bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Impacting Quality of Life in Multiple System Atrophy
Authors: Ali Nabila , Nesspor Vanessa , Bang Jee , Scholz Sonja W. , Pantelyat Alexander
Published: November 2022

Background

Multiple system atrophy (MSA) is an atypical parkinsonian disorder that involves parkinsonism, cerebellar ataxia, and autonomic dysfunction. Patient-reported quality of life is an important benchmark for clinicians and clinical trials. The Unified Multiple System Atrophy Rating Scale (UMSARS) allows healthcare providers to rate and assess MSA progression. The MSA-QoL questionnaire is a health-related quality of life scale intended to provide patient-reported outcome measures. In this article, we investigated inter-scale correlations between the MSA-QoL and UMSARS to determine factors impacting the quality of life of patients with MSA.

Methods

Twenty patients at the Johns Hopkins Atypical Parkinsonism Center’s Multidisciplinary Clinic with a diagnosis of clinically probable MSA and who filled out the MSA-QoL and UMSARS questionnaires within two weeks of each other were included. Inter-scale correlations between MSA-QoL and UMSARS responses were examined. Linear regressions were also performed to examine relationships between both scales.

Results

Significant inter-scale correlations were found between the MSA-QoL and UMSARS, both between MSA-QoL total score and UMSARS Part I subtotal scores and for individual scale items. There were no significant correlations between MSA-QoL life satisfaction rating and UMSARS subtotal scores or any specific UMSARS items. Linear regression analysis found significant associations between MSA-QoL total score and UMSARS Part I and total scores, and between MSA-QoL life satisfaction rating and UMSARS Part I, Part II, and total scores (after adjustment for age).

Conclusions

Our study demonstrates significant inter-scale correlations between MSA-QoL and UMSARS, particularly relating to activities of daily living and hygiene. MSA-QoL total score and UMSARS Part I subtotal scores, which assess patients’ functional status, were strongly and significantly correlated. The lack of significant associations between MSA-QoL life satisfaction rating and any UMSARS item suggests there may be aspects to quality of life that are not fully captured by this assessment. Larger cross-sectional and longitudinal analyses utilizing UMSARS and MSA-QoL are warranted and modification of the UMSARS should be considered.
Prioritizing interventions for cholera control in Kenya, 2015-2020
Authors: Boru Waqo , Xiao Shaoming , Amoth Patrick , Kareko David , Langat Daniel , Were Ian , Ali Mohammad , Sack David A. , Lee Elizabeth C. , Debes Amanda K.
Published: November 2022

Kenya has experienced cholera outbreaks since 1971, with the most recent wave beginning in late 2014. Between 2015-2020, 32 of 47 counties reported 30,431 suspected cholera cases. The Global Task Force for Cholera Control (GTFCC) developed aGlobal Roadmap for Ending Cholera by 2030, which emphasizes the need to target multi-sectoral interventions to priority areas known as “cholera burden hotspots.” This study utilizes the GTFCC’s hotspot method to identify hotspots in Kenya at the county and sub-county administrative levels from 2015 through 2020. 32 of 47 (68.1%) counties reported cholera cases during this time while only 149 of 301 (49.5%) sub-counties reported cholera cases. The analysis identifies hotspots based on the mean annual incidence (MAI) over the past five-year period and cholera’s persistence in the area. Applying a MAI threshold of 90thpercentile and the median persistence at both the county and sub-county levels, we identified 13 high risk sub-counties from 8 counties, including the 3 high risk counties of Garissa, Tana River and Wajir. This demonstrates that several sub-counties are high level hotspots while their counties are not. In addition, when cases reported by county versus sub-county hotspot risk are compared, 1.4 million people overlapped in the areas identified as both high-risk county and high-risk sub-county. However, assuming that finer scale data is more accurate, 1.6 million high risk sub-county people would have been misclassified as medium risk with a county-level analysis. Furthermore, an additional 1.6 million people would have been classified as living in high-risk in a county-level analysis when at the sub-county level, they were medium, low or no-risk sub-counties. This results in 3.2 million people being misclassified when county level analysis is utilized rather than a more-focused sub-county level analysis. This analysis highlights the need for more localized risk analyses to target cholera intervention and prevention efforts towards the populations most vulnerable.
Use of home pulse oximetry to enhance remote COVID-19 monitoring: Evaluating a single centre experience
Authors: France Megan W , Porter Angus H , Bennett Cameron J , McCarthy Kate L
Published: November 2022

Introduction

Telehealth and remote monitoring of patients of patients with mild COVID-19 infection have developed rapidly in response to the pandemic. Many healthcare systems have embraced telehealth for remote clinical monitoring and pulse oximetry for enhanced monitoring.

Methods

The experience of a large healthcare centre’s COVID Virtual Ward was reviewed retrospectively with a particular focus on evaluating the effectiveness, safety and utility of finger pulse oximetry within the home. Data from a 2 month period in early 2022 during a BA1 Omicron wave was retrospectively reviewed.

