bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of variation in canal and root number in human post-canine teeth
Authors: Gellis Jason J. , Foley Robert A.
Published: February 2022

Descriptive morphology of tooth roots traditionally focuses on number of canals and roots. However, how or if canal and root number are related is poorly understood. While it is often assumed that canal number is concomitant with root number and morphology, in practice canal number and morphology do not always covary with external root features. To investigate the relationship between canal and root number, fully developed, adult post-canine teeth were examined and quantified from medical computerized tomography scans from a global sample of 945 modern humans. We tested the hypotheses that root and canal number do not follow a 1:1 ratio, that canal to root ratios differ between teeth, and that canal to root ratios differ across populations. Results indicate that not only is root number dependent on canal number, but that this relationship become more variable as canal number increases, varies both between individual teeth and by population, and changes as populations increase in distance from Sub-Saharan Africa. These results show that the ratio of canal number to root number is an important indicator of variation in dental phenotypes.
Novel neutrophil subsets associated with sepsis, vascular dysfunction and metabolic alterations identified using systems immunology
Authors: Parthasarathy U. , Kuang Y. , Thakur G. , Hogan J.D. , Wyche T.P. , Norton J.E. , Killough J.R. , Sana T.R. , Beakes C. , Shyong B. , Zhang N.R. , Gutierrez D.A. , Filbin M. , Christiani D.C. , Therien A. G. , Woelk C.H. , White C.H. , Martinelli R.
Published: February 2022

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in sepsis patients. Our findings identify novel differentially expressed immature neutrophil subsets in sepsis patients. These and other subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2 and lysophosphatidylcholines, in sepsis patients. These results enabled the construction of a predictive model based on weighted multi-omics linear regression analysis for patient classification. These findings could help inform earlier patient stratification and treatment options, as well as facilitate future mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.
Windborne migration amplifies insect-mediated pollination services
Authors: Jia Huiru , Liu Yongqiang , Li Xiaokang , Li Hui , Pan Yunfei , Hu Chaoxing , Zhou Xianyong , Wyckhuys Kris A.G. , Wu Kongming
Published: February 2022

Worldwide, hoverflies (Syrphidae: Diptera) provide crucial ecosystem services (ES) such as pollination and biological pest control. Although many hoverfly species exhibit migratory behavior, the spatiotemporal facets of these movement dynamics and their ES implications are poorly understood. In this study, we use long-term (16 yr) trapping records, trajectory analysis and intrinsic (i.e., isotope, genetic, pollen) markers to describe migration patterns of the hoverflyEpisyrphus balteatusin China. Our work reveals long-range, windborne migration with spring migrants originating in northern China and exhibiting return migration during autumn. Given the substantial night-time dispersal ofE. balteatus, this species possibly adopts a ‘dual’ migration strategy. The extensive genetic mixing and high genetic diversity ofE. balteatuspopulations underscore its adaptive capacity to environmental disturbances e.g., climate change. Pollen markers and molecular gut-analysis further illuminate howE. balteatusvisits min. 1,012 flowering plant species (39 orders) over space and time. By thus delineatingE. balteatustrans-regional movements and pollination networks, we advance our understanding of its migration ecology and facilitate the design of targeted strategies to conserve and enhance its ecosystem services.
High-Resolution Ultrasound and Speckle Tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development
Authors: Sicard Pierre , Falco Amandine , Faure Sandrine , Thireau Jérome , Lindsey Stéphanie E. , Chauvet Norbert , de Santa Barbara Pascal
Published: February 2022

Gastrointestinal motor activity has been extensively studied in adults, conversely only few studies have investigated fetal motor skills. When the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development are not known. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos. We found that although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determinates the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allow visualizing and quantifying gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.
Lymphatic-Preserving Treatment Sequencing with Immune Checkpoint Inhibition Unleashes cDC1-Dependent Antitumor Immunity in HNSCC
Authors: Saddawi-Konefka Robert , O’Farrell Aoife , Faraji Farhoud , Clubb Lauren , Allevato Michael M. , Anang Nana-Ama A. S. , Jensen Shawn M. , Wang Zhiyong , Wu Victoria H. , Yung Bryan S. , Msari Riyam Al , Pietryga Ida Franiak , Molinolo Alfredo A. , Mesirov Jill P. , Simon Aaron B. , Fox Bernard A. , Bui Jack D. , Sharabi Andrew , Cohen Ezra E. W. , Califano Joseph A. , Silvio Gutkind J.
Published: February 2022

Immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 has revolutionized oncology; however, response rates remain limited in most cancer types, highlighting the need for more effective immune oncology (IO) treatment strategies. Paradoxically, head and neck squamous cell carcinoma (HNSCC), which bears a mutational burden and immune infiltrate commensurate with cancers that respond robustly to ICI, has demonstrated no response to anti- CTLA-4 in any setting or to anti-PD-1 for locally-advanced disease. Scrutiny of the landmark clinical trials defining current IO treatments in HNSCC reveals that recruited patients necessarily received regional ablative therapies per standard of care, prompting us to hypothesize that standard therapies, which by design ablate locoregional lymphatics, may compromise host immunity and the tumor response to ICI. To address this, we employed tobacco-signature HNSCC murine models in which we mapped tumor-draining lymphatics and developed models for regional lymphablation with surgery or radiation. Remarkably, we found that lymphablation eliminates the tumor ICI response, significantly worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observed an upregulation of cDC1 cells and IFN-I signaling, showed that both are necessary for the ICI response and lost with lymphablation. Ultimately, we defined rational IO sequences that mobilize peripheral immunity, achieve optimal tumor responses, confer durable immunity and control regional lymphatic metastasis. In sum, we provide a mechanistic understanding of how standard regional, lymphablative therapies impact the response to ICI, which affords insights that can be applied to define rational, lymphatic-preserving IO treatment sequences for cancer.

One Sentence Summary

Despite the promise of immune checkpoint inhibition, therapeutic responses remain limited, raising the possibility that standard of care treatments delivered in concert may compromise the tumor response; here, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, confer durable antitumor immunity, and control regional metastatic disease.

Graphical Abstract
Augmented efficacy of uttroside B over sorafenib in a murine model of human hepatocellular carcinoma
Authors: Swetha Mundanattu , Keerthana C.K. , Rayginia Tennyson P , Nath Lekshmi R , Haritha Nair Hariprasad , Kalimuthu Kalishwaralal , Janet Somaraj , Pillai Sreekumar , Harikumar Kuzhuvelil B , Sundaram Sankar , Anto Nikhil Ponnoor , Wu Dee H , Lankalapalli Ravi Shankar , Towner Rheal , Isakov Noah , Sathyaseelan Deepa , Anto Ruby John
Published: February 2022

Background

We previously reported the potency ofS. nigrum-derived uttroside B (Utt-B). Recently Utt-B is flagged as an ‘orphan drug’ against hepatocellular carcinoma (HCC) by the US FDA. The current study aims to validate the enhancedin vivoefficacy of Utt-B over sorafenib, the first-line treatment option against HCC.

Methods

Human liver cancer cell line, HepG2 was employed as an HCC model and the comparison between Utt-Bvssorafenib therapeutic efficacies against HCCin vivowere evaluated in NOD.CB17-Prkdcscid/J mice that bear HepG2-induced HCC xenografts.

Results

Our data indicate that Utt-B is a more potent anti-HCC drug than sorafenib,in vivo. Apart from the superior therapeutic benefit over sorafenib, Utt-B is pharmacologically saferin vivo, and owing to this virtue, the drug-induced side effects are largely alleviated in the context of HCC chemotherapy.

Conclusions

Our data demonstrate the superior therapeutic index of Utt-B over sorafenib against HCC. Clinical studies in HCC patients utilizing Utt-B, which now holds the US FDA approval as an ‘orphan drug’, is an essential step to promote this drug from bench to bedside.
SARS-CoV-2 Omicron variant, lineage BA.1, is associated with lower viral load in nasopharyngeal samples compared to Delta variant
Authors: Sentis Célia , Billaud Geneviève , Bal Antonin , Frobert Emilie , Bouscambert Maude , Destras Gregory , Josset Laurence , Lina Bruno , Morfin Florence , Gaymard Alexandre ,   the COVID-Diagnosis HCL Study Group
Published: February 2022

High viral load in upper respiratory tract specimens observed for Delta cases may contributed to its increased infectivity compared to the Alpha variant. Herein, we showed that the RT-PCR Ct values in Health Care Workers sampled within five days after symptom onset were significantly higher for Omicron cases than Delta cases (+2.84 Ct, p=0.008). This result comfort the studies showing that the increased transmissibility of Omicron is related to other mechanisms than higher virus excretion.
Impact of SARS-CoV-2 variants on inpatient clinical outcome
Authors: Robinson Matthew L. , Morris C. Paul , Betz Josh , Zhang Yifan , Bollinger Robert , Wang Natalie , Thiemann David R , Fall Amary , Eldesouki Raghda E. , Norton Julie M. , Gaston David C. , Forman Michael , Luo Chun Huai , Zeger Scott L. , Gupta Amita , Garibaldi Brian T. , Mostafa Heba H.
Published: February 2022

Background

Prior observation has shown differences in COVID-19 hospitalization rates between SARS-CoV-2 variants, but limited information describes differences in hospitalization outcomes.

Methods

Patients admitted to 5 hospitals with COVID-19 were included if they had hypoxia, tachypnea, tachycardia, or fever, and data to describe SARS-CoV-2 variant, either from whole genome sequencing, or inference when local surveillance showed ≥95% dominance of a single variant. The average effect of SARS-CoV-2 variant on 14-day risk of severe disease, defined by need for advanced respiratory support, or death was evaluated using models weighted on propensity scores derived from baseline clinical features.

