bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytocapsular tube network-tumor system is an integrated physical target for the highly effective and efficient pharmacotherapy of solid cancers
Authors: Yi Tingfang , Wagner Gerhard
Published: January 2022

Cancer is a leading cause of human lethality and cancer drug pan-resistant tumor metastasis (cdp-rtm) is a major source of cancer death. The integrated cytocapsular tube (CCT) networktumor system (CNTS) is essential for cancer evolution procedures including cancer cell proliferation, migration and dissemination in CCT networks, new tumor growth in CCT terminals, conventional cancer drug pan-resistance, and tumor relapse. The preclinical screening experimentations with CCTs and networks are necessary prerequisites for the discovery and development of cancer drug candidates for efficient clinical trials, and effective and precise clinical cancer pharmacotherapy. However, it is unknown whether the popularly employed conventional mouse experimentations for preclinical therapeutic development generate CCTs and networks. Here, we comprehensively investigated the cancer cell line derived xenografts (CDX) of 8 kinds of cancer cell lines, and patient cancer cells derived-xenografts (PDX) with 16 kinds of clinical primary and metastatic malignant tumor cells in multiple cancer stages by immunohistochemistry staining assays with CCT marker protein antibodies of anti-CM-01 antibodies. We found that there are no CCTs or CCT networks in all these examined 16 CDX and 22 PDX transplanted tumors. Our data evidenced that the conventional transplantation tumors for preclinical therapeutic development do not engender CCTs or CNTS, which is consistent with and provides an explanation of the poor clinical outcomes of the marketed cancer drugs. This study demonstrated that CCT network-tumor system (CNTS) is an integrated physical target for pharmacotherapy, and that preclinical experimentations engendering CNTS (such as CCT xenograft, CCTX) should be employed for the discovery and development of highly effective and efficient cancer drugs aimed for cure of solid cancers.
Selective activation of subthalamic nucleus output quantitatively scales movements
Authors: Friedman Alexander D. , Yin Henry H.
Published: January 2022

The subthalamic nucleus (STN), a diencephalic nucleus strongly connected with the basal ganglia, is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. The STN is thought to suppress movement by enhancing inhibitory basal ganglia output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson’s patients. However, previous studies on STN DBS usually relied on electrical stimulation, which cannot selectively target STN output neurons. Moreover, most studies did not measure behavior precisely during STN manipulations. Here we selectively stimulated STN projection neurons, by expressing channelrhodopsin in vesicular glutamate transporter 2 (VGlut2)-positive projection neurons in the STN. We also quantified behavior in freely moving male mice with high spatial and temporal resolution using 3D motion capture at 200 frames per second. We found STN stimulation resulted in movements with very short latencies (10-15 ms). Unilateral stimulation quantitatively determines orientation, head yaw, and head roll consistently in the ipsiversive direction, toward thee side of stimulation. On the other hand, head raising (increased head pitch) was observed after stimulation on either side. Strikingly, a single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematics. These results question the common assumption that STN suppresses movement; instead they suggest that STN output can precisely specific action parameters via direct projections to brainstem regions.
Persistent delirium in older hospital patients: an updated systematic review and meta-analysis
Authors: Whitby Jonathan , Nitchingham Anita , Caplan Gideon , Davis Daniel , Tsui Alex
Published: January 2022

Introduction

Persistent delirium is recognised as a substantial problem, but there are few insights into which patient groups might be particularly affected. Delirium is associated with future dementia progression. Yet whether this occurs subclinically over months and years, or persistent delirium merges into worsened dementia is not understood.

Methods

We adopted an identical approach to a previous systematic review, only including studies using a recognised diagnostic framework for ascertaining delirium at follow-up (persistent delirium). We applied risk of bias assessments based on Standards of Reporting of Neurological Disorders criteria. Estimates were pooled across studies using random-effects meta-analysis, and we estimated associations with age and follow-up duration using meta-regression.

Results

We identified 13 new cohorts, which we added to 8 from the previous systematic review (21 relevant studies reporting persistent delirium over 37 time points). Studies were mainly at low risk of bias. Pooled delirium prevalence estimates at discharge were 40% (95% CI 24% to 54%, 10 studies). Meta-regression showed variation in prevalence of persistent delirium over time (0.6% per week, 95% CI −1.2 to −0.1, p=0.02). Older study sample age was associated with higher prevalence of persistent delirium (8.8% per SD age, 95% CI 1.1% to 17%). The rate of improvement was the same regardless of age, but the overall burden was higher with older age such that 44% (95% CI 11% to 76%) of 95-year-olds would be expected to have persistent delirium at 12 months.

