bluuebunny/crossref_metadata_2025 huggingface dataset:
Cervical cancer screening improvements with self-sampling during the COVID-19 pandemic
Authors: Elfström K. Miriam , Dillner Joakim
Published: July 2022

Background

At the onset of the COVID-19 pandemic cervical screening in the capital region of Sweden was cancelled for several months. A series of measures to preserve and improve the cervical screening under the circumstances were instituted, including a switch to screening with HPV self-sampling to enable screening in compliance with social distancing recommendations.

Methods

We describe the major changes implemented, which were i) nationwide implementation of HPV screening ii) switch to primary self-sampling instead of clinician sampling iii) implementation of HPV screening in all screening ages and iv) combined HPV vaccination and HPV screening in the cervical screening program.

Results

A temporary government regulation allowed primary self-sampling with HPV screening in all ages. In the Stockholm region, 330,000 self-sampling kits were sent to the home address of screening-eligible women, instead of an invitation to clinician sampling. An increase in population test coverage was seen (from 66% to 70% in just one year). In addition, a national campaign for faster elimination of cervical cancer with concomitant screening and vaccination for women in ages 23-28 was launched.

Conclusions

The COVID-19 pandemic necessitated major changes in the cervical cancer preventive strategies, where it can already be concluded that the strategy with organised primary self-sampling for HPV has resulted in a major improvement of population test-coverage.

Funding

Funded by the Swedish Association of Local Authorities and Regions, the Swedish Cancer Society, the European Union’s Horizon 2020 Research and Innovation Program, the Swedish government and the Stockholm county.
Biomarkers and Outcomes in Hospitalized Covid-19 Patients: A Prospective Registry
Authors: Khedar Raghubir S , Gupta Rajeev , Sharma Krishna Kumar , Mittal Kartik , Ambaliya Harshad C , Gupta Jugal B , Singh Surendra , Sharma Swati , Singh Yogendra , Mathur Alok
Published: July 2022

Objectives

To determine association of biomarkers high sensitivity C-reactive protein (hsCRP), D-dimer, interleukin-6 (IL-6), lactic dehydrogenase (LDH), ferritin and neutrophil-lymphocyte ratio (NLR) at hospital admission with clinical features and outcomes in Covid-19.

Methods

Successive virologically confirmed Covid-19 patients hospitalized from April 2020 to July 2021 were recruited in a prospective registry. Details of clinical presentation, investigations, management and outcomes were recorded. All the biomarkers were divided into tertiles to determine associations with clinical features and outcomes. Numerical data are presented in median and interquartile range (IQR 25-75). Univariate and multivariate (age, sex, risk factor, comorbidity adjusted) odds ratio (OR) and 95% confidence intervals (CI) were calculated to determine association of deaths with each biomarker.

Results

We identified 3036 virologically confirmed Covid-19 patients during the study period, 1215 were hospitalized and included in the present study. Men were 70.0%, aged >60y 44.8%, hypertension 44.8% diabetes 39.6% and cardiovascular disease 18.9%. Median symptom duration was 5 days (IQR 4-7) and SpO2 95% (90-97). Total white cell count was 6.9×103/µl, (5.0-9.8), neutrophils 79.2% (68.1-88.2) and lymphocytes 15.8% (8.7-25.5). Medians (IQR) for biomarkers were hsCRP 6.9 mg/dl (2.2-18.9), D-dimer 464 ng/dl (201-982), IL-6 20.1 ng/dl (6.5-60.4), LDH 284 mg/dl (220-396) and ferritin 351 mg/dl (159-676). Oxygen support at admission was in 38.6%, and non-invasive or invasive ventilatory support in 11.0% and 11.6% respectively. 173 (13.9%) patients died and 15 (1.2%) transferred to hospice care. For each biomarker, those in the second and third tertiles, compared to the first, had worse clinical and laboratory abnormalities, and greater oxygen and ventilatory support. Multivariate adjusted OR (95% CI) for deaths in second and third vs first tertiles, respectively, were for hsCRP 2.29(1.14-4.60) and 13.39(7.23-24.80); D-dimer 3.26(1.31-7.05) and 13.89(6.87-28.27); IL-6 2.61(1.31-5.18) and 10.96(5.88-20.43); ferritin 3.19(1.66-6.11) and 9.13(4.97-16.78); LDH 1.85(0.87-3.97) and 10.51(5.41-20.41); and NLR 3.34(1.62-6.89) and 17.52(9.03-34.00) (p<0.001).

Conclusions

In Covid-19, high levels of biomarkers-hsCRP, D-dimer, IL-6, LDH, ferritin and NLR are associated with more severe illness and significantly greater in-hospital mortality. NLR, a simple, widely available and inexpensive investigation provides prognostic information similar to the more expensive biomarkers.
Histone 4 lysine 5/12 acetylation provides a plasticity code with epigenetic memory of environmental exposure
Authors: Werner Michael S. , Loschko Tobias , King Thomas , Theska Tobias , Franz-Wachtel Mirita , Macek Boris , Sommer Ralf J.
Published: July 2022

Development can be altered to match phenotypes with the environment, and the genetic mechanisms that direct such alternative phenotypes are beginning to be elucidated1,2. Yet, the rules that govern environmental sensitivityvs. invariant development (canalization), and potential epigenetic memory, remain unknown. Here, we show that plasticity of nematode mouth forms is determined by histone 4 lysine 5 and 12 acetylation (H4K5/12ac). Acetylation in early larval stages provides a permissive chromatin state at specific switch genes, which is susceptible to induction during the critical window of environmental sensitivity. As development proceeds deacetylation shuts off switch gene expression to end the critical period. We show that inhibiting deacetylase enzymes leads to long-term epigenetic memory, demonstrating that histone modifications in juveniles can carry environmental information to affect organismal traits in adults. This epigenetic regulation of plasticity appears to be derived from an ancient mechanism of licensing developmental speed that is conserved between flies and nematodes. Thus, H4K5/12ac provides a histone ‘plasticity’ code with epigenetic potential that can be stored and erased by acetylation and deacetylation, respectively.