Results

Severe disease or death within 14 days occurred for 950 of 3,365 (28%) unvaccinated patients and 178 of 808 (22%) patients with history of vaccination or prior COVID-19. Among unvaccinated patients, the relative risk of 14-day severe disease or death for Delta variant compared to ancestral lineages was 1.34 (95% confidence interval [CI] 1.13-1.55). Compared to Delta variant, this risk for Omicron patients was 0.78 (95% CI 0.62-0.97) and compared to ancestral lineages was 1.04 (95% CI 0.84-1.24). Among Omicron and Delta infections, patients with history of vaccination or prior COVID-19 had one-half the 14-day risk of severe disease or death (adjusted hazard ratio 0.46, IQR 0.34-0.62) but no significant outcome difference between Delta and Omicron infections.

Conclusions

Although the risk of severe disease or death for unvaccinated patients with Omicron was lower than Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated patients, but there was no difference between Delta and Omicron infections.
Monitoring rapid evolution of plant populations at scale with Pool-Sequencing
Authors: Czech Lucas , Peng Yunru , Spence Jeffrey P. , Lang Patricia L.M. , Bellagio Tatiana , Hildebrandt Julia , Fritschi Katrin , Schwab Rebecca , Rowan Beth A. ,   GrENE-net consortium, Weigel Detlef , Scheepens J.F. , Vasseur François , Exposito-Alonso Moises
Published: February 2022

The change in allele frequencies within a population over time represents a fundamental process of evolution. By monitoring allele frequencies, we can analyze the effects of natural selection and genetic drift on populations. To efficiently track time-resolved genetic change, large experimental or wild populations can be sequenced as pools of individuals sampled over time using high-throughput genome sequencing (called the Evolve & Resequence approach, E&R). Here, we present a set of experiments using hundreds of natural genotypes of the model plantArabidopsis thalianato showcase the power of this approach to study rapid evolution at large scale. First, we validate that sequencing DNA directly extracted from pools of flowers from multiple plants -- organs that are relatively consistent in size and easy to sample -- produces comparable results to other, more expensive state-of-the-art approaches such as sampling and sequencing of individual leaves. Sequencing pools of flowers from 25-50 individuals at ∼40X coverage recovers genome-wide frequencies in diverse populations with accuracyr> 0.95. Secondly, to enable analyses of evolutionary adaptation using E&R approaches of plants in highly replicated environments, we provide open source tools that streamline sequencing data curation and calculate various population genetic statistics two orders of magnitude faster than current software. To directly demonstrate the usefulness of our method, we conducted a two-year outdoor evolution experiment withA. thalianato show signals of rapid evolution in multiple genomic regions. We demonstrate how these laboratory and computational Pool-seq-based methods can be scaled to study hundreds of populations across many climates.
Neural mechanism of acute stress management by trace aminergic signalling in the lateral habenula
Authors: Yang Soo Hyun , Yang Esther , Lee Jaekwang , Kim Jin Yong , Yoo Hyeijung , Park Hyung Sun , Jung Jin Taek , Lee Dongmin , Chun Sungkun , Lee Hyun Woo , Kim Hyun
Published: February 2022

Stress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system1. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg)2–10. However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown11–14. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons)15 in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, local activation of trace amine-associated receptor 1 (TAAR1; a trace amine receptor) in the RMTg is sufficient to rescue the despair-like behaviour produced by the loss of AADC expression. Our results identify a novel efferent pathway from the LHb to the RMTg whereby trace aminergic signalling allows the brain to manage acute stress by preventing VTA dopaminergic neuron hypoactivity. The TAAR1-mediated trace aminergic signalling in the LHb-RMTg pathway may hold promise as a therapeutic target for stress-mediated psychological diseases.
Development and optimisation of a high-throughput screening assay for in vitro anti–SARS-CoV-2 activity: evaluation of 5676 phase 1 passed structures
Authors: Chiu Winston , Verschueren Lore , Van den Eynde Christel , Buyck Christophe , De Meyer Sandra , Jochmans Dirk , Bojkova Denisa , Ciesek Sandra , Cinatl Jindrich , De Jonghe Steven , Leyssen Pieter , Neyts Johan , Van Loock Marnix , Van Damme Ellen
Published: February 2022

Although vaccines are currently used to control the coronavirus disease 2019 (COVID-19) pandemic, treatment options are urgently needed for those who cannot be vaccinated and for future outbreaks involving new severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) strains or coronaviruses not covered by current vaccines. Thus far, few existing antivirals are known to be effective against SARS-CoV-2 and clinically successful against COVID-19.