Conclusions

This systematic review emphasises the key importance of delirium as a persistent and extensive problem, particularly in the oldest-old. Addressing persistent delirium will require a whole-system, integrated approach in order to detect, follow-up and implement opportunities for recovery across all healthcare settings.
Reevaluation of Seroprevalence using a Semi-quantitative Anti-spike IgG in Health Care workers at an Academic Medical Center in Boston, Massachusetts
Authors: Cole Manisha , Duffy Elizabeth R. , Osterland Jordyn N , Gawel Susan , Ye Lei , de la Cena Kyle , Ragan Elizabeth J. , Weber Sarah E. , M- Schechter-Perkins Elissa , Bouton Tara C. , Jacobson Karen R. , Andry Chris , Kataria Yachana
Published: January 2022

Background

Accurate measurement of antibodies is a necessary tool for assessing exposure to SARS-CoV-2 and facilitating understanding of the role of antibodies in immunity. Most assays are qualitative in nature and employ a threshold to determine presence of antibodies. Semi-quantitative assays are now available. Here we evaluate the semi-quantitative SARS-CoV-2 IgG II (anti-spike (S)) assay. We aim to reassess the seroprevalence using anti-S assay and subsequently compare it to the previously measured IgG (anti-nucleoprotein (N)) in health care workers at an academic medical center in Boston.

Methods

1743 serum samples from HCWs at Boston Medical Center were analyzed for SARS-CoV-2 anti-S IgG and IgM using the Abbott SARS-CoV-2 IgG II and□Abbott AdviseDx□SARS-CoV-2 IgM assay, respectively. Precision, linearity, positive and negative concordance with prior RT-PCR test were evaluated for anti-S IgG. Seroprevalence and its association with demographics variables was also assessed.

Results

Linearity and precision results were clinically acceptable. The positive and negative concordance for anti-S IgG with RT-PCR was 88.2% (95% CI: 79.4% - 94.2%) and 97.43% (95% CI: 95.2% - 98.8%), respectively. Overall, 126 (7.2%) of 1,743 participants were positive by anti-S IgG. Among the 1302 participants with no prior RT-PCR, 40 (3.1%) were positive for anti-S IgG antibody. The original agreement in this population with the qualitative, anti-N IgG assay was 70.6%. Upon optimizing the threshold from 1.4 to 0.49 S/CO of the anti-N IgG assay, the positive agreement of the assay increases to 84.7%.

Conclusion

The anti-S IgG assay demonstrated reproducible and reliable measurements. This study highlights the presence of asymptomatic transmission among individuals with no prior history of positive RT-PCR. It also highlights the need for optimizing thresholds of the qualitative SARS-CoV-2 IgG assay for better agreement between assays by the same vendor.
Effects of amyloid and APOE4 on medial temporal lobe subregions in cognitively unimpaired elderly
Authors: de Flores Robin , Demeilliez-Servouin Solène , Kuhn Elizabeth , Chauveau Léa , Landeau Brigitte , Delcroix Nicolas , Gonneaud Julie , Chételat Gaël
Published: January 2022

Medial temporal lobe (MTL) sub-structures are differentially affected in early Alzheimer’s disease (AD), with a specific involvement of the entorhinal cortex (ERC), the perirhinal cortex (PRC) and CA1. However, the impact of amyloid (Aβ) pathology and APOE ε4 on MTL subregional atrophy remains relatively unknown. Our aim was to uncover these effects to further our understanding of the mechanisms underlying MTL atrophy in a population at-risk for AD.

We used baseline data from 130 unimpaired older adults (mean age: 68.9 ± 3.8 years) from the Age-Well randomized controlled trial for whom high-resolution structural MRI (T2-weighted; 0.4×0.4×2.5mm3), amyloid-PET (Florbetapir) and APOE genotype were available. Participants were dichotomized into amyloid positive (Aβ+, n=27) and negative (Aβ-, n=103), and APOE ε4 carrier (ε4+, n=35) and non-carriers (ε4-, n=95). Hippocampal subfield (CA1, CA2, CA3, dentate gyrus [DG], subiculum [SUB]) and extra-hippocampal region (ERC, Brodmann area [BA] 35 and 36, and parahippocampal cortex [PHC]) volumes were estimated using ASHS and normalized by total intracranial volume. For each subregion, group comparisons were performed (Aβ+ vs Aβ- and ε4+ vs ε4-) using ANCOVAs, including age, sex and education as covariates. Interactions with age (i.e., Aβ status * age and APOE ε4 status * age) were also investigated for each subregion.

No significant differences were observed between Aβ+ and Aβ-, nor between ε4+ and ε4-. However, a significant Aβ status * age interaction were observed for CA1 (p<0.05), where volumes were negatively associated with age in the Aβ+ group only. In addition, significant APOE ε4 status * age interactions were found for CA1, SUB, ERC, DG and the whole hippocampus (p<0.05), where volumes were negatively associated with age in the ε4+ group only.