551 high risk patients were issued with pulse oximeters for monitoring oxygen saturations within their home. All patients received daily clinical review via telephone by a nurse or doctor. The group was highly vaccinated with only 6.4% of the cohort unvaccinated. Oximeters were promptly delivered via a courier service across a vast geographical area.

Results

Pulse oximetry was well utilised by almost all patients. Only 2.7% of the cohort demonstrated resting oxygen saturations of <94% during their Virtual Ward admission. 91% of patients reporting dyspnoea were able to be safely managed without escalation to an emergency department due to reassuring clinical and oximetry assessment. Home oxygen saturations correlated well with saturations recorded within the ED, with no patients found to have lower saturations compared with home saturations.

Discussion

Within a high risk population experiencing COVID-19 infection, pulse oximetry was a useful tool in clinical assessment, correlated well with hospital-based pulse oximetry and allowed a substantial reduction in COVID-19 related ED presentations.
Corticostriatal connectivity mediates the reciprocal relationship between sleep and impulsivity in early adolescents
Authors: Yang Fan Nils , Liu Tina Tong , Wang Ze
Published: November 2022

Background

Adolescence, a developmental period characterized by major changes in sleep and circadian rhythms, is associated with normative increases in impulsivity. While insufficient sleep has been linked to elevated impulsivity, the neural mechanism underlying the relationship remains poorly understood.

Methods

We analyzed a dataset of 7,884 drug-naive 9-10 year-olds from the Adolescent Brain Cognitive Development (ABCD) study. Among them, 5,166 have 2-year follow-up neuroimaging data. Linear mixed-effects models, mediation analysis, and longitudinal mediation analysis were used to investigate the relationship between sleep, impulsivity, and brain functional and structural connectivity between the cortex and the striatum.

Results

We found that less sleep is significantly associated with higher impulsivity and disrupted functional connectivity between the cingulo-opercular network and the left caudate, and between the cingulo-parietal network and the right pallidum. These two connectivity measurements mediate the effect of sleep duration on impulsivity at both baseline and two-year follow-up. Longitudinal mediation analyses further revealed that sleep duration and impulsivity can reinforce each other through cortical-striatum connectivities in a reciprocal manner.

Conclusions

These results reveal neural mechanisms underlying the robust reciprocal relationship between insufficient sleep and impulsivity. Our findings highlight the role of early sleep intervention in helping early adolescents control their impulses, which might in turn prevent the development of substance use.
Disability and Post-traumatic Stress Symptoms in the Ukrainian General Population During the 2022 Russian Invasion
Authors: Kang Tarandeep S. , Goodwin Robin , Hamama-Raz Yaira , Leshem Elazar , Ben-Ezra Menachem
Published: November 2022

Background

Previous research has shown that people with disabilities are disproportionately vulnerable to symptoms of psychological distress after exposure to armed conflict. Past work has also shown that individuals displaced by conflict are at heightened risk of post-traumatic stress. However, we know of no research that has attempted to examine the association between disability severity and post-traumatic stress symptoms in a general population affected by armed conflict.

Method

We examined the association between levels of functional disability in the Ukrainian population and symptoms of post-traumatic stress during the 2022 Russian invasion of Ukraine. We analysed data from a national sample of 2000 participants from across this country, assessing disability using the WHODAS-12 (six domains of disability) and the ITQ assessment of ICD-11 PTSD symptomatology. Moderated regression examined the impact of displacement status on the disability-post-traumatic stress relationship.

Results

Different domains of disability predicted post-traumatic stress symptoms to varying extents, with overall disability score significantly associated with post-traumatic stress symptoms. This relationship was not moderated by displacement status. Consistent with previous research, females reported higher levels post-traumatic stress.

Conclusions

In a study of a general population during a time of armed conflict individuals with more severe disabilities were at greater risk of post-traumatic stress symptoms.

Psychiatrists and related professionals should consider pre-existing disability as a risk factor for conflict -related post-traumatic stress.

Highlights

What is already known on this topic

People with disabilities are vulnerable to a variety of forms of psychological distress after experiencing disasters of various kinds, including armed conflict. However, associations between levels of disability in the general population and post-traumatic stress during a period of conflict have not previously been examined.

What this study adds

Increasing severity of functional disability in the general population is associated with increasing post-traumatic stress symptoms in a conflict exposed population.

How this study might affect research, practice or policy

Mental health professionals dealing with conflict affected populations should take account of the additional vulnerabilities caused by disability status, and work to mitigate this by providing access to functional and social support.
Heat Exposure Among Adult Women in Rural Tamil Nadu, India
Authors: Deshpande Aniruddha , Scovronick Noah , Clasen Thomas F. , Waller Lance , Aravindalochanan Vigneswari , Balakrishnan Kalpana , Puttaswamy Naveen , Peel Jennifer , Pillarisetti Ajay
Published: November 2022