As part of an immediate response to the COVID-19 pandemic, a high-throughput, high content imaging–based SARS-CoV-2 infection assay was developed in VeroE6-eGFP cells and was used to screen a library of 5676 compounds that passed phase 1 clinical trials. Eight candidates (nelfinavir, RG-12915, itraconazole, chloroquine, hydroxychloroquine, sematilide, remdesivir, and doxorubicin) with in vitro anti–SARS-CoV-2 activity in VeroE6-eGFP and/or Caco-2 cell lines were identified. However, apart from remdesivir, toxicity and pharmacokinetic data did not support further clinical development of these compounds for COVID-19 treatment.
COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism
Authors: Smeyne Richard J , Eells Jeffrey , Chatterjee Debotri , Byrne Matthew , Akula Shaw M. , Sriramula Srinivas , O’Rourke Dorcas P. , Schmidt Peter
Published: February 2022

Background

Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection.

Objectives

To determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism.

Methods

hACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone.

Results

hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p□<□0.05).

Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone.

Conclusions

Our observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination.

Funding

This work was supported by grant from the State of North Carolina (PS, JE, DOR, RJS) and R21 NS122280 (RJS).
PRMT5 regulates ATF4 transcript splicing and oxidative stress response
Authors: Szewczyk Magdalena M. , Luciani Genna M. , Vu Victoria , Murison Alex , Dilworth David , Lupien Mathieu , Arrowsmith Cheryl H , Minden Mark D. , Barsyte-Lovejoy Dalia
Published: February 2022

Protein methyltransferase 5 (PRMT5) symmetrically dimethylates arginine residues leading to regulation of transcription and splicing programs. Although PRMT5 has emerged as an attractive oncology target, the molecular determinants of PRMT5 dependency in cancer remain incompletely understood. Our transcriptomic analysis identified PRMT5 regulation of the activating transcription factor 4 (ATF4) pathway in acute myelogenous leukemia (AML). PRMT5 inhibition resulted in the expression of unstable, intron-retaining ATF4 mRNA that is detained in the nucleus. Concurrently, the decrease in the spliced cytoplasmic transcript of ATF4 led to lower levels of ATF4 protein and downregulation of ATF4 target genes. Upon loss of functional PRMT5, cells with low ATF4 displayed increased oxidative stress, growth arrest, and cellular senescence. Interestingly, leukemia cells with EVI1 oncogene overexpression demonstrated dependence on PRMT5 function. EVI1 and ATF4 regulated gene signatures were inversely correlated. We show that EVI1-high AML cells have reduced ATF4 levels, elevated baseline reactive oxygen species and increased sensitivity to PRMT5 inhibition. Thus, EVI1-high cells demonstrate dependence on PRMT5 function and regulation of oxidative stress response. Overall, our findings identify the PRMT5-ATF4 axis to be safeguarding the cellular redox balance that is especially important in high oxidative stress states, such as those that occur with EVI1 overexpression.
Apolipoprotein E4 has extensive conformational heterogeneity in lipid free and bound forms
Authors: Stuchell-Brereton Melissa D. , Zimmerman Maxwell I. , Miller Justin J. , Mallimadugula Upasana L. , Incicco J. Jeremias , Roy Debjit , Smith Louis G. , Baban Berevan , DeKoster Gregory T. , Frieden Carl , Bowman Gregory R. , Soranno Andrea
Published: February 2022

The ε4-allele variant of Apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease, though it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. We apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically-detailed model of monomeric ApoE4 and probe the effect of lipid association. Our data reveal that ApoE4 is far more disordered than previously thought and retains significant conformational heterogeneity after binding lipids. In particular, the behavior of the hinge region and C-terminal domain of ApoE4 differs substantially from that proposed in previous models and provides a crucial foundation for understanding how ApoE4 differs from non-pathogenic and protective variants of the protein.
Maternal Wnt11b regulates cortical rotation duringXenopusaxis formation: analysis of maternal-effectwnt11bmutants
Authors: Houston Douglas W. , Elliott Karen L. , Coppenrath Kelsey , Wlizla Marcin , Horb Marko E.
Published: February 2022