Overall, our analyses showed that both Aβ and APOE ε4 status interact with age on CA1, which is known to be specifically atrophied in early AD. In addition, APOE ε4 status mediated the effects of age on other subregions (SUB, ERC, DG), suggesting a more important contribution of APOE ε4 than amyloid to MTL atrophy in cognitively unimpaired population. These results are particularly important to develop MRI-based biomarkers to detect early AD and further our understanding of the mechanisms underlying MTL atrophy.
“I feel like my body is broken”: Exploring the experiences of people living with long COVID
Authors: Wurz Amanda , Culos-Reed S. Nicole , Franklin Kelli , DeMars Jessica , Wrightson James G. , Twomey Rosie
Published: January 2022

Background

Long COVID, an illness affecting a subset of individuals after COVID-19, is distressing and poorly understood. Exploring the experiences of people with long COVID could help inform current conceptualizations of the illness, guide supportive care strategies, and validate patients’ perspectives on the condition. Thus, the objective of this study was to better understand and explore individuals’ experiences with long COVID and commonly reported symptoms, using qualitative data collected from open-ended survey responses.

Methods

Data were collected from adults living with long COVID following a confirmed or suspected SARS-CoV-2 infection who participated in a larger observational, online survey. Within the larger survey, participants had the option of answering seven open-ended items. Data from the open-ended items were analyzed following guidelines for reflective thematic analysis.

Results

From the 213 who were included in the online survey, 169 participants who primarily self-identified as women (88.2%), aged 40-49 (33.1%), and who had been experiencing long COVID symptoms for ≥ 6 months (58.6%) responded to the open-ended questions. Four overlapping and interconnected themes were identified: (1) My long COVID symptoms are numerous, hard to describe, and debilitating, (2) All aspects of my day-to-day functioning have been impacted, (3) I can no longer be physically active, and (4) I keep asking for help, but no one is listening, and very little is working.

Conclusion

Findings highlight the complex nature of long COVID and show the ways in which individuals affected by the illness are negatively impacted. Participants recounted struggling and altering their daily activities while managing relapsing-remitting symptoms, an uncertain prognosis, lost pre-COVID identities, and a healthcare system (that does not always offer guidance nor take them seriously). More support and recognition for the condition are needed to help this cohort navigate the process of adapting to long COVID.
Molecular diagnosis of SARS-CoV-2: a validation of saliva samples
Authors: da Silva Natalia Verissimo Rodrigues , Neves Pereira Samyra Stéphane , Kavalco Karine Frehner , Menegídio Fabiano Bezerra , Medeiros-Santana Luanda , Visôtto Liliane Evangelista , Pasa Rubens
Published: January 2022

Nasopharyngeal swabs are the most used in sample collecting for covid-19 tests in SARS-CoV-2 molecular diagnosis. However, this sampling method presents some disadvantages, since, in addition to being dependent on imported materials, it is invasive, causes discomfort in patients, and, presents the risk of contamination for the medical collection team. This study aimed at validating saliva samples to obtain viral RNA to be used in the molecular diagnostic test for SARS-CoV-2 using the RT-qPCR technique. Results presented 93,44% concordance in in comparison to nasopharyngeal swabs sampling. Therefore, saliva samples used in SARS-CoV-2 RT-qPCR detection tests presented consistent results.
ECS1 and ECS2 regulate polyspermy and suppress the formation of haploid plants by promoting double fertilization
Authors: Mao Yanbo , Nakel Thomas , Serbes Isil Erbasol , Tekleyohans Dawit G. , Joshi Saurabh , Baum Thomas , Groß-Hardt Rita
Published: January 2022

In flowering plants, the number of pollen tubes that provide sperm cells to the female gametes is restricted by a pollen tube block. This safeguard mechanism is only activated after successful fertilization of both female gametes and involves the disintegration of pollen tube attracting synergid cells. Yu and coworkers previously reported that the endopeptidase ECS1 and ECS2, which are secreted by fertilized egg cells, prevent the attraction of supernumerary pollen tubes by cleaving the pollen tube attractant LURE11. Here we report on an earlier defect in ecs1 ecs2 mutants that is manifested by single rather than double fertilization of either egg or central cell. The defect is accompanied by a delay in synergid disintegration providing an alternative explanation for the extra pollen tubes observed in the double mutant. These results are corroborated by our finding that ecs1 ecs2 plants segregate both, haploid as well as polyspermy derived triploid plants.
AbLang: An antibody language model for completing antibody sequences
Authors: Olsen Tobias H. , Moal Iain H. , Deane Charlotte M.
Published: January 2022

Motivation

General protein language models have been shown to summarise the semantics of protein sequences into representations that are useful for state-of-the-art predictive methods. However, for antibody specific problems, such as restoring residues lost due to sequencing errors, a model trained solely on antibodies may be more powerful. Antibodies are one of the few protein types where the volume of sequence data needed for such language models is available, for example in the Observed Antibody Space (OAS) database.

Results

Here, we introduce AbLang, a language model trained on the antibody sequences in the OAS database. We demonstrate the power of AbLang by using it to restore missing residues in antibody sequence data, a key issue with B-cell receptor repertoire sequencing, over 40% of OAS sequences are missing the first 15 amino acids. AbLang restores the missing residues of antibody sequences better than using IMGT germlines or the general protein language model ESM-1b. Further, AbLang does not require knowledge of the germline of the antibody and is seven times faster than ESM-1b.

