bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting 3 Tiers of Psychiatric Problems in Patient-focused Psychiatric Practice: Diagnostic Signs, Symptoms, and Impairments; Specific Complex Subjective Complaints; and Contributing Meta-problems
Authors: Yager Joel
Published: November 2021

Background:

While contemporary psychiatric assessments ordinarily focus on signs, symptoms, and impairments comprising formal diagnoses, these assessments sometimes minimize or ignore specific complaints and other contributing problems that are the sources of patients’ and families’ greatest distress. Neglect of these problems may decrease patient satisfaction and reduce the quality of care.

Methods:

The author reviewed limitations of previous problem-oriented efforts in psychiatry and limitations of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders. This review provided the basis for reconceptualizing how problems might be identified and framed in clinical assessments.

Results:

A clinically practical 3-tier framework for psychiatric problems is suggested. The first tier encompasses diagnostic contents, including subjective symptoms, observable signs, and impairments. The second tier consists of additional specific complex subjective complaints in the patient’s and family’s own words, comprised of highly individualized distressing intrapsychic, interpersonal, and environmental situations and conflicts. The third tier consists of contributing meta-problems, comprised of significant additional patient-related or systems-related difficulties noted by clinicians that contribute substantially to complicated clinical problem sets.

Conclusions:

Diagnostic or not, specific problems expressed by patients and families and contributing meta-problems should be integrated into initial formulations and tracked during treatment. Whereas only some of these problems may fall within a clinician’s scope of responsibilities, all should fall within the scope of concern, some to be referred to others, and some exceeding caregivers’ capacities. Periodic review of problem lists for patients’ and families’ most distressing concerns can contribute to the therapeutic alliance, increase patient satisfaction, and perhaps improve outcomes.
Pseudomonas guryensis sp. nov. and Pseudomonas ullengensis sp. nov., isolated from soil
Authors: Kim Chung Mi , Jeong Ji Won , Lee Dong Hyeon , Kim Seung Bum
Published: November 2021

Two Gram-staining-negative, aerobic, rod-shaped bacteria designated strains SR9T and UL070T, were isolated from soil and subjected to taxonomic characterization. Strain SR9T grew at 10–37 °C (optimum 30 °C), at pH 4.0–10.0 (optimum pH 8.0) and in the presence of 0–1 % NaCl (optimum 0 %), and UL070T at 4–33 °C (optimum 30 °C), at pH 4.0–10.0 (optimum pH 7.0) and in the presence of 0–2 % NaCl (optimum 0 %), respectively. Strain UL070T was motile with flagella. Analysis of 16S rRNA gene sequences indicated that the two strains fell into phylogenetic clusters belonging to the genus

Pseudomonas

. Both strains SR9T and UL070T were mostly related to

Pseudomonas campi

S1-A32-2T with 99.70 and 99.01% sequence similarities, and the similarity between the two isolates was 98.90 %. The genome-based in silico analyses indicated that each of the strains SR9T and UL070T was clearly separated from other species of

Pseudomonas

, as the orthologous average nucleotide identity (OrthoANI) and the digital DNA–DNA hybridization (dDDH) values were no higher than 93.09 and 50.03% respectively with any related species, which were clearly below the cutoff for species distinction. The fatty acid profiles of the two strains mainly consisting of unsaturated components, the presence of ubiquinone 9 (Q-9) as the major respiratory quinone, and phosphatidylethanolamine (PE) and diphosphatidylglycerol (DPG) as the diagnostic polar lipids were consistent with their classification into

Pseudomonas

. The DNA G+C contents of strains SR9T and UL070T were 63.2 mol% and 63.6 mol% respectively. On the basis of both phenotypic and phylogenetic evidences, each of the isolated strains should be classified as a novel species, for which the names Pseudomonas guryensis sp. nov. (type strain=SR9T=KCTC 82228T=JCM 34509T) and Pseudomonas ullengensis sp. nov. (type strain=UL070T=KCTC 82229T=JCM 34510T) are proposed.
Robust and unbiased estimation of the background distribution for automated quantitative imaging
Authors: Silberberg Mauro , Grecco Hernán E.
Published: November 2021

Quantitative analysis of high-throughput microscopy images requires robust automated algorithms. Background estimation is usually the first step and has an impact on all subsequent analysis, in particular for foreground detection and calculation of ratiometric quantities. Most methods recover only a single background value, such as the median. Those that aim to retrieve a background distribution by dividing the intensity histogram yield a biased estimation in images in non-trivial cases. In this work, we present the first method to recover an unbiased estimation of the background distribution directly from an image and without any additional input. Through a robust statistical test, our method leverages the lack of local spatial correlation in background pixels to select a subset of pixels that accurately represent the background distribution. This method is both fast and simple to implement, as it only uses standard mathematical operations and an averaging filter. Additionally, the only parameter, the size of the averaging filter, does not require fine tuning. The obtained background distribution can be used to test for foreground membership of individual pixels, or to estimate confidence intervals in derived quantities. We expect that the concepts described in this work can help to develop a novel family of robust segmentation methods.
Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60
Authors: Wang Xinrui , Wan Tina C. , Kulik Katherine , Lauth Amelia , Smith Brian C. , Lough John W. , Auchampach John A.
Published: November 2021