Asymmetric signalling centres in the early embryo are essential for axis formation in vertebrates. These regions, namely the dorsal morula, yolk syncytial layer, and distal hypoblast/anterior visceral endoderm (in amphibians, teleosts and mammals, respectively), require the localised stabilisation of nuclear Beta-catenin (Ctnnb1), implying that localised Wnt/Beta-catenin signalling activity is critical in their establishment. However, it is becoming increasingly apparent that the stabilisation of Beta-catenin in this context may be initiated independently of secreted Wnt growth factor activity. InXenopus, dorsal Beta-catenin stabilisation is initiated by a requisite microtubule-mediated symmetry-breaking event in the fertilised egg: “cortical rotation”. Vegetally-localisedwnt11bmRNA has been implicated upstream of Beta-catenin in this context, as has the dorsal enrichment of Wnt ligand-independent activators of Beta-catenin, but the extent that each of these processes contribute to axis formation in this paradigm remains unclear. Here we describe a maternal effect mutation inXenopus laevis wnt11b.L, generated by CRISPR mutagenesis. We demonstrate a maternal requirement for timely and complete gastrulation morphogenesis and a zygotic requirement for proper left-right asymmetry. We also show that a subset of maternalwnt11bmutants have axis and dorsal gene expression defects, but that Wnt11b likely does not act through the Wnt coreceptor Lrp6 or through Dishevelled, which we additionally show (using exogenous constructs) do not exhibit patterns of activity consistent with roles in early Beta-catenin stabilisation. Instead, we find that microtubule assembly and cortical rotation are reduced inwnt11bmutant eggs, leading to less organised and directed vegetal microtubule arrays. In conclusion, we propose that Wnt11b signals to the cytoskeleton in the egg or early zygote to enable robust cortical rotation, and thus acts in the distribution of putative dorsal determinants rather than as a component or effector of the determinants themselves.
Superstitious learning of abstract order from random reinforcement
Authors: Jin Yuhao , Jensen Greg , Gottlieb Jacqueline , Ferrera Vincent P.
Published: February 2022

Survival depends on identifying learnable features of the environment that predict reward, and avoiding others that are random and unlearnable. However, humans and other animals often infer spurious associations among unrelated events, raising the question of how well they can distinguish learnable patterns from unlearnable events. Here, we tasked monkeys with discovering the serial order of two pictorial sets: a “learnable” set in which the stimuli were implicitly ordered and monkeys were rewarded for choosing the higher-rank stimulus and an “unlearnable” set in which stimuli were unordered and feedback was random regardless of the choice. We replicated prior results that monkeys reliably learned the implicit order of the learnable set. Surprisingly, the monkeys behaved as though some ordering also existed in the unlearnable set, showing consistent choice preference that transferred to novel untrained pairs in this set, even under a preference-discouraging reward schedule that gave rewards more frequently to the stimulus that was selected less often. In simulations, a model-free RL algorithm (Q-learning) displayed a degree of consistent ordering among the unlearnable set but, unlike the monkeys, failed to do so under the preference, discouraging reward schedule. Our results suggest that monkeys infer abstract structures from objectively random events using heuristics that extend beyond stimulus-outcome conditional learning to more cognitive model-based learning mechanisms.
Population Estimates of People with Spina Bifida in the United States in 2020
Authors: Briggs Virginia G.
Published: February 2022

Introduction

Spina bifida is a birth defect that results in deficits of neurological function. Individuals diagnosed with spina bifida often require a lifetime of medical care to manage this condition. Currently, the number of people living with spina bifida in the United States is unclear. The purpose of this study is to provide estimates of the magnitude of this condition, and its distribution by gender and age.

Methods

Total births affected by spina bifida were calculated using rates from the Birth Defects Monitoring Program (BDMP) and state-based birth defects tracking systems supported by the Centers for Disease Control (CDC), over an 80-year period (1940-2020). Spina bifida mortality rates were determined using death certificate data available through the Centers for Disease Control and Prevention, National Center for Health Statistics. Life tables were created for each year of birth between 1940 and 2020 to estimate the total number of people with spina bifida alive in 2020 in the United States.

Results

In 2020, the estimated number of people in the U.S. living with spina bifida (0-80 years of age) was 124,150 (67,662 female; 56,488 male). The majority were adults aged 30 to 80 years (66.6%), compared to children and young adults (33.4%).

Conclusion

Understanding the approximate size and distribution by age and gender may assist health care providers in planning services for this changing population.
Biologic correlates of beneficial convalescent plasma therapy in a COVID-19 patient reveal disease resolution mechanisms
Authors: Bruiners Natalie , Guerrini Valentina , Ukey Rahul , Dikdan Ryan , Yang Jason , Mishra Pankaj Kumar , Onyuka Alberta , Handler Deborah , Vieth Joshua , Carayannopulos Mary , Guo Shuang , Pollen Maressa , Pinter Abraham , Tyagi Sanjay , Feingold Daniel , Philipp Claire , Libutti Steven , Gennaro Maria Laura
Published: February 2022

Background

While the biomarkers of COVID-19 severity have been thoroughly investigated, the key biological dynamics associated with COVID-19 resolution are still insufficiently understood.

Main body

We report a case of full resolution of severe COVID-19 due to convalescent plasma transfusion in a patient with underlying multiple autoimmune syndrome. Following transfusion, the patient showed fever remission, improved respiratory status, and rapidly decreased viral burden in respiratory fluids and SARS-CoV-2 RNAemia. Longitudinal unbiased proteomic analysis of plasma and single-cell transcriptomics of peripheral blood cells conducted prior to and at multiple times after convalescent plasma transfusion identified the key biological processes associated with the transition from severe disease to disease-free state. These included (i) temporally ordered upward and downward changes in plasma proteins reestablishing homeostasis and (ii) post-transfusion disappearance of a particular subset of dysfunctional monocytes characterized by hyperactivated Interferon responses and decreased TNF-α signaling.