Availability and Implementation

AbLang is a python package available at https://github.com/oxpig/AbLang.
Uncovering hidden assembly artifacts: when unitigs are not safe and bidirected graphs are not helpful
Authors: Rahman Amatur , Medvedev Paul
Published: January 2022

Recent assemblies by the T2T and VGP consortia have achieved significant accuracy but required a tremendous amount of effort and resources. More typical assembly efforts, on the other hand, still suffer both from mis-assemblies (joining sequences that should not be adjacent) and from under-assemblies (not joining sequences that should be adjacent). To better understand the common algorithm-driven causes of these limitations, we investigated the unitig algorithm, which is a core algorithm at the heart of most assemblers. We prove that, contrary to popular belief, even when there are no sequencing errors, unitigs are not always safe (i.e. they are not guaranteed to be substrings of the sequenced genome). We also prove that the unitigs of a bidirected de Bruijn graph are different from those of a doubled de Bruijn graph and, contrary to our expectations, result in under-assembly. Using experimental simulations, we then confirm that these two artifacts exist not only in theory but also in the output of widely used assemblers. In particular, when coverage is low then even error-free data results in unsafe unitigs; also, unitigs may unnecessarily split palindromes in half if special care is not taken. To the best of our knowledge, this paper is the first to theoretically predict the existence of these assembler artifacts and confirm and measure the extent of their occurrence in practice.
Development and validation of Arc nanobodies: new tools for probing Arc dynamics and function
Authors: Ishizuka Yuta , Mergiya Tadiwos F. , Baldinotti Rodolfo , Xu Ju , Hallin Erik I. , Markússon Sigurbjörn , Kursula Petri , Bramham Clive R.
Published: January 2022

Activity-regulated cytoskeleton-associated (Arc) protein plays key roles in long-term synaptic plasticity, memory, and cognitive flexibility. However, an integral understanding of Arc mechanisms is lacking. Arc is proposed to function as an interaction hub in neuronal dendrites and the nucleus, yet Arc can also form retrovirus-like capsids with proposed roles in intercellular communication. Here, we sought to develop anti-Arc nanobodies (ArcNbs) as new tools for probing Arc dynamics and function. Six ArcNbs representing different clonal lines were selected from immunized alpaca. Immunoblotting with recombinant ArcNbs fused to a small ALFA-epitope tag demonstrated binding to recombinant Arc as well as endogenous Arc from rat cortical tissue. ALFA-ArcNb also provided efficient immunoprecipitation of stimulus-induced Arc after carbachol-treatment of SH-SY5Y neuroblastoma cells and induction of long-term potentiation in the rat dentate gyrus in vivo. Epitope mapping showed that all Nbs recognize the Arc C-terminal region containing the retroviral Gag capsid homology domain, comprised of tandem N-and C-lobes. ArcNbs E5 and H11 selectively bound the N-lobe, which harbors a peptide ligand binding pocket specific to mammals. Four additional ArcNbs bound the region containing the C-lobe and terminal tail. For use as genetically encoded fluorescent intrabodies, we show that ArcNbs fused to mScarlet-I are uniformly expressed, without aggregation, in the cytoplasm and nucleus of HEK293FT cells. Finally, mScarlet-I-ArcNb H11 expressed as intrabody selectively bound the N-lobe and enabled co-immunoprecipitation of full-length intracellular Arc. ArcNbs are versatile tools for live-cell labeling and purification of Arc and analysis of capsid domain specific functions.
Computational modeling of the evolutionary transition from C3 to C4 photosynthesis
Authors: Dadras Armin , Marashi Sayed-Amir , Kavousi Kaveh , Banaei-Moghaddam Ali-Mohammad
Published: January 2022

C4 photosynthesis is an evolutionary adaptation that minimizes the adverse effects of the high photorespiration rate. Although it is widely accepted that the C4 plants are evolved from C3 ancestors, the knowledge about the details of this process is yet to be complete. One application of constraint-based metabolic network modeling is to simulate evolutionary trajectories that an organism endures under a certain selective pressure. However, this approach is barely used to predict the evolution of a complex trait in eukaryotes. Here, we utilized a genetic algorithm combined with a constraint-based metabolic network model of Arabidopsis thaliana to simulate the trajectories of C3 to C4 conversion under high photorespiration rate conditions combined with different environmental conditions. Our modeling predicted that the C3-C4 intermediates and C4 strategies are superior to C3 photosynthesis in these environmental conditions. Besides, resource scarcities drive different evolutionary trajectories toward the emergence of C4 photosynthesis.

