan NJC, Requena D, Lalazar G, Ramos-Espiritu L, Ng D, Levin S, Shebl B, Wang RS, Hammond WJ, Saltsman JA, Gehart H, Torbenson MS, Clevers H, LaQuaglia MP, Simon SM
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Human liver organoids for disease modeling of fibrolamellar carcinoma

STEM CELL REPORTS 2022 AUG 9; 17(8):1874-1888
Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochem-istry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.
Soto LF, Requena D, Bass JIF
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Epitope-Evaluator: An interactive web application to study predicted T-cell epitopes

PLOS ONE 2022 AUG 26; 17(8):? Article e0273577
Multiple immunoinformatic tools have been developed to predict T-cell epitopes from protein amino acid sequences for different major histocompatibility complex (MHC) alleles. These prediction tools output hundreds of potential peptide candidates which require further processing; however, these tools are either not graphical or not friendly for non-programming users. We present Epitope-Evaluator, a web tool developed in the Shiny/R framework to interactively analyze predicted T-cell epitopes. Epitope-Evaluator contains six tools providing the distribution of epitopes across a selected set of MHC alleles, the promiscuity and conservation of epitopes, and their density and location within antigens. Epitope-Evaluator requires as input the fasta file of protein sequences and the output prediction file coming out from any predictor. By choosing different cutoffs and parameters, users can produce several interactive plots and tables that can be downloaded as JPG and text files, respectively. Using Epitope-Evaluator, we found the HLA-B*40, HLA-B*27:05 and HLA-B*07:02 recognized fewer epitopes from the SARS-CoV-2 proteome than other MHC Class I alleles. We also identified shared epitopes between Delta, Omicron, and Wuhan Spike variants as well as variant-specific epitopes. In summary, Epitope-Evaluator removes the programming barrier and provides intuitive tools, allowing a straightforward interpretation and graphical representations that facilitate the selection of candidate epitopes for experimental evaluation. The web server Epitope-Evaluator is available at
Hartweger H, Nussenzweig MC
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CRISPR comes a-knock-in to reprogram antibodies in vivo

NATURE BIOTECHNOLOGY 2022 AUG; 40(8):1183-1184
Reprogramming of antibody responses in mice is achieved via adeno-associated virus delivery of SaCas9, single guide RNA (sgRNA) and a repair template targeting immunoglobulin genes.
Dussex N, Robertson BC, Dalen L, Jarvis ED
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The kakapo (Strigops habroptilus)

TRENDS IN GENETICS 2022 AUG; 38(8):881-882
Sunkari YK, Meijer L, Flajolet M
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The protein kinase CK1: Inhibition, activation, and possible allosteric modulation

Protein kinases play a vital role in biology and deregulation of kinases is implicated in numerous diseases ranging from cancer to neurodegenerative diseases, making them a major target class for the pharmaceutical industry. However, the high degree of conservation that exists between ATP-binding sites among kinases makes it difficult for current inhibitors to be highly specific. In the context of neurodegeneration, several groups including ours, have linked different kinases such as CK1 and Alzheimer's disease for example. Strictly CK1-isoform specific regulators do not exist and known CK1 inhibitors are inhibiting the enzymatic activity, targeting the ATP-binding site. Here we review compounds known to target CK1, as well as other inhibitory types that could benefit CK1. We introduce the DNA-encoded library (DEL) technology that might represent an interesting approach to uncover allosteric modulators instead of ATP competitors. Such a strategy, taking into account known allosteric inhibitors and mechanisms, might help designing modulators that are more specific towards a specific kinase, and in the case of CK1, toward specific isoforms.