Highlights

Reciprocal transplant experiments reveal a critical time window of mouth-form plasticity.

Entry and exit of the critical window is determined by H4K5/12ac at the switch geneeud-1.

H4K12ac maintains transcriptional competence by supporting elongation.

Inhibition of deacetylation freezes an initial developmental trajectory, resulting in long-term epigenetic memory.

H4K5/12 acetylation control of plasticity was co-opted from an ancestral role in controlling developmental speed.
Integrative analysis of the MD Anderson Prostate Cancer Patient-Derived Xenograft Series (MDA PCa PDX)
Authors: Anselmino Nicolas , Labanca Estefania , Song Xiaofei , Yang Jun , Shepherd Peter DA , Dong Jiabin , Kundra Ritika , Schultz Nikolas , Zhang Jianhua , Araujo John C. , Aparicio Ana M , Subudhi Sumit K. , Corn Paul G. , Pisters Louis L. , Ward John F. , Davis John W. , Gueron Geraldine , Vazquez Elba S. , Logothetis Christopher J , Futreal Andrew , Troncoso Patricia , Chen Yu , Navone Nora M
Published: July 2022

Progress in understanding prostate cancer (PCa) metastasis and therapy resistance has been hampered by the lack of models, representative of the clinical spectrum and biologic complexity of the disease. Our laboratory is home to one of the largest worldwide repositories of PCa patient-derived xenografts (PDXs), the MDA PCa PDX series, a collection of clinically annotated PDXs reflecting the full spectrum of potentially lethal disease, that includes tumors that are not end stage and not castration-resistant PCa. We performed whole genome sequencing, targeted sequencing and RNA sequencing of 46 MDA PCa PDX models derived from biopsy and surgical specimens from 39 patients, selected in order to reflect the clinicopathological PCa subtypes (data available in cBioPortal). MDA PCa PDXs genomic characterization shows that the cohort recapitulates the mutational landscape found in PCa, highlighting the clinical relevance of these models. Interestingly and consistently with the clinic, certain models lack the typical PCa driver alterations, thus providing a suitable tool for discovery of novel drivers. Our cohort also includes PDXs derived from different areas of the same tumor and longitudinal samples, allowing to study disease heterogeneity and progression. Finally, we have developed a procedure to grow organoids from PDXs, thus providing a powerful in vitro platform that supports hypothesis generation, and testing of clinically relevant observations. Genomic and transcriptomic characterization of MDA PCa PDXs together with the ability to grow them as organoids for in vitro experimentation, provides a unique resource to address the existing clinical gap in PCa, helping to better understand mechanisms of response and resistance.

One Sentence Summary

MDA PCa PDX series is a dynamic resource capturing the molecular landscape of prostate cancer; a platform for discovery and personalized medicine
The novel compensatory reciprocal interplay between neutrophils and monocytes drives cancer progression
Authors: Chen Zhihong , Soni Nishant , Pinero Gonzalo , Giotti Bruno , Eddins Devon J. , Lindblad Katherine E. , Ross James L , Tsankova Nadejda , Gutmann David H. , Lira Sergio A. , Lujambio Amaia , Ghosn Eliver E.B. , Tsankov Alexander M. , Hambardzumyan Dolores
Published: July 2022

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genomic editing, we generated a mouse model that is deficient of all monocyte chemoattractant proteins (MCP). Using this strain, we effectively abolished monocyte infiltration in glioblastoma (GBM) and hepatocellular carcinoma (HCC) murine models, which were enriched for monocytes or neutrophils, respectively. Remarkably, eliminating monocyte chemoattraction invokes a significant compensatory neutrophil influx in GBM, but not in HCC. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Importantly, genetic or pharmacological inhibiting neutrophil in HCC or qMCP-KO GBM extended the survival of tumor-bearing mice. Our findings emphasize the importance of targeting both monocytes and neutrophils simultaneously for cancer immunotherapy.

In Brief

Eliminating monocyte chemoattraction invokes compensatory neutrophil influx in tumor, and vice versa, rendering current myeloid-targeted therapies ineffective. Using genetic and pharmacological approaches combined with novel mouse models of GBM and HCC, we provide credence advocating for combinational therapies aiming at inhibiting both monocytes and neutrophils simultaneously.

Highlights

•

Blocking monocyte chemoattraction results in increased neutrophil infiltration.

•

Increased neutrophil recruitment induces GBM PN to MES transition.

•

Inhibiting neutrophil infiltration in monocyte-deficient tumors improves mouse GBM survival.