AUTHOR SUMMARY

It is estimated that high photorespiration reduces C3 crops productivity up to 50% [1]. Carbon concentrating mechanisms have evolved in many plants to overcome adverse effects of high photorespiration rate in especial environments. C4 photosynthesis is one of these adaptations that separate carbon assimilation reactions spatially between mesophyll and bundle sheath cells of the leaves. It is reported that C4 photosynthesis is evolved more than 65 times in 19 different families of angiosperms independently from C3 ancestors. Therefore, it is hypothesized that the potential modules, at the level of metabolism, anatomy, and gene regulation, which are needed to perform C4 photosynthesis are present in C3 plants. Since C4 plants grow better than C3 plants in hot and dry environments, scientists are working on converting C3 crops such as rice to C4 plants. However, several challenges, including a lack of understanding of the evolutionary paths toward manifestation of C4 trait, have hampered the C3-to-C4 engineering ([2]). Here, we used a metabolic network model of Arabidopsis thaliana as a C3 model plant and attempted to understand the possible evolutionary events leading to emerging of C4 photosynthesis in various scenarios and examined the results.
Outbreak.info Research Library: A standardized, searchable platform to discover and explore COVID-19 resources
Authors: Tsueng Ginger , Mullen Julia L. , Alkuzweny Manar , Cano Marco , Rush Benjamin , Haag Emily ,   Outbreak Curators, Lin Jason , Welzel Dylan J. , Zhou Xinghua , Qian Zhongchao , Latif Alaa Abdel , Hufbauer Emory , Zeller Mark , Andersen Kristian G. , Wu Chunlei , Su Andrew I. , Gangavarapu Karthik , Hughes Laura D.
Published: January 2022

To combat the ongoing COVID-19 pandemic, scientists have been conducting research at breakneck speeds, producing over 52,000 peer-reviewed articles within the first year. To address the challenge in tracking the vast amount of new research located in separate repositories, we developedoutbreak.infoResearch Library, a standardized, searchable interface of COVID-19 and SARS-CoV-2 resources. Unifying metadata from sixteen repositories, we assembled a collection of over 350,000 publications, clinical trials, datasets, protocols, and other resources as of October 2022. We used a rigorous schema to enforce consistency across different sources and resource types and linked related resources. Researchers can quickly search the latest research across data repositories, regardless of resource type or repository location, via a search interface, public API, and R package. Finally, we discuss the challenges inherent in combining metadata from scattered and heterogeneous resources and provide recommendations to streamline this process to aid scientific research.
Development and characterization of a human model of arteriovenous malformation (AVM)-on-a-chip
Authors: Soon Kayla , Li Mengyuan , Wu Ruilin , Turner Williamson D. , Wythe Joshua D. , Fish Jason E. , Nunes Sara S
Published: January 2022

Brain arteriovenous malformations (AVMs) are a disorder wherein abnormal, enlarged blood vessels connect arteries directly to veins, without an intervening capillary bed. AVMs are one of the leading causes of hemorrhagic stroke in children and young adults. Most human sporadic brain AVMs are associated with genetic activating mutations in the KRAS gene. Our goal was to develop an in vitro model that would allow for simultaneous morphological and functional phenotypic data capture in real time during AVM disease progression. By generating human endothelial cells harboring a clinically relevant mutation found in most human patients (activating mutations within the small GTPase KRAS) and seeding them in a dynamic microfluidic cell culture system that enables vessel formation and perfusion, we demonstrate that vessels formed by KRAS4AG12V mutant endothelial cells (ECs) were significantly wider and more leaky than vascular beds formed by wild-type ECs, recapitulating key structural and functional hallmarks of human AVM pathogenesis. Immunofluorescence staining revealed a breakdown of adherens junctions in mutant KRAS vessels only, leading to increased vascular permeability, a hallmark of hemorrhagic stroke. Finally, pharmacological blockade of MEK kinase activity, but not PI3K inhibition, improved endothelial barrier function (decreased permeability) without affecting vessel diameter. Collectively, our studies describe the creation of human KRAS-dependent AVM-like vessels in vitro in a self-assembling microvessel platform that is amenable to phenotypic observation and drug delivery.
Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank
Authors: Green Harry D , Merriel Samuel WD , Oram Richard A , Ruth Katherine S , Tyrrell Jessica , Jones Samuel E , Thirlwell Chrissie , Gillings Mireille , Weedon Michael N , Bailey Sarah ER
Published: January 2022

Objectives

To assess how accurately a genetic risk score (GRS) can identify incident prostate cancer in men seeing their general practitioner with lower urinary tract symptoms.

Design

Cohort study.

Setting

UK Biobank data linked to primary care records.

Participants

Men registered with the UK Biobank, eligible for the primary care data linkage, with a record showing that they consulted their general practitioner with lower urinary tract symptoms (LUTS) that could indicate possible undiagnosed prostate cancer.

Main outcome measures

A diagnosis of prostate cancer within two years of the patient’s first consultation with their general practitioner for LUTS.