Conclusions

Monitoring specific subsets of innate immune cells in peripheral blood may provide prognostic keys in severe COVID-19. Moreover, understanding disease resolution at the molecular and cellular level should contribute to identify targets of therapeutic interventions against severe COVID-19.
Predicting personalised risk of disability worsening in multiple sclerosis with machine learning
Authors: Eshaghi Arman , Wijeratne Peter A , Oxtoby Neil P , Arnold Douglas L , Collins Louis , Narayanan Sridar , Guttmann Charles R. G. , Thompson Alan J , Alexander Daniel C , Barkhof Frederik , Chard Declan , Ciccarelli Olga
Published: February 2022

Multiple sclerosis is a heterogeneous disease with an unpredictable course. We applied machine learning to generate individualised risk scores of disability worsening and stratify patients into subgroups with different prognosis.

Clinical data and MRI scans from published randomised clinical trials in patients with relapsing-remitting and progressive MS were divided into training (n=5,483) and external validation data sets (n=2,668). We processed brain MRI scans to obtain 18 measures for lobar grey matter, deep grey matter and lesion volumes, and T1-/T2-weighted ratio of the normal-appearing white matter regions. We developed a machine learning model, called subpopulation risk stratification (SunRiSe), that combines multi-parametric clinical and MRI data to estimate individualised risk scores and stratify patients into subgroups on the basis of this risk; in particular, we entered MRI measures, the Expanded Disability Status Scale, age and gender to generate risk scores of disability worsening (i.e., the time to confirmed disability worsening). Based on SunRiSe risk scores, high-, medium-, and low-risk subpopulations were defined at study entry. We assessed whether selecting patients at high risk of disability worsening reduces sample size compared to when all risk groups were sampled together.

In both the training and external validation data sets, SunRiSe-stratified patients in three groups associated with different levels of risk of disability worsening. In the external validation data set, patients at high risk were mainly progressive MS and had more disability events compared to those at medium-risk (hazard ratio [HR]=1.34, p<0.0001) and low-risk (HR=1.51, p<0.0001). At study entry, male gender, older age, higher lesion load, higher disability, lower lobar cortical grey matter, lower normal-appearing white matter T1/T2 ratio and lower deep grey matter volumes, were the most important variables in defining the SunRiSe risk score.

The inclusion of patients predicted to be at high risk, reduced (i) duration of an event-driven trial by an average of 4.5 months (±2.1 months); (ii) the number of participants in a randomised trial by approximately 200, with 80% statistical power to detect a 30% treatment effect.

Machine learning provides a personalised risk score that can identify patients who have the greatest risk of disability worsening and therefore should be treated with the most effective medications and monitored more closely. Risk stratification allows the enrichment of clinical trials with patients more likely to worsen, and thereby reduces trial duration and sample size.
Concordance of B and T cell responses to SARS-CoV-2 infection, irrespective of symptoms suggestive of COVID-19
Authors: Österdahl Marc F. , Christakou Eleni , Hart Deborah , Harris Ffion , Shahrabi Yasaman , Pollock Emily , Wadud Muntaha , Spector Tim D. , Brown Matthew A. , Seow Jeffrey , Malim Michael H. , Steves Claire J. , Doores Katie J. , Duncan Emma L , Tree Timothy
Published: February 2022

Objectives

To assess T cell responses in individuals with and without a positive antibody response to SARS-CoV-2, in symptomatic and asymptomatic individuals during the COVID-19 pandemic.

Methods

Participants were drawn from the TwinsUK cohort, selected according to a) presence or absence of COVID-associated symptoms (S+, S-), logged prospectively through the COVID Symptom Study app, and b) Anti-IgG Spike and anti-IgG Nucleocapsid antibodies measured by ELISA (Ab+, Ab-), during the first wave of the UK pandemic. T cell helper and regulatory responses after stimulation with SARS-CoV-2 peptides were assessed.

Results

32 participants were included in final analysis. 14 of 15 with IgG Spike antibodies had a T cell response to SARS-CoV-2-specific peptides; none of 17 participants without IgG Spike antibodies had a T cell response (Chi-squared 28.2, p<0.001). Quantitative T cell responses correlated strongly with fold-change in IgG Spike antibody titre (rho=0.79, p<0.0001) but not to symptom score (rho=0.17, p=0.35).