•

Blocking neutrophil, but not monocyte, infiltration in HCC prolongs mouse survival.
Decoding the Effects of Spike Receptor Binding Domain Mutations on Antibody Escape Abilities of Omicron Variants
Authors: Chakraborty Sandipan , Saha Aditi , Saha Chiranjeet , Ghosh Sanjana , Mondal Trisha
Published: July 2022

Recent times witnessed an upsurge in the number of COVID cases which is primarily attributed to the emergence of several omicron variants, although there is substantial population vaccination coverage across the globe. Currently, many therapeutic antibodies have been approved for emergency usage. The present study critically evaluates the effect of mutations observed in several omicron variants on the binding affinities of different classes of RBD-specific antibodies using a combined approach of immunoinformatics and binding free energy calculations. Our binding affinity data clearly show that omicron variants achieve antibody escape abilities by incorporating mutations at the immunogenic hotspot residues for each specific class of antibody. K417N and Y505H point mutations are primarily accountable for the loss of class I antibody binding affinities. The K417N/Q493R/Q498R/Y505H combined mutant significantly reduces binding affinities for all the class I antibodies. E484A single mutation, on the other hand, drastically reduces binding affinities for most of the class II antibodies. E484A and E484A/Q493R double mutations cause a 33-38% reduction in binding affinity for the approved therapeutic monoclonal antibodies, Bamlanivimab (LY-CoV555). The Q498R RBD mutation observed across all the omicron variants can reduce ~12% binding affinity for REGN10987, a class III therapeutic antibody, and the L452R/Q498R double mutation causes a ~6% decrease in binding affinities for another class III therapeutic antibody, LY-CoV1404. Our data suggest that achieving the immune evasion abilities appears to be the selection pressure behind the emergence of omicron variants.
The chromosome-scale genome assembly of the yellowtail clownfishAmphiprion clarkiiprovides insights into melanic pigmentation of anemonefish
Authors: Moore Billy , Herrera Marcela , Gairin Emma , Li Chengze , Miura Saori , Jolly Jeffrey , Mercader Manon , Izumiyama Michael , Kawai Erina , Ravasi Timothy , Laudet Vincent , Ryu Taewoo
Published: July 2022

Anemonefish are an emerging group of model organisms for studying genetic, ecological, evolutionary, and developmental traits of coral reef fish. The yellowtail clownfishAmphiprion clarkiipossesses species-specific characteristics such as inter-species co-habitation, high intra-species color variation, no anemone specificity, and a broad geographic distribution, that can increase our understanding of anemonefish evolutionary history, behavioral strategies, fish-anemone symbiosis, and color pattern evolution. Despite its position as an emerging model species, the genome ofA. clarkiiis yet to be published. Using PacBio long-read sequencing and Hi-C chromatin capture technology, we generated a high-quality chromosome-scale genome assembly initially comprised of 1,840 contigs with an N50 of 1,203,211 bp. These contigs were successfully anchored into 24 chromosomes of 843,582,782 bp and annotated with 25,050 protein-coding genes encompassing 97.0 % of conserved actinopterygian genes, making the quality and completeness of this genome the highest amongst all published anemonefish genomes to date. Transcriptomic analysis identified tissue-specific gene expression patterns, with the brain and optic lobe having the largest number of expressed genes. Further analyses revealed higher copy numbers oferbb3b(a gene involved in melanophore development) inA. clarkiicompared to other anemonefish, thus suggesting a possible link betweenerbb3band the natural melanism polymorphism observed inA. clarkii. The publication of this high-quality genome, along withA. clarkii’s many unique traits, position this species as an ideal model organism for addressing scientific questions across a range of disciplines.
Flexible selection of task-relevant features through population gating
Authors: Barbosa Joao , Proville Remi , Rodgers Chris C. , DeWeese Michael R. , Ostojic Srdjan , Boubenec Yves
Published: July 2022

Brains can gracefully weed out irrelevant stimuli to guide behavior. This feat is believed to rely on a progressive selection of task-relevant stimuli across the cortical hierarchy, but the specific across-area interactions enabling stimulus selection are still unclear. Here, we propose that population gating, occurring within A1 but controlled by top-down inputs from mPFC, can support across-area stimulus selection. Examining single-unit activity recorded while rats performed an auditory context-dependent task, we found that A1 encoded relevant and irrelevant stimuli along a common dimension of its neural space. Yet, the relevant stimulus encoding was enhanced along an extra dimension. In turn, mPFC encoded only the stimulus relevant to the ongoing context. To identify candidate mechanisms for stimulus selection within A1, we reverse-engineered low-rank RNNs trained on a similar task. Our analyses predicted that two context-modulated neural populations gated their preferred stimulus in opposite contexts, which we confirmed in further analyses of A1. Finally, we show in a two-region RNN how population gating within A1 could be controlled by top-down inputs from PFC, enabling flexible across-area communication despite fixed inter-areal connectivity.
Molecular insight into the enzymatic macrocyclization of multiply backbone N-methylated peptides
Authors: Matabaro Emmanuel , Song Haigang , Sonderegger Lukas , Gherlone Fabio , Giltrap Andrew , Liver Sam , Gossert Alvar , Künzler Markus , Naismith James H
Published: July 2022