Results

A GRS is associated with prostate cancer in men with symptoms (OR=2.54 [2.16 to 2.99] p=5e-29). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer with an AUC of 0.768 (0.739 to 0.796). Men aged 40 years and under in the bottom four GRS quintiles, aged 50 years and under in the bottom two GRS quintiles, and aged 50 to 60 years in the bottom GRS quintile had a two-year prostate cancer incidence below 1%, despite the presence of symptoms. The negative predictive value of the combined model exceeded 99%.

Conclusions

This study is the first to apply a genetic risk score in a clinical setting to improve the triage of men with symptoms of prostate cancer. It demonstrates the added benefit of incorporating an estimate of genetic risk of prostate cancer into the clinical assessment of symptomatic men in primary care. Assessment of prostate cancer risk in men with LUTS is currently based on presenting clinical features alone. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, with adequate safety netting, whilst those identified with the greatest risk could be fast-tracked for further investigation.
Multi-trait selection to build resilience in conifer forests: a case study on spruce-shoot weevil interactions
Authors: Klápště Jaroslav , Jaquish Barry , Porth Ilga
Published: January 2022

Tree planting programs now need to consider climate change increasingly, therefore, the resistance to pests plays an essential role in enabling tree adaptation to new ranges through tree population movement. The weevil Pissodes strobi (Peck) is a major pest of spruces and substantially reduces lumber quality. We revisited a large Interior spruce provenance/progeny trial (2,964 genotypes, 42 families) of varying susceptibility, established in British Columbia. We employed multivariate mixed linear models to estimate covariances between, and genetic control of, juvenile height growth and resistance traits. We performed linear regressions and ordinal logistic regressions to test for impact of parental origin on growth and susceptibility to the pest, respectively. A significant environmental component affected the correlations between resistance and height, with outcomes dependent on families. Parents sourced from above 950 m a.s.l. elevation negatively influenced host resistance to attacks, probably due to higher P. engelmannii proportion. For the genetic contribution of parents sourced from above 1,200 m a.s.l., however, we found less attack severity, probably due to a marked mismatch in phenologies. This clearly highlights that hybrid status might be a good predictor for weevil attacks and delineates the boundaries of successful spruce population movement. Families resulting from crossing susceptible with resistant parents generally showed fast-growing trees were the least affected by weevil attacks. Such results indicate that these “hybrids” might be genetically better equipped with an optimized resource allocation between defence and growth and might provide the solution for concurrent improvement in resistance against weevil attacks, whilst maintaining tree productivity.
Global and local redistribution of somatic mutations enable the prediction of functional XPD mutations in bladder cancer
Authors: Barbour Jayne A. , Ou Tong , Fang Hu , Yue Noel C. , Zhu Xiaoqiang , Wong-Brown Michelle W. , Yang Haocheng , Wong Yuen T. , Bowden Nikola A. , Wu Song , Wong Jason W. H.
Published: January 2022

Xeroderma pigmentosum group D (XPD) is a DNA helicase with critical functions in transcription initiation and nucleotide excision repair. Missense mutations in XPD are putative drivers in around 10% of bladder cancers (BLCA), but the associated mutational process remains poorly understood. Here, we examine the somatic mutational landscape of XPD wild-type (n=343) and mutant (n=39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in XPD mutants, affecting both APOBEC and non-APOBEC associated mutational processes. Specifically, XPD mutants are enriched in T[C>T]N mutations (SBS2) with altered correlation with replication timing. At a locoregional genomic level, mutant XPD BLCA had striking T>G mutation hotspots at CTCF-cohesin binding sites (CBS) with evidence linking XPD to genomic uracil repair. Leveraging differential distribution of somatic mutations, we developed a machine-learning model for predicting pathogenic XPD mutations, which we validated in an independent TCGA cohort with 100% accuracy. Our model enabled the discovery of missed XPD mutation calls and uncovered pathogenic non-hotspot XPD mutations in bladder cancer. Our study reveals how XPD mutations redistribute somatic mutations in cancer genomes and provides a genome sequencing approach to differentiate driver and passenger XPD mutations.
Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors
Authors: Duan Jia , Shen Dan-Dan , Zhao Tingting , Guo Shimeng , He Xinheng , Yin Wanchao , Xu Peiyu , Ji Yujie , Chen Li-Nan , Liu Jinyu , Zhang Huibing , Liu Qiufeng , Shi Yi , Cheng Xi , Jiang Hualiang , Eric Xu H. , Zhang Yan , Xie Xin , Jiang Yi
Published: January 2022