It is estimated that up to one billion cardiomyocytes (CMs) can be lost during myocardial infarction (MI), which results in contractile dysfunction, adverse ventricular remodeling, and systolic heart failure. Pharmacologic strategies that target factors having both pro-apoptotic and anti-proliferative functions in CMs may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is a member of the MYST family of acetyltransferases known to acetylate both histone and non-histone protein targets that have been shown in cultured cancer cells to promote apoptosis and to initiate the DNA damage response (DDR) thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protected against the damaging effects of MI. In the experiments described here, in lieu of genetic targeting, we administered TH1834, an experimental drug designed to specifically inhibit the acetyltransferase domain of Tip60. We report that, similar to the effect of disrupting the Kat5 gene, daily systemic administration of TH1834 beginning 3 days after induction of MI and continuing for two weeks of a 4-week timeline resulted in improved systolic function assessed by echocardiography, reduced apoptosis and scarring, and increased activation of the CM cell-cycle. Our results support that idea that drugs that inhibit the acetyltransferase activity of Tip60 may be useful agents for the treatment of ischemic heart disease.
A vaccine targeting the L9 epitope of the malaria circumsporozoite protein confers protection from blood-stage infection in a mouse challenge model
Authors: Jelínková Lucie , Flores-Garcia Yevel , Shapiro Sarah , Roberts Bryce T. , Petrovsky Nikolai , Zavala Fidel , Chackerian Bryce
Published: November 2021

Pre-erythrocytic malaria vaccines that induce high-titer, durable antibody responses can potentially provide protection from infection. Here, we engineered a virus-like particle (VLP)-based vaccine targeting a recently described vulnerable epitope at the N-terminus of the central repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) that is recognized by the potently inhibitory monoclonal antibody L9 and show that immunization with L9 VLPs induces strong antibody responses that provide protection from blood-stage malaria in a mouse infection model.
The dimensionality of plant–plant competition
Authors: Stouffer Daniel B. , Godoy Oscar , Dalla Riva Giulio V. , Mayfield Margaret M.
Published: November 2021

To avoid extinction, every species must be able to exploit available resources at least as well as the other species in its community. All else being equal, theory predicts that the more distinct the niches of such co-occurring and competing species, the more species that can persist in the long run. However, both theoretical and experimental studies define a priori the nature and number of resources over which species compete. It therefore remains unclear whether or not species in empirically realistic contexts are actually exploiting all or some of the niches available to them. Here we provide a mathematical solution to this long-standing problem. Specifically, we show how to use the interactions between sets of co-occurring plant species to quantify their implied “niche dimensionality”: the effective number of resources over which those species appear to be competing. We then apply this approach to quantify the niche dimensionality of 12 plant assemblages distributed across the globe. Contrary to conventional wisdom, we found that the niche dimensionality in these systems was much lower than the number of competing species. However, two high-resolution experiments also show that changes in the local environment induce a reshuffling of plant’s competitive roles and hence act to increase the assemblages’ effective niche dimensionality. Our results therefore indicate that homogeneous environments are unlikely to be able to maintain high diversity and also shows how environmental variation impacts species’ niches and hence their opportunities for long-term survival.
Conditional Generative Modeling for De Novo Protein Design with Hierarchical Functions
Authors: Kucera Tim , Togninalli Matteo , Meng-Papaxanthos Laetitia
Published: November 2021

Motivation

Protein design has become increasingly important for medical and biotechnological applications. Because of the complex mechanisms underlying protein formation, the creation of a novel protein requires tedious and time-consuming computational or experimental protocols. At the same time, machine learning has enabled the solving of complex problems by leveraging large amounts of available data, more recently with great improvements on the domain of generative modeling. Yet, generative models have mainly been applied to specific sub-problems of protein design.

Results

Here we approach the problem of general purpose protein design conditioned on functional labels of the hierarchical Gene Ontology. Since a canonical way to evaluate generative models in this domain is missing, we devise an evaluation scheme of several biologically and statistically inspired metrics. We then develop the conditional generative adversarial network ProteoGAN and show that it outperforms several classic and more recent deep learning baselines for protein sequence generation. We further give insights into the model by analysing hyperparameters and ablation baselines. Lastly, we hypothesize that a functionally conditional model could generate proteins with novel functions by combining labels and provide first steps into this direction of research.