The enzyme OphP is essential for the biosynthesis of the macrocyclic peptide omphalotin A, a dodecamer with 9 backbone N-methylations produced by the wood-degrading fungusOmphalotus olearius. Heterologous expression of OphP and the peptide-precursor protein OphMA in yeast, yields omphalotin A. Thus, Oph P was hypothesized to have a dual function; catalyzing both endoproteolytic release of a peptide intermediate from OphMA, and macrocyclization of the multiply α-N-methylated core peptide with concomitant release of a C-terminal follower peptide. In ourin vitroactivity assays, OphP showed robust endoproteolytic and macrocyclase activity on α-N-methylated peptides but was unable to cleave OphMA. The enzyme had a strong preference for hydrophobic, highly α-N-methylated peptides and an α-N-methylated glycine residue at the P1 site. OphP adopts a canonical prolyl oligopeptidase (POP) fold with a predominantly hydrophobic substrate binding cleft, and a small and hydrophobic P1 binding pocket. We demonstrate that OphP is a POP-type macrocyclase with a specificity and a substrate route to the active site different from other members of the family. These results could be exploited for the biotechnological production of macrocyclic peptides with multiple backbone N-methylations, which are interesting due to their favorable pharmacological properties.
Metabolic activity organizes olfactory representations
Authors: Qian Wesley W. , Wei Jennifer N. , Sanchez-Lengeling Benjamin , Lee Brian K. , Luo Yunan , Vlot Marnix , Dechering Koen , Peng Jian , Gerkin Richard C. , Wiltschko Alexander B.
Published: July 2022

Hearing and vision sensory systems are tuned to the natural statistics of acoustic and electromagnetic energy on earth, and are evolved to be sensitive in ethologically relevant ranges. But what are the natural statistics ofodors, and how do olfactory systems exploit them? Dissecting an accurate machine learning model1for human odor perception, we find a computable representation for odor at the molecular level that can predict the odor-evoked receptor, neural, and behavioral responses of nearly all terrestrial organisms studied in olfactory neuroscience. Using this olfactory representation (PrincipalOdorMap, POM), we find that odorous compounds with similar POM representations are more likely to co-occur within a substance and be metabolically closely related; metabolic reaction sequences2also follow smooth paths in POM despite large jumps in molecular structure. Just as the brain’s visual representations have evolved around the natural statistics of light and shapes, the natural statistics of metabolism appear to shape the brain’s representation of the olfactory world.
Discovering non-additive heritability using additive GWAS summary statistics
Authors: Smith Samuel Pattillo , Darnell Gregory , Udwin Dana , Stamp Julian , Harpak Arbel , Ramachandran Sohini , Crawford Lorin
Published: July 2022

LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and popular approach. In this work, we present interaction-LD score (i-LDSC) regression: an extension of the originalLDSCframework that accounts for interactions between genetic variants. By studying a wide range of generative models in simulations, and by re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals in the UK Biobank and up to 159,095 individuals in BioBank Japan, we show that the inclusion of acis-interaction score (i.e., interactions between a focal variant and proximal variants) recovers genetic variance that is not captured byLDSC. For each of the 25 traits analyzed in the UK Biobank and BioBank Japan,i-LDSCdetects additional variation contributed by genetic interactions. Thei-LDSCsoftware and its application to these biobanks represent a step towards resolving further genetic contributions of sources of non-additive genetic effects to complex trait variation.
AutoPhy: Automated phylogenetic identification of novel protein subfamilies
Authors: Ortiz-Velez Adrian , Sukumaran Jeet , Kelley Scott T.
Published: July 2022

Phylogenetic analysis of protein sequences provides a powerful means of identifying novel protein functions and subfamilies, and for identifying and resolving annotation errors. However, automation of functional clustering based on phylogenetic trees has been challenging, and most of it is done manually. Clustering phylogenetic trees usually requires the delineation of tree-based thresholds (e.g., distances), leading to an ad hoc problem. We propose a new phylogenetic clustering approach that identifies clusters without using ad hoc distances or other pre-defined values. Our workflow combines uniform manifold approximation and projection (UMAP) with Gaussian mixture models as a k-means like procedure to automatically group sequences into clusters. We then apply a “second pass” clade identification algorithm to resolve non-monophyletic groups. We tested our approach with several well-curated protein families (outer membrane porins, acyltransferase, and dehydrogenases) and showed our automated methods recapitulated known subfamilies. We also applied our methods to a broad range of different protein families from multiple databases, including Pfam, PANTHER, and UNIPROT. Our results showed that AutoPhy rapidly generated monophyletic clusters (subfamilies) within phylogenetic trees evolving at very different rates both within and among phylogenies. The phylogenetic clusters generated by AutoPhy resolved misannotations, determined new protein functional groups, and detected novel viral strains.
A quaternion model for single cell transcriptomics
Authors: Frost H. Robert
Published: July 2022