Conclusions

Humoral and cellular immune responses to SARS-CoV-2 are highly correlated, with no evidence that cellular immunity differs from antibody status four months after acute illness.
COVID-19 Vaccination is Associated with Decreasing Cases, Hospitalizations, and Deaths Across Age Groups and Variants over 9 months in Switzerland
Authors: Jucker Jean-Luc
Published: February 2022

Recent studies assessing COVID-19 vaccine efficacy at the population level found counterintuitive results, such as positive associations between vaccination and infections or deaths. These ecological studies have limitations, including too short observation periods, focusing on infections, and not controlling for age groups and dominant variants. The current study addresses these limitations by investigating the relations between vaccination and COVID-19 cases, hospitalizations, and deaths over a longer period (9½ months) while also considering age groups (from 10 to 80+ years old) and variants (Alpha and Delta), utilizing data from Switzerland. Results suggest that vaccination is negatively related to cases overall and in all cantons of Switzerland, and that vaccination is negatively related to hospitalizations and deaths from 50 years old. Furthermore, vaccination is a significant predictor of cases, hospitalizations, and deaths while holding the effects of age and dominant variant constant.
MACHINE LEARNING IMPACT ASSESSMENT OF CLIMATE FACTORS ON DAILY COVID-19 CASES
Authors: Afrifa Stephen , Ato Essien Felix , Appiahene Peter , Wiafe Isaac , Mensah Gyening Rose-Mary Owusuaa , Opoku Michael
Published: February 2022

Coronavirus disease 2019 (also known as COVID-19) is a vastly infectious virus instigated by the coronavirus-2, which causes severe acute respiratory illness (SARS-Cov-2). Scientists and researchers are conducting a number of studies to better understand the COVID-19 pandemic’s behavioral nature and spread, and machine learning provides useful tools. We used machine learning techniques to study the effect of climate conditions on daily instances of COVID-19 in this study. The study has three main objectives: first, to investigate the most climatic features that could affect the spread of novel COVID-19 cases; second, to assess the influence of government strategies on COVID-19 using our dataset; third, to do a comparative analysis of two different machine learning models, and develop a model to predict accurate response to the most features on COVID-19 spread. The goal of this research is to assist health-care facilities and governments with planning and decision-making. The study compared random forest and artificial neural network models for analysis. In addition, feature importance among the independent variables (climate variables) were identified with the random forest. The study used publicly available datasets of COVID-19 cases from the World Health Organization and climate variables from National Aeronautics and Space Administration websites respectively. Our results showed that relative humidity and solar had significant impact as a feature of weather variables on COVID-19 recorded cases; and that random forest predicted accurate response to the most climatic features on COVID-19 spread. Based on this, we propose the random forest model to predict COVID-19 cases using weather variables.
Structural features of mTORC2 that control substrate-specific activities
Authors: Yu Zanlin , Chen Junliang , Takagi Enzo , Wang Feng , Saha Bidisha , Liu Xi , Joubert Lydia-Marie , Gleason Catherine E. , Jin Mingliang , Li Chengmin , Nowotny Carlos , Agard David , Cheng Yifan , Pearce David
Published: February 2022

mTORC2 is a multi-subunit kinase complex that is central to multiple essential signaling pathways. Two core subunits, Rictor and mSin1 distinguish it from its relative, mTORC1 and support context-dependent phosphorylation of its substrates. mTORC2 structures have been determined previously, however, important questions remain, particularly regarding structural determinants of substrate specificity and context dependent activities. We used cryo-EM to obtain high resolution structures of the human mTORC2 apo-complex, as well as structures in the presence of substrates, Akt and SGK1. Specific predictions suggested by substrate-induced structural changes were tested in functional assays. First, side chain interactions between Rictor and mTOR that prevent recruitment of mTORC1 substrates and confer resistance to the mTORC1 inhibitor rapamycin were visualized for the first time in the apo-state, demonstrating the steric occlusion that prevents mTORC2 interaction with mTORC1 substrates and rapamycin. Also in the apo-state, mSin1 was seen to form extensive contacts with Rictor, including a pair of short α-helices nestled between two Rictor helical repeat clusters, followed by an extended strand, which makes multiple weak contacts with Rictor helical cluster 1. In co-complex structures, SGK1, but not Akt, markedly altered the conformation of the mSin1 N-terminal extended strand, disrupting multiple weak interactions while inducing a large rotation of mSin1/Arg-83, which comes to interact with a negative patch within Rictor. Mutation of Arg-83 to Ala selectively disrupted mTORC2 dependent phosphorylation of SGK1 but not of Akt, supporting context-dependent substrate selection. These findings provide new structural and functional insights into mTORC2 specificity and context-dependent activities.
Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications
Authors: Giriyappagoudar Muttanagouda , Vastrad Basavaraj , Horakeri Rajeshwari , Vastrad Chanabasayya
Published: February 2022