Availability

Code and data is available at https://github.com/timkucera/proteogan

Contact

tim.kucera@bsse.ethz.ch, mt@visium.ch, lpapaxanthos@google.com
ODGI: understanding pangenome graphs
Authors: Guarracino Andrea , Heumos Simon , Nahnsen Sven , Prins Pjotr , Garrison Erik
Published: November 2021

Motivation

Pangenome graphs provide a complete representation of the mutual alignment of collections of genomes. These models offer the opportunity to study the entire genomic diversity of a population, including structurally complex regions. Nevertheless, analyzing hundreds of gigabase-scale genomes using pangenome graphs is difficult as it is not well-supported by existing tools. Hence, fast and versatile software is required to ask advanced questions to such data in an efficient way.

Results

We wrote ODGI, a novel suite of tools that implements scalable algorithms and has an efficient in-memory representation of DNA pangenome graphs in the form of variation graphs. ODGI supports pre-built graphs in the Graphical Fragment Assembly format. ODGI includes tools for detecting complex regions, extracting pangenomic loci, removing artifacts, exploratory analysis, manipulation, validation, and visualization. Its fast parallel execution facilitates routine pangenomic tasks, as well as pipelines that can quickly answer complex biological questions of gigabase-scale pangenome graphs.

Availability

ODGI is published as free software under the MIT open source license. Source code can be downloaded fromhttps://github.com/pangenome/odgiand documentation is available athttps://odgi.readthedocs.io. ODGI can be installed via Biocondahttps://bioconda.github.io/recipes/odgi/README.htmlor GNU Guixhttps://github.com/pangenome/odgi/blob/master/guix.scm.

Contact

egarris5@uthsc.edu
Lipophorin receptors regulate mushroom bodies development and participate in learning, memory and sleep in flies
Authors: Rojo-Cortés Francisca , Tapia-Valladares Victoria , Fuenzalida-Uribe Nicolás , Hidalgo Sergio , Roa Candy B. , González-Ramírez María-Constanza , Oliva Carlos , Campusano Jorge M. , Marzolo María-Paz
Published: November 2021

Background

Drosophila melanogaster Lipophorin Receptors (LpRs), LpR1 and LpR2, mediate lipid uptake. The orthologs of these receptors in vertebrates, ApoER2 and VLDL-R, bind Reelin, a glycoprotein not present in flies. These receptors are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain. It is currently unknown whether LpRs play similar roles in the Drosophila brain.

Results

We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the Mushroom Bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurites. This effect depends on LpRs and Dab, the Drosophila ortholog of the reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin.

Conclusions

These findings demonstrate that LpRs contribute to MB development and function, supporting the existence of LpR-dependent signaling in Drosophila.
Foraging behavior and patch size distribution jointly determine population dynamics in fragmented landscapes
Authors: Nauta Johannes , Simoens Pieter , Khaluf Yara , Martinez-Garcia Ricardo
Published: November 2021

Increased fragmentation caused by habitat loss represents a major threat to the persistence of animal populations. How fragmentation affects populations depends on the rate at which individuals move between spatially separated patches. Whereas negative effects of habitat loss on biodiversity are well-known, effects of fragmentationper seon population dynamics and ecosystem stability remain less understood. Here, we use a spatially explicit predator-prey model to investigate how the interplay between fragmentation and optimal foraging behavior affects predator-prey interactions and, subsequently, ecosystem stability. We study systems wherein prey occupies isolated patches and are consumed by predators that disperse following Lévy random walks. Our results show that the Lévy exponent and the degree of fragmentation jointly determine coexistence probabilities. In highly fragmented landscapes, Brownian and ballistic predators go extinct and only scale-free predators can coexist with prey. Furthermore, our results confirm that predation causes irreversible habitat loss in fragmented landscapes due to overexploitation of smaller patches of prey. Moreover, we show that predator dispersal can reduce, but not prevent nor minimize, the amount of lost habitat. Our results suggest that integrating optimal foraging theory into population- and landscape ecology is crucial to assessing the impact of fragmentation on biodiversity and ecosystem stability.
Human Sex Matters: Y-linked lysine demethylase 5D drives accelerated male osteogenic differentiation
Authors: Merten Madlen , Greiner Johannes F.W. , Niemann Tarek , Venhaus Meike Grosse , Kronenberg Daniel , Stange Richard , Wähnert Dirk , Kaltschmidt Christian , Vordemvenne Thomas , Kaltschmidt Barbara
Published: November 2021

Female sex is increasingly associated to a loss of bone mass during aging and an increased risk for fractures developing nonunion. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global trancriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrate craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects.
Necroptosis inhibition counteracts neurodegeneration, memory decline and key hallmarks of aging, promoting brain rejuvenation
Authors: Arrázola Macarena S. , Lira Matías , Quiroz Gabriel , Véliz-Valverde Felipe , Iqbal Somya , Eaton Samantha L , Kline Rachel A , Lamont Douglas J , Huerta Hernán , Ureta Gonzalo , Bernales Sebastián , Cárdenas J César , Cerpa Waldo , Wishart Thomas M. , Court Felipe A.
Published: November 2021

Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here we show that the loss of the necroptotic effectorMlklwas sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis in aged mice reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to the age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline.
Quantitative effects of environmental variation on stomatal anatomy and gas exchange in a grass model
Authors: Nunes Tiago DG , Slawinska Magdalena W , Lindner Heike , Raissig Michael T
Published: November 2021

Stomata are cellular pores on the leaf epidermis that allow plants to regulate carbon assimilation and water loss. Stomata integrate environmental signals to regulate pore apertures and optimize gas exchange to fluctuating conditions. Here, we quantified intraspecific plasticity of stomatal gas exchange and anatomy in response to seasonal variation in Brachypodium distachyon. Over the course of two years we (i) used infrared gas analysis to assess light response kinetics of 120 Bd21-3 wild-type individuals in an environmentally fluctuating greenhouse and (ii) microscopically determined the seasonal variability of stomatal anatomy in a subset of these plants. We observed systemic environmental effects on gas exchange measurements and remarkable intraspecific plasticity of stomatal anatomical traits. To reliably link anatomical variation to gas exchange, we adjusted anatomical gsmax calculations for grass stomatal morphology. We propose that systemic effects and variability in stomatal anatomy should be accounted for in long-term gas exchange studies.
X-linked palindromic gene families4930567H17RikandMageb5are dispensable for male mouse fertility
Authors: Stark-Dykema Evan R. , Dulka Eden A. , Gerlinger Emma R. , Mueller Jacob L.
Published: November 2021

Mammalian sex chromosomes are enriched for large, nearly-identical, palindromic sequences harboring genes expressed predominately in testicular germ cells. Discerning if individual palindrome-associated gene families are essential for male reproduction is difficult due to challenges in disrupting all copies within a gene family. Here we generate precise, independent, deletions to assess the reproductive roles of two X-linked palindromic gene families with spermatid-predominant expression,4930567H17RikorMageb5. Via sequence comparisons, we find mouse4930567H17RikandMageb5have human orthologs,4930567H17Rikis rapidly diverging in rodents and primates, and4930567H17Rikis harbored in a palindrome in humans and mice, whileMageb5is not. Mice lacking either4930567H17RikorMageb5gene families do not have detectable defects in male fertility, fecundity, spermatogenesis, or in gene regulation, but do show differences in sperm head morphology, suggesting a potential role in sperm function. We conclude that while all palindrome-associated gene families are not essential for male fertility, large palindromes influence the evolution of their associated gene families.

Summary sentence

Mice lacking X-palindromic gene families display normal male fertility, fecundity, spermatogenesis, and gene expression but exhibit differences in sperm head morphology, suggesting a potential role for these gene families in sperm development.
Legume plant defenses and nutrients mediate indirect interactions between soil rhizobia and chewing herbivores
Authors: Basu Saumik , Lee Benjamin W , Clark Robert E , Bera Sayanta , Casteel Clare L , Crowder David W.
Published: November 2021

Soil bacteria that form mutualisms with plants, such as rhizobia, affects susceptibility of plants to herbivores and pathogens. Soil rhizobia also promote nitrogen fixation, which mediates host nutrient levels and defenses. However, whether aboveground herbivores affect the function of soil rhizobia remains poorly understood. We assessed reciprocal interactions betweenSitona lineatus, a chewing herbivore, and pea (Pisum sativum) plants grown with or without rhizobia (Rhizobium leguminosarumbiovarviciae). We also examined the underlying plant-defense and nutritional mechanisms of these interactions. In our experiments, soil rhizobia influenced feeding and herbivory by chewing herbivores. Leaf defoliation byS. lineatuswas lower on plants treated with rhizobia, but these insects had similar amino acid levels compared to those on un-inoculated plants. Plants grown with soil rhizobia had increased expression of gene transcripts associated with phytohormone-mediated defense, which may explain decreased susceptibility toS. lineatus. Rhizobia also induced expression of gene transcripts associated with physical and antioxidant-related defense pathways inP. sativum. Conversely,S. lineatusfeeding reduced the number of root nodules and nodule biomass, suggesting a disruption of the symbiosis between plants and rhizobia. Our study shows that aboveground herbivores can engage in mutually antagonistic interactions with soil microbes mediated through a multitude of plant-mediated pathways.
SARS-CoV-2 Envelope protein (E) binds and activates TLR2: A novel target for COVID-19 interventions
Authors: Planès Rémi , Bert Jean-Baptiste , Tairi Sofiane , Benmohamed Lbachir , Bahraoui Elmostafa
Published: November 2021

In this study, we present a molecular characterization of the interaction between the SARS-CoV-2 envelope protein E with TLR2. We demonstrated that E protein interacts physically with TLR2 receptor in a specific and dose-dependent manner. Furthermore, we showed that this interaction is able to engage TLR2 pathway as demonstrated by its capacity to activate NF-κB transcription factor and to stimulate the production of CXCL8 inflammatory chemokine in a TLR2-dependent manner. Furthermore, in agreement with the importance of NF-κB in TLR signaling pathway, we showed that the chemical inhibition of this transcription factor led to significant inhibition of CXCL8 production, while blockade of P38 and ERK1/2 MAP kinases resulted only in a partial CXCL8 inhibition. Overall, our findings suggest considering the envelope protein E as a novel target for COVID-19 interventions: (i) either by exploring the therapeutic effect of anti-E blocking/neutralizing antibodies in symptomatic COVID-19 patients, or (ii) as a promising non-Spike SARS-CoV-2 antigen candidate to include in the development of next generation prophylactic vaccines against COVID-19 infection and disease.