We present an approach for modeling single cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) data using quaternions. Quaternions are four dimensional hypercomplex numbers that, along with real numbers, complex numbers and octonions, represent one of the four normed division algebras. Quaternions have been primarily employed to represent three-dimensional rotations in computer graphics with most biomedical applications focused on problems involving the structure and orientation of biomolecules, e.g., protein folding, chromatin conformation, etc. In this paper, we detail an approach for mapping the cells/locations in a scRNA-seq/ST data set to quaternions. According to this model, the quaternion associated with each cell/location represents a vector in ℝ3with vector length capturing sequencing depth and vector direction capturing the relative expression profile. Assuming that biologically interesting features of an scRNA-seq/ST data set are preserved within a rank three reconstruction of the unnormalized counts, this representation has several benefits for data analysis. First, it supports a novel approach for scRNA-seq/ST data visualization that captures cell state uncertainty. Second, the model implies that transformations between cell states can be viewed as three-dimensional rotations, which have a corresponding representation as rotation quaternions. The fact that these rotation quaternions can be interpreted as cells enables a novel approach for characterizing cell state transitions with specific relevance to the analysis of pseudo-temporal ordering trajectories. Most importantly, a quaternion representation supports the genome-wide spectral analysis of scRNA-seq/ST data relative to a single variable, e.g., pseudo-time, or two variables, e.g., spatial coordinates, using a one or two-dimensional hypercomplex discrete Fourier transform. An R package supporting this model and the hypercomplex Fourier analysis of ST data along with several example vignettes is available athttps://hrfrost.host.dartmouth.edu/QSC.
Learning from pre-pandemic data to forecast viral escape
Authors: Thadani Nicole N. , Gurev Sarah , Notin Pascal , Youssef Noor , Rollins Nathan J. , Sander Chris , Gal Yarin , Marks Debora S.
Published: July 2022

Effective pandemic preparedness relies on anticipating viral mutations that are able to evade host immune responses in order to facilitate vaccine and therapeutic design. However, current strategies for viral evolution prediction are not available early in a pandemic – experimental approaches require host polyclonal antibodies to test against and existing computational methods draw heavily from current strain prevalence to make reliable predictions of variants of concern. To address this, we developed EVEscape, a generalizable, modular framework that combines fitness predictions from a deep learning model of historical sequences with biophysical structural information. EVEscape quantifies the viral escape potential of mutations at scale and has the advantage of being applicable before surveillance sequencing, experimental scans, or 3D structures of antibody complexes are available. We demonstrate that EVEscape, trained on sequences available prior to 2020, is as accurate as high-throughput experimental scans at anticipating pandemic variation for SARS-CoV-2 and is generalizable to other viruses including Influenza, HIV, and understudied viruses with pandemic potential such as Lassa and Nipah. We provide continually updated escape scores for all current strains of SARS-CoV-2 and predict likely additional mutations to forecast emerging strains as a tool for ongoing vaccine development (evescape.org).
linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells
Authors: Tornini Valerie A. , Lee Ho-Joon , Miao Liyun , Tang Yin , Dube Sarah E. , Gerson Timothy , Schmidt Valeria J. , Du Katherine , Kuchroo Manik , Kroll François , Vejnar Charles E. , Bazzini Ariel A. , Krishnaswamy Smita , Rihel Jason , Giraldez Antonio J.
Published: July 2022

Thousands of long intergenic non-coding RNAs (lincRNAs) are transcribed throughout the vertebrate genome. A subset of lincRNAs enriched in developing brains has recently been found to contain cryptic open reading frames and are speculated to encode micropeptides. However, systematic identification and functional assessment of these transcripts have been hindered by technical challenges caused by their small size. Here we show that two putative lincRNAs (linc-mipep and linc-wrb) encode micropeptides with homology to the vertebrate-specific chromatin architectural protein, Hmgn1, and demonstrate that they are required for development of vertebrate-specific brain cell types. Specifically, we show that NMDA receptor-mediated pathways are dysregulated in zebrafish lacking these micropeptides and that their loss preferentially alters the gene regulatory networks that establish cerebellar cells and oligodendrocytes – evolutionarily newer cell types that develop postnatally in humans. These findings highlight the power of screening for unexplored micropeptide functions by revealing a key missing link in the evolution of vertebrate brain cell development and illustrating a genetic basis for how some neural cell types are more susceptible to chromatin disruptions, with implications for neurodevelopmental disorders and disease.
Communication under sharply degraded auditory input and the “2-sentence” problem
Authors: Svirsky Mario A , Neukam Jonathan D , Capach Nicole H , Amichetti Nicole M , Lavender Annette , Wingfield Arthur
Published: July 2022

Introduction

Many cochlear implant (CI) users who do quite well in standard clinical tests of speech perception report that a great amount of effort is required when listening in real-world situations. We hypothesize that the combined constraints of the sharply degraded signal provided by a CI and finite cognitive resources may lead to a “tipping point” when listeners are confronted with speech material that is more complex than the single words or single sentences that are used in clinical tests. Beyond this tipping point, communication may become too difficult, even for CI users whose standard speech intelligibility scores are above average.

Methods

Here, we investigate whether speech identification performance and processing effort (indexed by pupil dilation measures) are affected when CI users or normal hearing control subjects are asked to repeat two sentences presented sequentially instead of just one sentence.

Results

Response accuracy was minimally affected in normal hearing listeners, but CI users showed a wide range of outcomes, from no change to decrements of up to 45 percentage points. The amount of decrement was not predictable from the CI users’ performance in standard clinical tests. Pupillometry measures tracked closely with effort in both the CI group and the normal hearing group, even though the latter had speech perception scores near ceiling levels for all conditions.