The ongoing pandemic of coronavirus disease 2019 (COVID-19) has made a serious public health threat globally. To discover key molecular changes in COVID-19 and its secondary complications, we analyzed next-generation sequencing (NGS) data of COVID-19. NGS data (GSE163151) was screened and downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) were identified in the present study, using DESeq2 package in R programming software. Gene ontology (GO) and pathway enrichment analysis were performed, and the protein-protein interaction (PPI) network, module analysis, miRNA-hub gene regulatory network and TF-hub gene regulatory network were established. Subsequently, receiver operating characteristic curve (ROC) analysis was used to validate the diagonostics valuesof the hub genes. Firstly, 954 DEGs (477 up regulated and 477 down regulated) were identified from the four NGS dataset. GO enrichment analysis revealed enrichment of DEGs in genes related to the immune system process and multicellular organismal process, and REACTOME pathway enrichment analysis showed enrichment of DEGs in the immune system and formation of the cornified envelope. Hub genes were identified from the PPI network, module analysis, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, the ROC analysis indicate that COVID-19 and its secondary complications with following hub genes, namely, RPL10, FYN, FLNA, EEF1A1, UBA52, BMI1, ACTN2, CRMP1, TRIM42 and PTCH1, had good diagnostics values. This study identified several genes associated with COVID-19 and its secondary complications, which improves our knowledge of the disease mechanism.
2’-O-methylation of the second transcribed nucleotide within mRNA 5’ cap impacts protein production level in a cell specific manner and contributes to RNA immune evasion
Authors: Drazkowska Karolina , Baran Natalia , Warminski Marcin , Tomecki Rafal , Depaix Anaïs , Cysewski Dominik , Kasprzyk Renata , Kowalska Joanna , Jemielity Jacek , Sikorski Pawel J.
Published: February 2022

In higher eukaryotes, m7G-adjacent nucleotides undergo extensive modifications. Ribose of the first or first and second transcribed nucleotides can be subjected to 2’-O-methylation to form cap1 or cap2, respectively. Additionally, when the first transcribed nucleotide is adenosine, it can not only undergo 2’-O-methylation but can also be methylated at position N6 forming N6,2’-O-dimethyladenosine (m6Am). Recent studies have shed some light on the functions of cap1, showing that cap1 in mammalian cells plays a crucial role in distinguishing between ‘self’ and ‘non-self’ RNA during viral infection. Here, we attempted to understand the impact of other cap methylations on RNA-related processes. Therefore, we synthesized tetranucleotide cap analogs and used them for efficient co-transcriptional RNA capping during in vitro transcription. Using this tool, we found that 2’-O-methylation of the second transcribed nucleotide within the mRNA 5’ cap influences protein production levels in a cell-specific manner. The presence of this modification can strongly hamper protein biosynthesis or do not influence protein production levels. Interestingly, 2’-O-methylation of the second transcribed nucleotide as well as the presence of N6,2’-O-dimethyladenosine as the first transcribed nucleotide serve as determinants that define transcripts as ‘self’ and contribute to transcript escape from the host innate immune response. Additionally, cap methylation status does not influence transcript affinity towards translation initiation factor 4E or in vitro susceptibility to decapping by DCP2; however what we observe is resistance of RNA capped with cap2 to DXO-mediated decapping and degradation.

Significance Statement

Methylation of mRNA cap structure regulates protein biosynthesis in a cell-dependent manner. Among the three known m7G cap modifications, the 2’-O-methylation is dominant. 2’-O-methylation of the first transcribed nucleotide can boost protein production, whereas the same modification of the second transcribed nucleotide can strongly decrease translation. Interestingly, we show that in the JAWS II cell line, 2’-O-methylation of mRNA cap had a prominent impact on the composition of the protein interactome associated with the RNA bearing mentioned modifications. Further analysis revealed that 2’-O-methylation of the second transcribed nucleotide and N6-methylation of adenosine as the first transcribed nucleotide serve as determinants defining transcripts as ‘self’ and contribute to transcript escape from the host innate immune response.
Gal1 repression memory in budding yeast
Authors: Schuh Lea , Kukhtevich Igor , Bheda Poonam , Schulz Melanie , Bordukova Maria , Schneider Robert , Marr Carsten
Published: February 2022

Cells must continuously adapt to changing environments and, thus, have evolved mechanisms allowing them to respond to repeated stimuli. For example, faster gene induction upon a repeated stimulus aids adaptation - a process known as reinduction memory. However, whether such a memory exists for gene repression is unclear. Here, we studied gene repression across repeated carbon source shifts in over 2,500 single Saccharomyces cerevisiae cells. By monitoring the expression of a carbon source-responsive gene, galactokinase 1 (Gal1), and mathematical modeling, we discovered repression memory at the population and single-cell level. Using a repressor model to estimate single-cell repression parameters, we show that repression memory is due to a shortened repression delay, the estimated time gap between carbon source shift and Gal1 expression termination, upon the repeated carbon source shift. Additionally, we show that cells lacking Elp6 display a gain-of-repression-memory phenotype characterized by a stronger decrease in repression delay between two consecutive carbon source shifts. Collectively, our study provides the first quantitative description of repression memory in single cells.