Peptide hormones and neuropeptides are complex signaling molecules that predominately function through G protein-coupled receptors (GPCRs). Two fundamental questions remained in the field of peptide-GPCR signaling systems are the basis for the diverse binding mode of peptide ligands and the specificity of G protein coupling. Here we report the structures of a neuropeptide, galanin, bound to its receptors, GAL1R and GAL2R, in complex with their primary G protein subtypes Giand Gq, respectively. The structures reveal a unique binding pose of galanin, which almost ‘lay flat’ on the top of the receptor transmembrane domain pocket in an α-helical conformation, and acts as an ‘allosteric-like’ agonist via a distinct signal transduction cascade. The structures also uncover the important features of intracellular loop 2 (ICL2) that mediate specific interactions with Gq, thus determining the selective coupling of Gqto GAL2R. ICL2 replacement in Gi-coupled GAL1R, μOR, 5-HT1AR, and Gs-coupled b2AR and D1R with that of GAL2R promotes Gqcoupling of these receptors, highlighting the dominant roles of ICL2 in Gqselectivity. Together our results provide important insights into peptide ligand recognition and allosteric activation of galanin receptors and uncover a general structural element for Gqcoupling selectivity.
Salesperson’s spiritual response to job burnout: the role of karma and the moderating impact of thought self-leadership
Authors: Singh Ramendra , Singh Rakesh Kumar , Shukla Keerti
Published: January 2022

Purpose

In this conceptual paper, anchoring on the Hindu philosophical doctrine of karma, this study models the impact of salesperson’s karma orientation (KO) (a relatively new construct), in alleviating his/her job burnout. This study also explores the moderating impact of thought self-leadership (TSL).

Design/methodology/approach

This study theorizes the impact of KO on salesperson’s burnout by integrating the job demand–resource model with spirituality and TSL literatures.

Findings

Using multi-dimensional construct of KO, this study proposes several research propositions to theorize the impact of each of the four dimensions (i.e. work as selfless action, work as duty towards others, detachment from work-related rewards and equanimity under environmental influences) on three aspects of job burnout (i.e. emotional exhaustion, depersonalization and reduced personal accomplishment). Additionally, this study also theorizes the moderating impact of TSL on the above-mentioned relationships.

Practical implications

Organizations can adopt the karma doctrine for designing new sales jobs that provide higher meaningfulness and a greater sense of purpose to their salespeople, going beyond extrinsic rewards such as money. Higher KO among the business to business salespersons would lead them to derive higher intrinsic motivation to make karmic investments with their customers knowing that their good deeds with customers would eventually lead to good rewards for themselves, reducing their burnout, while also enhancing their well-being.

Originality/value

The paper makes an original theoretical contribution by theorizing the impact of Hindu philosophy of karma on salesperson’s job burnout, and hence well-being and eventual impact on organizational effectiveness.
Mechanisms of dietary resource partitioning in large‐herbivore assemblages: A plant‐trait‐based approach
Authors: Potter Arjun B. , Hutchinson Matthew C. , Pansu Johan , Wursten Bart , Long Ryan A. , Levine Jonathan M. , Pringle Robert M.
Published: January 2022

Sympatric large mammalian herbivore species differ in diet composition, both by eating different parts of the same plant and by eating different plant species. Various theories proposed to explain these differences are not mutually exclusive, but are difficult to reconcile and confront with data. Moreover, whereas several of these ideas were originally developed with reference to within‐plant partitioning (i.e. consumption of different tissues), they may analogously apply to partitioning of plant species; this possibility has received little attention.

Plant functional traits provide a novel window into herbivore diets and a means of testing multiple hypotheses in a unified framework. We used DNA metabarcoding to characterize the diets of 14 sympatric large‐herbivore species in an African savanna and analysed diet composition in light of 27 functional traits that we measured locally for 204 plant species.

Plant traits associated with the deep phylogenetic split between grasses and eudicots formed the primary axis of resource partitioning, affirming the generality and importance of the grazer–browser spectrum. A secondary axis comprised plant traits relevant to herbivore body size. Plant taxa in the diets of large‐bodied species were lower on average in digestible energy and protein, taller on average (especially among grazers), and tended to be higher in tensile strength, zinc, stem‐specific density, and potassium (and lower in sodium, stem dry matter content, and copper). These results are consistent with longstanding hypotheses linking body size with forage quality and height, yet they also suggest the existence of undiscovered links between herbivore body size and a set of rarely considered food–plant traits. We also tested the novel hypothesis that the leaf economic spectrum (LES), a major focus in plant ecology, is an axis of resource partitioning in large‐herbivore assemblages; we found that the LES was a minor axis of individual variation within a few species, but had little effect on interspecific dietary differentiation.

Synthesis. These results identify key plant traits that underpin the partitioning of food–plant species in large‐herbivore communities and suggest that accounting for multiple plant traits (and trade‐offs among them) will enable a deeper understanding of herbivore–plant interaction networks.
Functional traits predict species responses to environmental variation in a California grassland annual plant community
Authors: Kandlikar Gaurav S. , Kleinhesselink Andrew R. , Kraft Nathan J. B.
Published: January 2022

Turnover in species composition and the dominant functional strategies in plant communities across environmental gradients is a common pattern across biomes, and is often assumed to reflect shifts in trait optima. However, the extent to which community‐wide trait turnover patterns reflect changes in how plant traits affect the vital rates that ultimately determine fitness remain unclear.