Discussion

A communicative tipping point may be reached in many (but not all) CI users in response to input that is only minimally more challenging than standard clinical tests; specifically, when two sentences are presented sequentially before requesting a response, instead of presenting just a single sentence at a time. This potential “2-Sentence Problem” represents one of the simplest possible scenarios that go beyond presentation of a single word or sentence, and it raises the possibility that even good performers in clinical tests of speech perception may be brought beyond the tipping point by other ecologically relevant manipulations. The present findings also raise the possibility that a clinical version of a 2-sentence test may provide actionable information for counseling and rehabilitating CI users.
Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model
Authors: Hartmann Laura , Osen Wolfram , Eichmüller Oliver L. , Kordaß Theresa , Furkel Jennifer , Dickes Elke , Reid Carissa , Debus Jürgen , Brons Stephan , Abdollahi Amir , Moustafa Mahmoud , Rieken Stefan , Eichmüller Stefan B.
Published: July 2022

Radiotherapy can act as an in situ vaccine thereby activating tumor-specific immune responses that prevent tumor outgrowth in treated patients. While carbon ion radiotherapy has shown superior biophysical properties over conventional photon irradiation, the immunological effects induced have remained largely uncovered. The combination of radiotherapy with immune checkpoint inhibition (radioimmunotherapy) aims at further enhancement of anti-tumor immunity; however, studies on the immune cell composition in irradiated and distant tumors following radioimmunotherapy with carbon ions are scarce. We have established a bilateral tumor model by time shifted transplantation of murine, Her2+ EO771 tumor cells onto the flanks of immune competent mice followed by selective irradiation of the primal tumor, while sparing the consecutive tumor. We demonstrate that αCTLA4-but not αPD-L1-based radioimmunotherapy induces complete tumor rejection in our model. Intriguingly, local tumor control caused in situ immunization resulting even in eradication of non-irradiated, distant tumors. Moreover, cured mice were protected against EO771 rechallenge indicative of long lasting, tumor-protective immunological memory. Deconvolution of the treatment induced immunological effects by single cell RNA-sequencing (scRNA-seq) and concomitant flow cytometric analyses revealed in irradiated tumors predominating myeloid cells that developed into distinct tumor-associated macrophage clusters with upregulated expression of TNF and IL1 responsive genes, as well as activation of NK cells. Non-irradiated tumors showed higher frequencies of naïve T cells in irradiated mice, which were activated when combined with CTLA4 blockade. In conclusion, radioimmunotherapy with carbon ions plus CTLA4 inhibition reshapes the tumor-infiltrating immune cell composition and can induce complete rejection even of non-irradiated tumors. Our data present a rationale to combine radiotherapy approach with CTLA4 blockade to achieve durable anti-tumor immunity. Evaluation of future radioimmunotherapy approaches should thus not only focus on the immunological impacts at the site of irradiation but should also consider systemic immunological effects that might affect outgrowth of non-irradiated tumors.
PDB ProtVista: A reusable and open-source sequence feature viewer
Authors: Deshpande Mandar , Varadi Mihaly , Paysan-Lafosse Typhaine , Nair Sreenath , Piovesan Damiano , Mir Saqib , Gutmanas Aleksandras , Tosatto Silvio C. E. , Velankar Sameer
Published: July 2022

The PDB ProtVista is a reusable and customisable sequence feature viewer that provides intuitive and detailed 2D visualisation of residue-level annotations while supporting interactive communication with 3D viewers. The Protein Data Bank in Europe (PDBe) team develops and maintains PDB ProtVista. Several public web services use it to display structural and functional annotations such as macromolecular interaction interfaces, intrinsic disorder predictions, sequence variants, and sequence conservation. The PDB ProtVista is freely available fromhttps://github.com/PDBeurope/protvista-pdb. We provide extensive documentation and step-by-step user guides on integrating PDB ProtVista with existing web applications and 3D molecular viewers. We also offer examples of displaying the user’s custom data and functional annotations for PDB and UniProt entries powered by a rich set of PDBe API endpoints.
Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 receptors in the head twitch response induced by 5-hydroxytryptophan and psilocybin: Translational implications
Authors: Shahar Orr , Botvinnik Alexander , Esh-Zuntz Noam , Brownstien Michal , Wolf Rachel , Wolf Gilly , Lerer Bernard , Lifschytz Tzuri
Published: July 2022

There is increasing interest in the therapeutic potential of psilocybin in psychiatric disorders. In common with other serotonergic psychedelics, psilocybin is thought to act via the 5-HT2A receptor (5-HT2AR). Serotonin is the endogenous ligand of 5-HTR. In rodents, the serotonin precursor, 5-hydroxytryptophan (5-HTP), and psilocybin, induce a characteristic head twitch response (HTR), which is correlated with the human psychedelic trip in intensity and duration. We examined the role of other serotonergic receptors and the trace amine associated receptor 1 (TAAR1) in modulating HTR induced by 5-HTP and psilocybin. Male C57BL/6J mice (11 weeks old, ~30g) were administered 5-HTP, 50-250 mg/kg intraperitoneally (i.p.) or 200 mg/kg i.p. after pretreatment with 5-HT/TAAR1 receptor modulators. Psilocybin was administered at 0.1-51.2 mg/kg i.p. or at 4.4 mg/kg i.p. preceded by 5-HT/TAAR1 receptor modulators. HTR was assessed in a custom-built magnetometer. 5-HTP and psilocybin induced a dose dependent increase in the frequency of HTR over 20 minutes with attenuation by the 5-HT2AR antagonist, M100907 (volanserin), and the 5-HT1AR agonist, 8-OH-DPAT. The 5-HT2CR antagonist, RS102221, enhanced HTR at lower doses but reduced it at higher doses for 5-HTP and psilocybin. The TAAR1 antagonist, EPPTB, reduced 5-HTP-but not psilocybin-induced HTR. We have confirmed the key role of 5-HT2AR in HTR and have demonstrated an effect of 5-HT1AR and a bimodal contribution of 5-HT2CR as well as a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate HTR induced by psychedelics have a potentially important role in the emerging therapeutic use of these compounds.