Importance

Although, the exact mechanisms of COVID-19 pathogenesis are unknown, recent data demonstrated that elevated levels of pro-inflammatory cytokines in serum is associated with enhanced disease pathogenesis and mortality. Thus, determining the molecular mechanisms responsible for inflammatory cytokine production in the course of SARS-CoV-2 infection could provide future therapeutic targets. In this context, to the best of our knowledge, our report is first to use a detailed molecular characterization to demonstrate that SARS-CoV-2 Envelope E protein binds to TLR2 receptor. Specifically, we showed that SARS-CoV-2 Envelope E protein binds to TLR2 in a direct, specific and dose-dependent manner. Investigating signalling events that control downstream activation of cytokine production show that E protein / TLR2 binding leads to the activation of NF-κB transcription factor that control the expression of multiple pro-inflammatory cytokines including CXCL8. Overall, our findings suggest considering the envelope protein E as a novel target for COVID-19 interventions.
Development of a core measurement set for research in degenerative cervical myelopathy: a study protocol (AO Spine RECODE-DCM CMS)
Authors: Davies Benjamin M. , Touzet Alvaro Yanez , Mowforth Oliver D. , Lee Keng Siang , Khan Danyal , Furlan Julio C. , Fehlings Michael G. , Harrop James , Zipser Carl M. , Rodrigues-Pinto Ricardo , Milligan James , Sarewitz Ellen , Curt Armin , Rahimi-Movaghar Vafa , Aarabi Bizhan , Boerger Timothy F. , Tetreault Lindsay , Chen Robert , Guest James D. , Kalsi-Ryan Sukhvinder , Sadler Iwan , Widdop Shirley , McNair Angus G. K. , Kotter Mark R. N.
Published: November 2021

Introduction

Progress in degenerative cervical myelopathy (DCM) is hindered by inconsistent measurement and reporting of outcomes. This can, for example, impede the aggregation of data and comparison of outcomes between studies. This limitation can be reversed by developing a core measurement set (CMS) for use in DCM research. Previously, the AO Spine Research Objectives and Common Data Elements for DCM (AO Spine RECODE-DCM) defined ‘what’ should be measured in DCM: specifically, the core data elements and core outcome set of the disease. The next step of this initiative is to determine ‘how’ to measure these features. The current protocol outlines the steps necessary for the development of a CMS for DCM research and audit.

Methods and analysis

The CMS will be developed in accordance with the guidance developed by the Core Outcome Measures in Effectiveness Trials (COMET) and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN). The process will involve five phases: (1) agreement on the measurement constructs and approaches to their evaluation; (2) the formation of a long list of potential measurement instruments, by identifying existing instruments and assessing their psychometric properties; (3) the aggregation of evidence concerning ‘when’ measurements should be taken; (4) consensus about which instruments to include in the CMS; and (5) implementation.

Ethics and dissemination

Ethical approval was obtained from the University of Cambridge. Dissemination strategies to promote awareness and adoption of the CMS include peer-reviewed scientific publications; conference presentations; podcasts; the identification of AO Spine RECODE-DCM ambassadors; and engagement with relevant journals, funders, and the DCM community.

Impact of this work

The proposed project will enable standardised and comprehensive measurement in DCM clinical trials. The CMS will be established using a robust, global, and multi-stakeholder consensus process, with broad representation of healthcare professionals and individuals living with the disease. It will focus on measurement instruments currently in use. This ensures that the CMS will be immediately usable and suited for widespread adoption. The development of better outcome instruments in DCM remains a top 10 research priority and this work will hence facilitate knowledge generation for this important disease.
Intraoperative localization and preservation of reading in ventral occipitotemporal cortex
Authors: Woolnough Oscar , Snyder Kathryn M. , Morse Cale W. , McCarty Meredith J. , Lhatoo Samden D. , Tandon Nitin
Published: November 2021

Resective surgery in language-dominant ventral occipitotemporal cortex (vOTC) carries the risk of causing impairment to reading. As it is not on the lateral surface, it is not easily accessible for intraoperative mapping and extensive stimulation mapping can be time consuming. Here we assess the feasibility of using task-based electrocorticography (ECoG) recordings intraoperatively to help guide stimulation mapping of reading in vOTC.