Exposure to heat is associated with a substantial burden of disease and is an emerging issue in the context of climate change. Heat exposure is of particular concern in India – one of the world’s hotter countries and soon to be its most populous – where a large fraction of the population works outdoors, lives in dwellings that are thermally inefficient, and is unable to access cooling technologies. Despite these concerns, relatively little is known about personal heat exposure in India, particularly in rural areas. Here we leverage temperature data collected as part of a randomized controlled trial of cookstove replacement to describe personal temperature exposures of older adult women in rural Tamil Nadu. We also compare personal exposure measurements to the nearest ambient monitoring stations, as well as to commonly used modelled temperature data products. We find that temperatures differ across individuals in the same location on the same day – sometimes by more than 5 °C within the same hour – and that some individuals experience sharp increases in heat exposure in the early morning or evening, potentially a result of cooking with solid fuels. In comparisons with the personal exposure measurements, we find stronger correlations with the modelled products (R2of ∼0.74) than with ambient monitors (R2of ∼0.6). We did not find evidence of systematic biases, which indicates that adjusting for discrepancies between personal and ambient exposure estimates is not straightforward. This study indicates a need for improved heat exposure assessment in epidemiological and burden of disease studies in India.
A gene essentiality signature enables predicting the mechanism of action of drugs
Authors: Wang Wenyu , Bao Jie , Zheng Shuyu , Huang Shan , Aldahdooh Jehad , Wang Yinyin , Eriksson Johanna , Tanoli Ziaurrehman , Zhang Xuepei , Gaetani Massimiliano , Tang Jing
Published: November 2022

Cancer drugs often kill cells independent of their putative targets, suggesting the limitation of existing knowledge on the mechanisms of action. In this study, we explored whether the integration of loss-of-function genetic and drug sensitivity screening data can define a gene essentiality signature to better understand the drug target interactions. We showed that our gene essentiality signature can predict drug targets more accurately than chemical fingerprints and drug-perturbated gene expression signatures. We further showed how gene essentiality signature can help identify mechanisms of action of drugsde novo, including the EGFR inhibitor lapatinib, and drugs associated with DNA mismatch repair. Finally, we established gene essentiality signatures for noncancer drugs and used them to predict their anticancer targets. We have successfully validated the target predictions for multiple noncancer drugs, using cell-based drug target deconvolution by the proteome integral solubility alteration assay. Our study provides a novel signature of drugs that may facilitate the rational design of drug repurposing.
Limited emergence of resistance to Integrase strand transfer inhibitors (INSTIs) in HIV-experienced patients failing dolutegravir-based antiretroviral therapy: Cross-sectional analysis from a Northeast Nigerian cohort
Authors: Abdullahi Adam , Kida Ibrahim Musa , Maina Umar Abdullahi , Ibrahim Amina Husaini , Mshelia James , Wisso Haruna , Adamu Abdullahi , Onyemata James Ezenwa , Yusuph Haruna , Aliyu Sani H. , Charurat Man , Abimiku Alash’le , Abeler-Dorner Lucie , Fraser Christophe , Bonsall David , Kemp Steven A. , Gupta Ravindra K.
Published: November 2022

Background

Owing to high levels of resistance to previous first-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral therapy (ART), consolidated recommendations since 2019, from the WHO and others, have indicated that dolutegravir (DTG) is the preferred drug of choice for HIV treatment, globally. There is a paucity of resistance outcome data from non-B HIV subtypes circulating across West Africa.

Aim

We aimed to characterise the mutational profiles of HIV-positive patients from a small North-East Nigeria cohort, failing a DTG-based ART regimen.

Methods

Plasma samples were collected and stored from 61 HIV-1 infected participants. Following failure of DTG-based ART, all samples were sequenced by Illumina whole-genome, ultra-deep sequencing. Sequencing was successful in (n=33) participants with median age of 40 years and median time on ART of 9 years. HIV-1 subtyping was performed using SNAPPy. Haplotype reconstruction and transmission were inferred using standard phylogenetic methods.

Result

Most patients had mutational profiles that were reflective of prior exposure to first- and second-line ART including exposure to thymidine analogues, efavirenz and nevirapine. One patient had evidence of major INSTI DRMs (T66A, G118R, E138K and R263K), reducing efficacy of DTG. The participant was aged 18, infected with a subtype G virus and likely vertically infected.

Conclusion

This study found low level resistance to DTG in the cohort, with one patient having high-level resistance to DTG and other INSTIs. Critical population level and long-term data on DTG outcomes are required to guide implementation and policy action across the region.
Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease
Authors: Green Courtney R. , Bonelli Roberto , Ansell Brendan R.E. , Tzaridis Simone , Handzlik Michal , McGregor Grace H. , Hart Barbara , Trombley Jennifer , Reilly Mary M. , Bernstein Paul S. , Egan Catherine , Fruttiger Marcus , Wallace Martina , Bahlo Melanie , Friedlander Martin , Metallo Christian M. , Gantner Marin L.
Published: November 2022

The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insights into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we performed a targeted metabolomic analysis of these pathways in sera from patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. In a cohort of >350 participants, MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model indicates this depletion in complex sphingolipids can be driven by low dietary serine and glycine. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. These results highlight metabolic distinctions between these two diseases, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches.
Convergent Evolution and B-Cell Recirculation in Germinal Centers in a Human Lymph Node
Authors: Pelissier Aurelien , Stratigopoulou Maria , Donner Naomi , Dimitriadis Evangelos , Bende Richard J , Guikema Jeroen E , Martinez Maria Rodriguez , van Noesel Carel J M
Published: November 2022