Significance Statement

We have confirmed the key role of 5-HT2AR in in the induction of HTR by 5-HTP and psilocybin, have demonstrated the effect of a 5-HT1AR agonist to attenuate HTR and a bimodal contribution of 5-HT2CR as well as a role of TAAR1 in modulating HTR induced by 5-HTP. Compounds that modulate HTR induced by psychedelics have a potentially important role in the emerging therapeutic use of these compounds.

Visual Abstract
Harnessing machine translation methods for sequence alignment
Authors: Dotan Edo , Belinkov Yonatan , Avram Oren , Wygoda Elya , Ecker Noa , Alburquerque Michael , Keren Omri , Loewenthal Gil , Pupko Tal
Published: July 2022

The sequence alignment problem is one of the most fundamental problems in bioinformatics and a plethora of methods were devised to tackle it. Here we introduce BetaAlign, a novel methodology for aligning sequences using a natural language processing (NLP) approach. BetaAlign accounts for the possible variability of the evolutionary process among different datasets by using an ensemble of transformers, each trained on millions of samples generated from a different evolutionary model. Our approach leads to outstanding alignment accuracy, often outperforming commonly used methods, such as MAFFT, DIALIGN, ClustalW, T-Coffee, and MUSCLE. Notably, the utilization of deep-learning techniques for the sequence alignment problem brings additional advantages, such as automatic feature extraction that can be leveraged for a variety of downstream analysis tasks.
Model-Based Estimates for Operant Selection
Authors: Borgstede Matthias , Anselme Patrick
Published: July 2022

We present a new methodology to partition different sources of behavior change within a selectionist framework based on the Price equation – the Multilevel Model of Behavioral Selection (MLBS). The MLBS provides a theoretical background to describe behavior change in terms of operant selection. Operant selection is formally captured by the covariance based law of effect (CLOE) and accounts for all changes in individual behavior that involve a covariance between behavior and predictors of evolutionary fitness (e.g., food). In this article we show how the CLOE may be applied to different components of operant behavior (e.g., allocation, speed, and accuracy of responding), thereby providing quantitative estimates for various selection effects affecting behavior change using data from a published learning experiment in pigeons.
Analysis of the mechanism of castor tolerance to Cd metal based on proteomics and metabolomics
Authors: Huibo Zhao , Yong Zhao , Rui Luo , Guorui Li , Jianjun Di , Qi Wen , Xiaotian Liang , Mingda Yin , Yanpeng Wen , Zhiyan Wang , Fenglan Huang
Published: July 2022

The pollution of soil with heavy metals is an increasingly serious worldwide problem, and cadmium (Cd) has attracted attention because of its high toxicity to almost all plants. Since castor tolerates the accumulation of heavy metals, it has the potential for heavy metal soil remediation. We studied the mechanism of the tolerance of castor to Cd stress treatments at three doses: 300 mg/L, 700 mg/L, and 1,000 mg/L. Our research provides new ideas for revealing the defense and detoxification mechanisms of Cd-stressed castor. By combining the results of physiology, differential proteomics and comparative metabolomics, we conducted a comprehensive analysis of the networks that regulate the response of castor to Cd stress. The physiological results mainly emphasize the super-sensitive responses of castor plant roots to Cd stress and the effects of Cd stress on plants’ antioxidant system, ATP synthesis and ion homeostasis. We confirmed these results at the protein and metabolite levels. At the same time, proteomics and metabolomics show that castor plants mainly block the root system’s absorption of Cd2+ by enhancing the strength of the cell wall, and inducing programmed cell death in response to the three different doses of Cd stress. In addition, the plasma membrane ATPase encoding gene (RcHA4), which was significantly upregulated in our differential proteomics and RT-qPCR studies, was transgenically overexpressed in wild type Arabidopsis thaliana for functional verification. The results indicated that this gene plays an important role in improving plant Cd tolerance.
Asteroid: a new minimum balanced evolution supertree algorithm robust to missing data
Authors: Morel Benoit , Williams Tom A. , Stamatakis Alexandros
Published: July 2022

Motivation

Missing data and incomplete lineage sorting are two major obstacles to accurate species tree inference. Gene tree methods such as ASTRAL and ASTRID have been developed to account for incomplete lineage sorting. However, they can be severely affected by high levels of missing data.

Results

We present Asteroid, a novel supertree method that infers an unrooted species tree from a set of unrooted gene trees. We show on both empirical and simulated datasets that Asteroid is more robust to missing data than ASTRAL and ASTRID, while being several orders of magnitude faster than ASTRAL for datasets that contain thousands of genes. Asteroid offers advanced features such as parallelization, support value computation, and support for multi-copy and multifurcating gene trees.