In 11 patients undergoing extraoperative, intracranial seizure mapping we recorded induced broadband gamma activation (70 – 150 Hz) during a visual category localizer. Word-responsive cortex localized in this manner showed a high sensitivity (72%) to stimulation-induced reading deficits, and the confluence of ECoG and stimulation positive sites appears to demarcate the visual word form area.

In two additional patients, with pathologies necessitating resections in language-dominant vOTC, task-based functional mapping was performed intraoperatively using subdural ECoG, alongside direct cortical stimulation. Cortical areas critical for reading were mapped and successfully preserved, while enabling pathological tissue to be completely removed. Data collection is possible in <3 minutes and initial intraoperative data analysis takes <3 minutes, allowing for rapid assessment of broad areas of cortex.

Eloquent cortex in ventral visual cortex can be rapidly mapped intraoperatively using ECoG. This method acts to guide high-probability targets for stimulation, with limited patient participation, and can be used to avoid iatrogenic dyslexia following surgery.
Differentiating between infectious and non-infectious influenza A virus and coronavirus RNA levels using long-range RT-qPCR
Authors: Juozapaite Dovile , Rigby Charlotte V. , Olendraite Ingrida , Mathur Pankaj , Dhanorkar Kalyan , Hulle Vishalraj , Shah Tejas , Jadhao Vijeta , Mutha Shravan , Jalal Hamid , Gopal Vikram , te Velthuis Aartjan J.W.
Published: November 2021

During the Coronavirus Disease 2019 (COVID-19) pandemic, residual SARS-CoV-2 genome and subgenomic RNA fragments were observed in recovered COVID-19 patients. The presence of such RNAs in the absence of live virus leads to incorrectly positive RT-qPCR results, potentially delaying medical procedures and quarantine release. We here propose a simple modification to turn commercial COVID-19 RT-qPCR protocols into long-range RT-qPCR assays that can differentiate between infectious and non-infectious influenza and coronavirus RNA levels. We find that the long-range RT-qPCR method has a sensitivity that is indistinguishable from a commercial Taq-Path COVID-19 RT-qPCR assay when tested on clinical samples taken withing 5 days of the onset of symptoms. In clinical samples taken at least 15 days after the onset of symptoms when patients had recovered from COVID-19, the modified RT-qPCR protocol leads to significantly fewer positive diagnoses. These findings suggest that the long-range RT-qPCR method may improve test-to-release protocols and expand the tools available for clinical COVID-19 diagnosis.

Importance

Various molecular tests can detect viral RNA in clinical samples. However, these molecular tests cannot differentiate between RNA from infectious viruses or residual viral genome fragments that are not infectious. In several percent of COVID-19 patients, such residual viral RNAs can be detected long after recovery and the disappearance of infectious SARS-CoV-2. These “persistently-positive” RT-qPCR results are different from false-positive RT-qPCR results, which can be generated due to in vitro cross-reactivity or contaminations. However, the detection of RNA fragments leads to incorrect conclusions about the status of a COVID-19 patient and an incorrect diagnosis. We here modified the commercial Taq-Path COVID-19 RT-qPCR kit to make this test less sensitive to residual viral RNA genome fragments, reducing the likelihood that incorrect RT-qPCR results affect the treatment or quarantine status of recovered COVID-19 patients.
An outbreak inside an outbreak: rising incidence of carbapenem-resistant isolates during the COVID-19 pandemic. Report from a tertiary care center in Argentina
Authors: Castro Maximiliano Gabriel , Ubiergo Lucía , Vicino Macarena , Cuevas Gisel , Argarañá Fernanda
Published: November 2021

Introduction

COVID-19 outbreaks have left us to deal with an aftermath on many fronts. In particular, disproportionate use of antibiotics, high ICU burden and longer in-hospital stays during the pandemic have been proposed to aggravate the emergency posed by carbapenem-resistant isolates (CRI), specially through carbapenemase production. However, there have been few reports worldwide regarding changes in CRI incidence and little latinamerican literature.

Objective

We set out to determine whether the incidence of CRI rose in a tertiary care center in Santa Fe, Argentina during the time period with active cases of COVID-19.

Methods

Analytic epidemiologic study retrospectively designed. Two time periods were defined: P1 (without active cases of COVID-19) from September, 2019 to August, 2020 and P2 (starting at the onset of the first wave of COVID-19 in this institution) from September, 2020 to June 2021. All clinically-relevant microbiological samples -those meant for diagnostic purposes-taken during the study period from patients in the Internal Medicine and Surgical wards as well as the Intensive Care Units were included. Incidence was calculated by dividing the number of CRI during each time frame by the count of patient-day during that same period, multiplied by a hundred.

Results

9,135 hospitalizations, 50,145 patient-days of analysis. A total of 7285 clinical samples were taken, with an overall positivity for CRI of 12.1% (n=883). Overall CRI incidence during P2 was 2.5 times higher than in P1 (2.52 vs 0.955/100 patient-days, p <0.001). ICU CRI incidence raised from 6.78 to 8.69/100 patient-days in P2 (p=0.006).