Germinal centers (GCs) are specialized compartments within the secondary lymphoid organs where B cells proliferate, differentiate, and mutate their antibody genes in response to the presence of foreign antigens. They play a central role in generating an effective immune response against infectious pathogens, and failures in their regulating mechanisms can lead to the development of autoimmune diseases and cancer. While previous works study experimental systems of the immune response with mouse models that are immunized with specific antigens, our study focuses on a real life situation, with an ongoing GC response in a human lymph node (LN) involving multiple asynchronized GCs reacting simultaneously to unknown antigens. We combined laser capture microdissection (LCM) of individual GCs from human LN with next-generation repertoire sequencing (Rep-seq) to characterize individual GCs as distinct evolutionary spaces. In line with well-characterized GC responses in mice, elicited by immunization with model antigens such as NP-CGG, we observe a relatively low sequence similarity, as well as heterogeneous clonal diversity across individual GCs from the same human LN. Still, we identify shared clones in several individual GCs, and phylogenetic tree analysis combined with paratope modeling suggest the re-engagement and rediversification of B-cell clones across GCs as well as expanded clones exhibiting shared antigen responses across distinct GCs, indicating convergent evolution of the GCs. Finally, our study allows for the characterization of non-functional clones, where frequencies of V(D)J or SHM induced stop codons are quantified.
Effects of lactate, super-GDF9 and low oxygen tension during biphasic in vitro maturation on the bioenergetic profiles of mouse cumulus-oocyte-complex
Authors: Akin Nazli , Ates Gamze , Mengden Lucia von , Herta Anamaria-Cristina , Meriggioli Cecilia , Billooye Katy , Stocker William A. , Ghesquiere Brecht , Harrison Craig A. , Cools Wilfried , Klamt Fabio , Massie Ann , Smitz Johan , Anckaert Ellen
Published: November 2022

In vitro maturation (IVM) is an alternative assisted reproductive technology (ART) with reduced hormone related side-effects and treatment burden compared to conventional IVF. Capacitation (CAPA)-IVM is a biphasic IVM system with improved clinical outcomes compared to standard monophasic IVM. Yet, CAPA-IVM efficiency compared to conventional IVF is still suboptimal in terms of producing utilizable blastocysts. Previously we have shown that CAPA-IVM leads to a precocious increase in cumulus cell (CC) glycolytic activity during cytoplasmic maturation. In the current study, considering the fundamental importance of CCs for oocyte maturation and cumulus-oocyte complex (COC) microenvironment, we further analyzed the bioenergetic profiles of maturing CAPA-IVM COCs. Through a multi-step approach, we (i) explored mitochondrial function of the in vivo and CAPA-IVM matured COCs through real-time metabolic analysis with Seahorse analyzer; and to improve COC metabolism (ii) supplemented the culture media with lactate and/or super-GDF9 (an engineered form of growth differentiation factor 9) and (iii) reduced culture oxygen tension. Our results indicated that the pre-IVM step is delicate and prone to culture related disruptions. Lactate and/or super-GDF9 supplementations failed to eliminate pre-IVM induced stress on COC glucose metabolism and mitochondrial respiration. However, when performing pre-IVM culture under 5% oxygen tension, CAPA-IVM COCs showed a similar bioenergetic profiles compared to in vivo matured counterparts. This is the first study providing real-time metabolic analysis of the COCs from a biphasic IVM system. The currently used analytical approach provides the quantitative measures and the rational basis to further improve IVM culture requirements.
Plant secondary metabolite-dependent plant-soil feedbacks can improve crop yield in the field
Authors: Gfeller Valentin , Waelchli Jan , Pfister Stephanie , Deslandes-Hérold Gabriel , Mascher Fabio , Glauser Gaétan , Aeby Yvo , Mestrot Adrien , Robert Christelle A.M. , Schlaeppi Klaus , Erb Matthias
Published: November 2022

Plant secondary metabolites that are released into the rhizosphere alter biotic and abiotic soil properties, which in turn affect the performance of other plants. How such plant-soil feedbacks affect agricultural productivity and food quality in crop rotations is unknown. Here, we assessed the impact of maize benzoxazinoids on the performance, yield and food quality of three winter wheat varieties in a two-year field experiment. Following maize cultivation, we detected benzoxazinoid-dependent chemical and microbial fingerprints in the soil. The chemical fingerprint was still visible during wheat growth, while the microbial fingerprint was no longer detected. Benzoxazinoid soil conditioning by wild-type maize led to increased wheat emergence, tillering, growth and biomass compared to soil conditioning bybx1mutant plants. Weed cover remained unaffected, while insect damage decreased in a subset of varieties. Wheat yield was increased by over 4% without a reduction in grain quality across varieties. This improvement was directly associated with increased germination and tillering. Taken together, our experiments demonstrate that plant secondary metabolites can increase yield via plant-soil feedbacks under agronomically realistic conditions. If this phenomenon holds across different soils and environmental conditions, optimizing plant root exudation could be a powerful, genetically tractable strategy to enhance crop yields without additional inputs.
Complementary Ribo-seq approaches map the translatome and provide a small protein census in the foodborne pathogenCampylobacter jejuni
Authors: Froschauer Kathrin , Svensson Sarah L. , Gelhausen Rick , Fiore Elisabetta , Kible Philipp , Klaude Alicia , Kucklick Martin , Fuchs Stephan , Eggenhofer Florian , Engelmann Susanne , Backofen Rolf , Sharma Cynthia M.
Published: November 2022