Availability

Asteroid is freely available at https://github.com/BenoitMorel/Asteroid

Contact

benoit.morel@h-its.org online.
Comparing retinotopic maps of children and adults reveals a late-stage change in how V1 samples the visual field
Authors: Himmelberg Marc M. , Tünçok Ekin , Gomez Jesse , Grill-Spector Kalanit , Carrasco Marisa , Winawer Jonathan
Published: July 2022

Adult visual performance differs with angular location –it is better for stimuli along the horizontal than vertical, and lower than upper vertical meridian of the visual field. These perceptual asymmetries are paralleled by asymmetries in cortical surface area in primary visual cortex (V1). Children, unlike adults, have similar visual performance at the lower and upper vertical meridian. Do children have similar V1 surface area representing the upper and lower vertical meridian? Using MRI, we measure the surface area of retinotopic maps (V1-V3) in children and adults. Many features of the maps are similar between groups, including greater V1 surface area for the horizontal than vertical meridian. However, unlike adults, children have a similar amount of V1 surface area representing the lower and upper vertical meridian. These data reveal a late-stage change in V1 organization that may relate to the emergence of the visual performance asymmetry along the vertical meridian by adulthood.
An assessment of Nano-RECall: Interpretation of Oxford Nanopore sequence data for HIV-1 drug resistance testing
Authors: Delaney Kayla Eileen , Ngobeni Trevor , Woods Conan K. , Gordijn Carli , Claassen Mathilda , Parikh Urvi , Harrigan P. Richard , van Zyl Gert Uves
Published: July 2022

Introduction

Oxford Nanopore Technologies (ONT) offer sequencing with low-capital-layout sequencing options, which could assist in expanding HIV drug resistance testing to resource limited settings. However, sequence analysis remains time time-consuming and reliant on skilled personnel. Moreover, current ONT bioinformatic pipelines provide a single consensus sequence that is not equivalent to Sanger sequencing, as drug resistance is often detected in mixed populations. We have therefore investigated an integrated bioinformatic pipeline, Nano-RECall, for seamless drug resistance of low read coverage ONT sequence data from affordable Flongle or MinION flow cells.

Methods

We compared Sanger sequencing to ONT sequencing of the same HIV-1 subtype C polymerase chain reaction (PCR) amplicons, respectively using RECall and the novel Nano-RECall bioinformatics pipelines. Amplicons were from separate assays a) Applied Biosystems HIV-1 Genotyping Kit (ThermoFisher) spanning protease (PR) to reverse transcriptase (RT) (PR-RT) (n=46) and b) homebrew integrase (IN) (n=21). We investigated optimal read-depth by assessing the coefficient of variation (CV) of nucleotide proportions for various read-depths; and between replicates of 400 reads. The agreement between Sanger sequences and ONT sequences were assessed at nucleotide level, and at codon level for Stanford HIV drug resistance database mutations.

Results

The coefficient of variation of ONT minority variants plateaued after a read depth of 400-fold implying limited benefit of additional depth and replicates of 400 reads showed a CV of ∼6 % for a representative position. The average sequence similarity between ONT and Sanger sequences was 99.3% (95% CI: 99.1-99.4%) for PR-RT and 99.6% (95% CI: 99.4-99.7%) for INT. Drug resistance mutations did not differ for 21 IN sequences; 16 mutations were detected by both ONT- and Sanger sequencing. For the 46 PR and RT sequences, 245 mutations were detected by either ONT or Sanger, of these 238 (97.1%) were detected by both.

Conclusions

The Nano-RECall pipeline, freely available as a downloadable application on a Windows computer, provides Sanger-equivalent HIV drug resistance interpretation. This novel pipeline combined with a simple workflow and multiplexing samples on ONT flow-cells would contribute to making HIV drug resistance sequencing feasible for resource limited settings.
Multispecies biofilm architecture determines bacterial exposure to phages
Authors: Winans James B. , Wucher Benjamin R. , Nadell Carey D.
Published: July 2022

Numerous ecological interactions among microbes – for example, competition for space and resources, or interaction among phages and their bacterial hosts – are likely to occur simultaneously in multispecies biofilm communities. While biofilms formed by just a single species occur, multispecies biofilms are thought to be more typical of microbial communities in the natural environment. Previous work has shown that multispecies biofilms can increase, decrease, or have no measurable impact on phage exposure of a host bacterium living alongside another species that the phages cannot target. The reasons underlying this variability are not well understood, and how phage-host encounters change within multispecies biofilms remains mostly unexplored at the cellular spatial scale. Here, we study how the cellular scale architecture of model 2-species biofilms impacts cell-cell and cell-phage interactions controlling larger scale population and community dynamics. Our system consists of dual-culture biofilms ofEscherichia coliandVibrio choleraeunder exposure to T7 phages, which we study using microfluidic culture, high resolution confocal microscopy imaging, and detailed image analysis. As shown previously, sufficiently mature biofilms ofE. colican protect themselves from phage exposure via their curli matrix. Before this stage of biofilm structural maturity,E. coliis highly susceptible to phages, however we show that these bacteria can gain lasting protection against phage exposure if they have become embedded in the bottom layers of highly packed groups ofV. choleraein co-culture. This protection, in turn, is dependent on the cell packing architecture controlled byV. choleraebiofilm matrix secretion. In this manner,E. colicells that are otherwise susceptible to phage mediated killing can survive phage exposure in the absence ofde novoresistance evolution. While co-culture biofilm formation withV. choleraecan confer phage protection toE. coli, it comes at the cost of competing withV. choleraeand a disruption of normal curli-mediated protection forE. colieven in dual species biofilms grown over long time scales. This work highlights the critical importance of studying multispecies biofilm architecture and its influence on the community dynamics of bacteria and phages.

Short blurb

Multispecies bacterial biofilm architecture qualitatively alters the spatial patterns of phage exposure and the community dynamics of matrix production, interspecific competition, and phage propagation.