Conclusion

We found alarming rates of CRI in our center, 2.5 times higher than previous to the first COVID-19 wave, similar to other reports worldwide. To our knowledge, this is one of the few Latin-American reports on the effect of the COVID-19 pandemic on CRI incidence.
Linking extreme seasonality and gene expression in arctic marine protists
Authors: Wutkowska Magdalena , Vader Anna , Logares Ramiro , Pelletier Eric , Gabrielsen Tove M.
Published: November 2021

At high latitudes, strong seasonal differences in light availability affect marine organisms and restrict the timing of ecosystem processes. Marine protists are key players in Arctic aquatic ecosystems, yet little is known about their ecological roles over yearly cycles. This is especially true for the dark polar night period, which up until recently was assumed to be devoid of biological activity. A 12 million transcripts catalogue was built from 0.45-10 μm protist assemblages sampled over 13 months in a time series station in an arctic fjord in Svalbard. Community gene expression was correlated with seasonality, with light as the main driving factor. Transcript diversity and evenness were higher during polar night compared to polar day. Light-dependent functions had higher relative expression during polar day, except phototransduction. 64% of the most expressed genes could not be functionally annotated, yet up to 78% were identified in arctic samples from Tara Oceans, suggesting that arctic marine assemblages are distinct from those from other oceans. Our study increases understanding of the links between extreme seasonality and biological processes in pico- and nanoplanktonic protists. Our results set the ground for future monitoring studies investigating the seasonal impact of climate change on the communities of microbial eukaryotes in the High Arctic.
Human serum triggers antibiotic tolerance in Staphylococcus aureus
Authors: Ledger Elizabeth V. K. , Mesnage Stéphane , Edwards Andrew M.
Published: November 2021

Staphylococcus aureus is a frequent cause of bloodstream infections. Treatment can be challenging, even when isolates appear to be drug susceptible, with high rates of persistent and relapsing infection. This is particularly the case with infections caused by methicillin resistant S. aureus (MRSA) strains, which are resistant to frontline antibiotics. To understand how the host environment influences treatment outcomes in MRSA infections, we studied the impact of human serum on staphylococcal susceptibility to daptomycin, an antibiotic of last resort. This revealed that serum triggered a very high degree of tolerance to daptomycin, as well as several other classes of antibiotics and antimicrobial peptides, including gentamicin, nitrofurantoin, vancomycin, nisin and gramicidin. Serum-induced daptomycin tolerance was due to two independent mechanisms. Firstly, the host defence peptide LL-37 present in serum induced tolerance by triggering the staphylococcal GraRS two component system. This led to increased cell wall accumulation that reduced access of daptomycin to its membrane target. Secondly, GraRS-independent changes to the membrane resulted in increased cardiolipin abundance that also contributed to daptomycin tolerance. When both mechanisms were blocked, serum exposed S. aureus cells were as susceptible to daptomycin as bacteria growing in laboratory media. These data demonstrate that host factors can significantly modulate antibiotic susceptibility via diverse mechanisms, which may in turn contribute to treatment failure. The inhibition of serum-induced cell wall accumulation by fosfomycin reduced tolerance, suggesting that this antibiotic may form a useful combination therapy with daptomycin.
PTP1B is an intracellular checkpoint that limits T cell and CAR T cell anti-tumor immunity
Authors: Wiede Florian , Lu Kun-Hui , Du Xin , Zeissig Mara N. , Xu Rachel , Goh Pei Kee , Xirouchaki Chrysovalantou E. , Hogarth Samuel J. , Greatorex Spencer , Sek Kevin , Daly Roger J. , Beavis Paul A. , Darcy Phillip K. , Tonks Nicholas K. , Tiganis Tony
Published: November 2021

Immunotherapies aimed at alleviating the inhibitory constraints on T cells have revolutionised cancer management. To date, these have focused on the blockade of cell surface checkpoints such as PD-1. Herein we identify protein-tyrosine-phosphatase 1B (PTP1B) as an intracellular checkpoint that is upregulated in T cells in tumors. We show that the increased PTP1B limits T cell expansion and cytotoxicity to contribute to tumor growth. T cell-specific PTP1B deletion increased STAT-5 signaling and this enhanced the antigen-induced expansion and cytotoxicity of CD8+T cells to suppress tumor growth. The pharmacological inhibition of PTP1B recapitulated the T cell-mediated repression of tumor growth and enhanced the response to PD-1 blockade. Furthermore, the deletion or inhibition of PTP1B enhanced the efficacy of adoptively-transferred chimeric-antigen-receptor (CAR) T cells against solid tumors. Our findings identify PTP1B as an intracellular checkpoint whose inhibition can alleviate the inhibitory constraints on T cells and CAR T cells to combat cancer.