Background

Knowing the molecules encoded by bacterial pathogens and how their expression is regulated is essential to understand how they survive, colonize, and cause disease. RNA-seq technologies that map transcriptomes have revealed a wealth of new transcripts in bacterial pathogens. However, they do not provide direct evidence or coordinates for coding potential. In particular, they miss small proteins (≤ 50-100 amino acids) translated from small open reading frames (sORFs). However, this still poorly annotated component of bacterial genomes shows emerging roles in bacterial physiology and virulence.

Results

Here, we present an integrated approach based on complementary ribosome profiling (Ribo-seq) techniques to map the “translatome” ofCampylobacter jejuni, the most common cause of bacterial gastroenteritis. Besides conventional Ribo-seq, we employed translation initiation site (TIS) profiling to map start codons and reveal internal sORFs. We also developed a Ribo-seq approach for mapping of translation termination sites (TTS), which revealed stop codons not apparent from the reference genome in virulence-associated loci. Our translatome map confirms translation of leaderless ORFs and leader peptides, re-annotates start or stop codons of 35 genes, and reveals isoforms generated by internal start sites. It also adds 42 novel sORFs in diverse contexts to theC. jejuniannotation, such as within small RNAs, in 5′ untranslated regions (UTRs), or internal/out-of-frame/antisense in larger ORFs. Using epitope tagging/western blot and mass spectrometry we validated expression of almost 60 annotated and novel sORFs, includingcioY, which we show encodes a conserved, 34 amino acid component of the CioAB terminal oxidase.

Conclusions

Overall, we provide a blueprint for integrating several Ribo-seq approaches to refine and enrich bacterial annotations.
Confocal reflectance microscopy for mapping collagen fiber organization in the vitreous gel of the eye
Authors: Hwang Eileen S. , Morgan Denise J. , Sun Jieliyue , Hartnett M. Elizabeth , Toussaint Kimani C. , Coats Brittany
Published: November 2022

Vitreous collagen structure plays an important role in ocular mechanics, but capturing this structure with existing vitreous imaging methods is hindered by loss of sample position and orientation, low resolution, or small field of view. The objective of this study was to evaluate confocal reflectance microscopy as a solution to these limitations. The use of intrinsic reflectance avoids staining and optical sectioning eliminates the requirement for thin sectioning, minimizing processing for optimal preservation of natural structure. We developed a sample preparation and imaging strategy usingex vivogrossly sectioned porcine eyes. Imaging revealed a network of uniform diameter crossing fibers (1.1 ± 0.3 μm for a typical image) with generally poor alignment (alignment coefficient = 0.40 ± 0.21 for a typical image). To test the utility of our approach for detecting differences in fiber spatial distribution, we imaged eyes every 1 mm along an anterior-posterior axis originating at the limbus and quantified the number of fibers in each image. Fiber density was higher anteriorly near the vitreous base, regardless of imaging plane. These data demonstrate that confocal reflectance microscopy addresses the previously unmet need for a robust, micron-scale technique to map features of collagen networksin situacross the vitreous.
Challenges in antibody structure prediction
Authors: Fernández-Quintero Monica L. , Kokot Janik , Waibl Franz , Fischer Anna-Lena M. , Quoika Patrick K. , Deane Charlotte M. , Liedl Klaus R.
Published: November 2022

The tremendous advances in structural biology and the exponential increase of high-quality experimental structures available in the PDB motivated numerous studies to tackle the grand challenge of predicting protein structures. AlphaFold2 revolutionized the field of protein structure prediction, by combining artificial intelligence with evolutionary information.

Antibodies are one of the most important classes of biotherapeutic proteins. Accurate structure models are a prerequisite to advance biophysical property predictions and consequently antibody design. Various specialized tools are available to predict antibody structures based on different principles and profiting from current advances in protein structure prediction based on artificial intelligence. Here, we want to emphasize the importance of reliable protein structure models and highlight the enormous advances in the field. At the same time, we want to raise the awareness that protein structure models—and in particular antibody models—may suffer from structural inaccuracies, namely incorrect cis-amid bonds, wrong stereochemistry or clashes. We show that these inaccuracies affect biophysical property predictions such as surface hydrophobicity. Thus, we stress the significance of carefully reviewing protein structure models before investing further computing power and setting up experiments. To facilitate the assessment of model quality, we provide a tool “TopModel” to validate structure models.
Monitoring Functional Post-Translational Modifications Using a Data-Driven Proteome Informatic Pipeline Based on PEIMAN2
Authors: Nickchi Payman , Mirzaie Mehdi , Baumann Marc , Saei Amir Ata , Jafari Mohieddin
Published: November 2022

Post-translational modifications (PTMs) are under significant focus in molecular biomedicine due to their importance in signal transduction in most cellular and organismal processes. Characterization of PTMs, discrimination between functional and inert PTMs, quantification of their occupancies and PTM crosstalk are demanding tasks in each biosystem. On top of that, the study of each PTM often necessitates a particular laborious experimental design. Here, we present a PTM-centric proteome informatic pipeline for prediction of relevant PTMs in mass spectrometry-based proteomics data in the absence ofa prioriinformation. Upon prediction, such PTMs can be incorporated in a refined database search. As a practical application, we showed how this pipeline suggested performing glycoproteomics in oral squamous cell carcinoma based on proteome profile of primary tumors. Subsequently, using proteome profiling of treated cells with two PTM-modulating kinase inhibitors, we experimentally identified cellular proteins that are differentially expressed in response to multikinase inhibitors dasatinib and staurosporine. Computational enrichment analysis was employed to determine the potential PTMs of protein targets for both drugs. Finally, we conducted an additional round of database search with the predicted PTMs. Our pipeline helped to analyze the enriched PTMs and even the detected proteins that were not identified in the initial search. Our findings support the idea of PTM-centric searching of MS data in proteomics based on computational enrichment analysis and we propose that this approach be integrated into future proteomics search engines.
Bell Jar: A Semi-Automated Registration and Cell Counting Tool for Mouse Neurohistology Analysis
Authors: Soronow Alec L.R. , Jacobs Matthew W. , Dickson Richard G. , Kim Euiseok J.
Published: November 2022

To investigate the anatomical organization of neural circuits across the whole brain, it is essential to register the experimental brain tissues to a reference atlas accurately. This procedure is also a prerequisite to quantify the locations and numbers of cells of interest in specific regions. However, it remains challenging to do registration on experimental tissue due to the intrinsic variation among the specimens, tissue deformation introduced by histological processing, and the potential inconsistency in the judgment of the experimenter during manual annotation. Here, we introduce Bell Jar, a multi-platform analysis tool with semi-automated affine warping of atlas maps onto microscopic images of brain slices and machine learning-based cell detection. Bell Jar’s intuitive GUI and internal dependency management enable users of all skill levels to obtain accurate results without programming expertise. To compare the performance of Bell Jar with previously published methods1–4, we labeled neurons in the mouse visual cortex with either an engineered rabies virus or an adeno-associated virus (AAV) for neural circuit tracing5, and quantified Bell Jar’s performance at each step of the pipeline for image alignment, segmentation, and cell counting. We demonstrated that Bell Jar’s output is as reliable as manual counting by an expert; it is more accurate than currently available techniques even with noisy data and takes less time with fewer user interventions. Bell Jar is an easy-to-navigate application that provides a reproducible, automated analysis workflow to facilitate the precise mapping of histological images of the mouse brain to the reference atlas and the quantification of cellular signals it is trained to recognize.
Energy conservation by collective movement in schooling fish
Authors: Zhang Yangfan , Lauder George V.
Published: November 2022

Many animals moving through fluids exhibit highly coordinated group movement that is thought to reduce the cost of locomotion. However, direct energetic measurements demonstrating the energy-saving benefits of fluid-mediated collective movements remain elusive. By characterizing both aerobic and anaerobic metabolic energy contributions in schools of giant danio (Devario aequipinnatus), we discovered that fish schools have a concave upward shaped metabolism– speed curve, with a minimum metabolic cost at ∼1 body length s-1. We demonstrate that fish schools reduce total energy expenditure (TEE) per tail beat by up to 56% compared to solitary fish. When reaching their maximum sustained swimming speed, fish swimming in schools had a 44% higher maximum aerobic performance and used 65% less non-aerobic energy compared to solitary individuals, which lowered the TEE and total cost of transport by up to 53%, near the lowest recorded for any aquatic organism. Fish in schools also recovered from exercise 43% faster than solitary fish. The non-aerobic energetic savings that occur when fish in schools actively swim at high speed can considerably improve both peak and repeated performance which is likely to be beneficial for evading predators. These energetic savings may underlie the prevalence of coordinated group locomotion in fishes.