STATEMENT OF SIGNIFICANCE

Tumors subvert anti-tumor immunity by engaging checkpoints that promote T-cell exhaustion. Here we identify PTP1B as an intracellular checkpoint and therapeutic target. We show that PTP1B is upregulated in intra-tumoral T-cells and that its deletion or inhibition enhances T-cell anti-tumor activity and increases CAR T-cell effectiveness against solid tumors.
Spontaneous rotations in epithelia as an interplay between cell polarity and boundaries
Authors: Lo Vecchio S. , Pertz O. , Szopos M. , Navoret L. , Riveline D
Published: November 2021

Directed flows of cellsin vivoare essential in morphogenesis. They shape living matter in phenomena involving cell mechanics and regulations of the acto-myosin cytoskeleton. However the onset of coherent motion is still poorly understood. Here we show that coherence is associated with spontaneous alignments of cell polarity by designing cellular rings of controlled dimensions. A tug-of-war between polarities dictates the onset of coherence, as assessed by tracking live cellular shapes and motions in various experimental conditions. In addition, we identify an internally driven constraint set by cellular acto-myosin cables at boundaries as essential to ensure coherence, and active force is generated as evaluated by the high RhoA activity. The cables are required to trigger coherence as shown by our numerical simulations based on a novel Vicsek-type model including free active boundaries. We quantitatively reproducein silicocoherence onsets and we predict criteria leading to coherence. Altogether, spontaneous coherent motion results from basic competitions between cell orientations and active cables at boundaries.
Cryo-EM structure of the human NKCC1 transporter reveals mechanisms of ion coupling and specificity
Authors: Neumann Caroline , Rosenbæk Lena Lindtoft , Flygaard Rasmus Kock , Habeck Michael , Karlsen Jesper Lykkegaard , Wang Yong , Lindorff-Larsen Kresten , Gad Hans Henrik , Hartmann Rune , Lyons Joseph , Fenton Robert A. , Nissen Poul
Published: November 2021

The sodium-potassium-chloride transporter NKCC1 (SLC12A2) performs Na+-dependent Cl−and K+ion uptake across plasma membranes. NKCC1 is important for regulating e.g. cell volume, hearing, blood pressure, and chloride gradients defining GABAergic and glycinergic signaling in brain. Here, we present a 2.6 Å resolution cryo-electron microscopy (cryo-EM) structure of human NKCC1 in the substrate-loaded (Na+, K+, 2 Cl−) and inward-facing conformation adopting an occluded state that has also been observed for the SLC6 type transporters MhsT and LeuT. Cl−binding at the Cl1 site together with the nearby K+ion provide a crucial bridge between the LeuT-fold scaffold and bundle domains. Cl−ion binding at the Cl2 site seems to undertake a structural role similar to a conserved glutamate of SLC6 transporters and may allow for chloride-sensitive regulation of transport. Supported by functional studies in mammalian cells and computational simulations we describe the Na+binding site and a putative Na+release pathway along transmembrane helix 5. The results provide insight into the structure-function relationship of NKCC1 with broader implications for other SLC12 family members.
Abnormal (hydroxy)prolines deuterium content redefines hydrogen chemical mass
Authors: Gharibi Hassan , Chernobrovkin Alexey , Eriksson Gunilla , Saei Amir Ata , Timmons Zena , Kitchener Andrew C. , Kalthoff Daniela , Lidén Kerstin , Makarov Alexander A. , Zubarev Roman A.
Published: November 2021

Analysing the δ2H in individual amino acids of proteins extracted from vertebrates, we unexpectedly found in some samples, notably bone collagen from seals, more than twice as much deuterium in proline and hydroxyproline residues than in seawater. This corresponds to at least four times higher δ2H than in any previously reported biogenic sample. We ruled out diet as a plausible mechanism for such anomalous enrichment. This finding puts into question the old adage that you are what you eat.

The chemical mass of hydrogen is defined as an interval from the lowest to the highest content of deuterium 2H, hydrogen’s heavy stable isotope. Measurements of the deviations δ2H in the deuterium content from the standard (ocean water, δ2H = 0‰) are used to characterise biological samples, such as animal bone collagen. The results are often interpreted in terms of the trophic level and diet of the animal as well as prevailing climate during its lifetime. The majority of the published bone collagen δ2H data fall into a narrow δ2H range limited to ±100‰. Using novel analysis method, we unexpectedly found greatly higher δ2H values, up to 1500‰, in seal bone collagen. Such anomalous deuterium enrichment is detected only in two amino acid residues, proline and its derivative hydroxyproline, while other residues show much smaller δ2H values. Anomalously high δ2H values, albeit of lower magnitudes, are also found for these residues in other biological sources. This finding substantially expands the upper bound of the hydrogen chemical mass for biogenic sources. Since neither diet nor environment explain these mysteriously high enrichment levels amounting to more than twice deuterium content in sea water, our understanding of stable isotopes in nature, as well as the old adage “you are what you eat”, are put in question.