One-Sentence Summary

Fish schools showed aU-shaped metabolism-speed curve and reduced the energy use per tail beat up to 56% at high swimming speeds compared to solitary fish.
Inclusion of minor alleles improves catalogue-based prediction of fluoroquinolone resistance inMycobacterium tuberculosis
Authors: Brankin Alice E. , Fowler Philip W.
Published: November 2022

Synopsis

Fluoroquinolone resistance poses a threat to the successful treatment of tuberculosis. Whole genome sequencing (WGS), and the subsequent detection of catalogued resistance-associated mutations, offers an attractive solution to fluoroquinolone susceptibility testing. However, the bioinformatic pipelines used often mask the recognition of minor alleles which are implicated in fluoroquinolone resistance. Using the Comprehensive Resistance Prediction for Tuberculosis: an International Consortium’s (CRyPTIC) dataset of globally diverse WGSMycobacterium tuberculosisisolates, with matched minimum inhibitory concentrations for two fluoroquinolone drugs, we show that detecting minor alleles increased the sensitivity of WGS for moxifloxacin resistance prediction from 85.4% to 94.0%, without significantly reducing specificity. We also found no correlation between the proportion of anM. tuberculosispopulation containing a resistance-conferring allele and the magnitude of resistance. Together our results highlight the importance of detecting minor resistance conferring alleles when using WGS, or indeed any sequencing-based approach, to diagnose fluoroquinolone resistance.
Estimation of Vertex-wise Sulcal Width Maps on Cortical Surfaces
Authors: Fernández-Pena Alberto , Navas-Sánchez Francisco J. , Martín de Blas Daniel , Marcos-Vidal Luis , Gordaliza Pedro M. , Martínez-Tejada Isabel , Janssen Joost , Carmona Susanna , Desco Manuel , Alemán-Gómez Yasser
Published: November 2022

Sulcal width, defined as the physical distance between opposing sulcal banks, has shown promise as a biomarker. We present the first method to obtain a vertex-wise representation of this metric directly on the brain’s cortical surface. The algorithm samples the surface at different depths and estimates the distances between the opposing sulcal banks. The method is validated against a simulated sulcus and compared to other sulcal width tools based on regions of interest, showing solid correlations between the proposed algorithm and two widely-used reference methods. A vertex-wise assessment of the sulcal width is carried out by evaluating the correlation between sulcal width and age in a sample of an aging population, revealing clusters in the central, cingulate, and temporal sulcus regions associating wider sulci for older participants. The results confirm that the algorithm is reliable for obtaining sulcal width maps, allowing for vertex-wise analyses, and providing aggregated measures similar to the existing methods. The present algorithm is publicly available viahttps://github.com/HGGM-LIM/SWiM.
Global analysis of suppressor mutations that rescue human genetic defects
Authors: Ünlü Betül , Pons Carles , Ho Uyen Linh , Batté Amandine , Aloy Patrick , van Leeuwen Jolanda
Published: November 2022

Genetic suppression occurs when the deleterious effects of a primary “query” mutation, such as a disease-causing mutation, are rescued by a suppressor mutation elsewhere in the genome. To capture existing knowledge on suppression relationships between human genes, we examined 2,400 published papers for potential interactions identified through either genetic modification of cultured human cells or through association studies in patients. The resulting network encompassed 476 unique suppression interactions that frequently linked genes that function in the same biological process. Suppressors were strongly enriched for genes with a role in stress response or signaling, suggesting that deleterious mutations can often be buffered by modulating signaling cascades or immune responses. Suppressor mutations tended to be deleterious when they occurred in absence of the query mutation, in apparent contrast with their protective role in the presence of the query. We formulated and quantified mechanisms of genetic suppression that could explain 71% of interactions and provided mechanistic insight into disease pathology. Finally, we used these observations to accurately predict suppressor genes in the human genome. The emerging frequency of suppression interactions and range of underlying mechanisms suggest that compensatory mutations may exist for the majority of genetic diseases.
Tailored synthetic sRNAs dynamically tune multilayer genetic circuits
Authors: Velazquez Sanchez Ana K. , Klopprogge Bjarne , Zimmermann Karl-Heinz , Ignatova Zoya
Published: November 2022

Predictable and controllable tuning of genetic circuits to regulate gene expression, including modulation of existing circuits or constructs without the need for redesign or rebuilding, is a persistent challenge in synthetic biology. Here, we propose a rational design of de novo small RNAs (sRNAs) to dynamically modulate gene expression within a broad range, from high, medium to low repression, and implemented them inEscherichia coli. We designed multiple multilayer genetic circuits, in which the variable effector element is a transcription factor (TF) controlling downstream the production of a reporter protein. Our approach harnesses the intrinsic RNA-interference pathway inE. colito exert dynamic and modular control of the multilayer genetic circuits. The sRNAs were designed to target TFs instead of the reporter gene, which allowed for wide range of expression modulation of the reporter protein, including the most difficult to achieve dynamic switch to an OFF state. Out work provides a frame for achieving independent modulation of gene expression, by only including an independent control circuit expressing synthetic sRNAs, without altering the structure of existing genetic circuits.
Breast cancer mutations HER2V777Land PIK3CAH1047Ractivate the p21-CDK4/6 –Cyclin D1 axis driving tumorigenesis and drug resistance
Authors: Cheng Xiaoqing , Sun Yirui , Highkin Maureen , Vemalapally Nagalaxmi , Jin Xiaohua , Zhou Brandon , Prior Julie L. , Tipton Ashley R. , Li Shunqiang , Iliuk Anton , Achilefu Samuel , Hagemann Ian S. , Edwards John R. , Bose Ron
Published: November 2022

In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in thePIK3CA,TP53, or E-cadherin genes. Of these co-occurring mutations,HER2andPIK3CAmutations are the most prevalent gene pair, with approximately 40% ofHER2mutated breast cancers also having activating mutations inPIK3CA. To study the effects of co-occurringHER2andPIK3CAmutations, we bred genetically engineered mice with theHER2V777L;PIK3CAH1047Rtransgenes (HP mice) and studied the resulting breast cancers bothin vivoas well asex vivousing cancer organoids. HP breast cancers show accelerated tumor formationin vivoand increased invasion and migration inin vitroassays. HP breast cancers have resistance to the pan-HER tyrosine kinase inhibitor, neratinib, but are effectively treated by neratinib plus trastuzumab deruxtecan. Proteomic and RNA-Seq analysis of HP breast cancers showed increased gene expression of Cyclin D1 and p21WAF1/Cip1 and changes in cell cycle markers. Combining neratinib with CDK4/6 inhibitors was another effective strategy for HP breast cancers with neratinib plus palbociclib showing a statistically significant reduction in mouse HP tumors as compared to either drug alone. We validated both the neratinib plus trastuzumab deruxtecan and neratinib plus palbociclib combinations using a human breast cancer patient-derived xenograft that has very similar HER2 andPIK3CAmutations. Both of these drug combinations are being tested in phase 1 clinical trials and this study provides valuable preclinical evidence for them.
Microstimulation of sensory cortex engages natural sensory representations
Authors: Pancholi Ravi , Sun-Yan Andrew , Peron Simon
Published: November 2022

Cortical activity patterns occupy a small subset of possible network states. If this is due to intrinsic network properties, microstimulation of cortex should evoke activity patterns resembling those observed during natural sensory input. Here, we use optical microstimulation of virally transfected layer 2/3 pyramidal neurons in mouse primary vibrissal somatosensory cortex to compare artificially evoked activity with natural activity evoked by whisker touch and movement (‘whisking’). We find that photostimulation engages touch but not whisking responsive neurons more than expected by chance. Neurons that respond to photostimulation and touch or to touch alone exhibit higher spontaneous pairwise correlations than purely photoresponsive neurons. Exposure to several days of simultaneous touch and optogenetic stimulation raises both overlap and spontaneous activity correlations among touch and photoresponsive neurons. We thus find that cortical microstimulation engages existing cortical representations and that repeated co-presentation of natural and artificial stimulation enhances this effect.
Endosomal GLUT3 is essential for alternative macrophage signaling, polarization, and function
Authors: Yu Dong-Min , Zhao Jiawei , Lee Eunice E. , Rose Elysha K. , Mahapatra Ruchika , Choe Jun-Yong , Abel E Dale , Wang Richard C.
Published: November 2022

Macrophages play critical roles in both inflammation and tissue homeostasis. Classically activated (M1) macrophages promote antimicrobial and tumoricidal activity, while alternatively activated (M2) macrophages promote phagocytosis and tissue homeostasis. The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in different hematopoietic lineages, but their specific functions in macrophages is poorly understood. We discovered that GLUT3 expression was increased after M2-activation stimuli in macrophages. Notably, GLUT3 KO BMDM (bone marrow-derived macrophages) showed marked defects in M2, but not M1, polarization. Consistent with defects in M2 polarization, GLUT3 KO macrophages showed impaired wound healing and decreased inflammation in calcipotriol-induced, atopic dermatitislike inflammation. GLUT3 promoted IL-4/STAT6 signaling, the main signaling pathway for M2 polarization, in a glucose-transport independent manner. Unlike plasma membrane-localized GLUT1, GLUT3 and components of the IL-4 signaling pathway, localized primarily to endosomes. GLUT3, but not GLUT1, interacted with Ras through its intracytoplasmic loop, and Rac1-PAK-cofilin signaling and the endocytosis of IL4R subunits were impaired in the absence of GLUT3. Thus, GLUT3 is essential for alternative macrophage polarization and function and plays an unexpected role in the regulation of endosomal signaling.
Focal adhesion protein vinculin inhibits Mef2c-driven sclerostin expression in osteocytes to promote bone formation in mice
Authors: Wang Yishu , Huang Jianmei , Lin Sixiong , Qin Lei , Hao Dingyu , Zhang Peijun , Huo Shaochuan , Zou Xuenong , Chen Di , Xiao Guozhi
Published: November 2022

The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Deleting vinculin using the mouse 10-kbDmp1-Cretransgenic mice causes a severe osteopenia in both young and aged mice by impairing osteoblast function without affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. At the molecular level, vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of theSostgene, which encodes sclerostin. Vinculin interacts with Mef2c and vinculin loss enhances Mef2c nuclear translocation and binding to theSostenhancerECR5to promote sclerostin production in osteocytes. DeletingSostexpression reverses the osteopenic phenotypes caused by vinculin loss in mice. We demonstrate that estrogen is a major regulator of vinculin expression in osteocytes and that more importantly vinculin loss mediates estrogen deficiency induction of bone loss in mice. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.