We tested whether shifts in the community‐weighted means of four key functional traits across an environmental gradient in a southern California grassland reflect variation in how these traits affect species' germination and fecundity across the landscape.

We asked whether models that included trait–environment interactions help explain variation in two key vital rates (germination rates and fecundity), as well as an integrative measure of fitness incorporating both vital rates (the product of germination rate and fecundity). To do so, we planted seeds of 17 annual plant species at 16 sites in cleared patches with no competitors, and quantified the lifetime seed production of 1360 individuals. We also measured community composition and a variety of abiotic variables across the same sites. This allowed us to evaluate whether observed shifts in community‐weighted mean traits matched the direction of any trait–environment interactions detected in the plant performance experiment.

We found that commonly measured plant functional traits do help explain variation in species responses to the environment—for example, high‐SLA species had a demographic advantage (higher germination rates and fecundity) in sites with high soil Ca:Mg levels, while low‐SLA species had an advantage in low Ca:Mg soils. We also found that shifts in community‐weighted mean traits often reflect the direction of these trait–environment interactions, though not all trait–environment relationships at the community level reflect changes in optimal trait values across these gradients.

Synthesis. Our results show how shifts in trait–fitness relationships can give rise to turnover in plant phenotypes across environmental gradients, a fundamental pattern in ecology. We highlight the value of plant functional traits in predicting species responses to environmental variation, and emphasise the need for more widespread study of trait–performance relationships to improve predictions of community responses to global change.
Stakeholder perspectives of the sociotechnical requirements of a telehealth wheelchair assessment service in Aotearoa/New Zealand: A qualitative analysis
Authors: Graham Fiona , Boland Pauline , Jones Bernadette , Wallace Sally , Taylor William , Desha Laura , Maggo Jasjot , McKerchar Christina , Grainger Rebecca
Published: January 2022

Introduction

Telehealth is widely proposed to improve access and equity in provision of rehabilitation, including wheelchair assessment, yet the design requirements of telehealth wheelchair assessment that will be accepted and utilised at scale are unclear. Service design that addresses the existing inequities in outcomes for indigenous populations, such as Māori will be critical. The aim of this study was to examine the design requirements of a telehealth wheelchair assessment service from the perspectives of key stakeholders such as wheelchair users and their families, including indigenous (Māori) and health professionals including occupational therapist, and physiotherapist assessors and technicians.

Methods

Within a wider mixed methods design, inductive thematic analysis was applied to focus group and interview data from 23 assessors (19 occupational therapists and four physiotherapist assessors, one of whom was Māori) and 19 wheelchair users (three of whom were Māori).

Results

Eight themes were discerned with the final three themes emphasising the experiences of particular concern to Māori: (1) At the mercy of the system; (2) The hurdle of technology; (3) More efficient for all; (4) Lost information and connection; (5) Rights and the right way forward; (6) Cultural safety; (7) Whanaungatanga (relationship building); and (8) Summative disadvantage for Tāngata whaikaha (Māori with disabilities). Themes reflected a recognition of risks and uncertainty associated with tele‐delivered assessment. Conversely, advantages in access, equity, and professional competency were reimagined. Perspectives of Māori included both risks and advantages as perceived by Māori.

Conclusion

Substantial dissatisfaction with current wheelchair assessment services among wheelchair users provides context to the impetus for a successful design of a telehealth assessment service. Training in conducting telehealth wheelchair assessment is essential incorporating culturally safe communication practices and support of wheelchair user autonomy while identifying solutions that achieve wheelchair user goals.
Institutional solutions addressing disparities in compensation and advancement of emergency medicine physicians: A critical appraisal of gaps and associated recommendations
Authors: Madsen Tracy E. , Heron Sheryl , Lall Michelle D. , Blomkalns Andra , Arbelaez Christian , Lopez Bernard , Lin Michelle , Rounds Kirsten , Sethuraman Kinjal N. , Safdar Basmah
Published: January 2022

Background

Disparities in salary and advancement of emergency medicine (EM) faculty by race and gender have been consistently demonstrated for over three decades. Prior studies have largely focused on individual‐level solutions. To identify systems‐based interventions, the Society for Academic Emergency Medicine (SAEM) formed the Research Equity Task Force in 2018 with members from multiple academies (the Academy of Academic Chairs in Emergency Medicine [AACEM], the Academy of Academic Administrators in Emergency Medicine [AAAEM], the Academy for Women in Academic Emergency Medicine [AWAEM], and the Academy for Diversity and Inclusion in Emergency Medicine [ADIEM]) and sought recommendations from EM departmental leaders.

Methods

The task force conducted interviews containing both open‐ended narrative and closed‐ended questions in multiple phases. Phase 1 included a convenience sample of chairs of EM departments across the United States, and phase 2 included vice‐chairs and other faculty who lead promotion and advancement. The task force identified common themes from the interviews and then developed three‐tiered sets of recommendations (minimal, target, and aspirational) based on participant responses. In phase 3, iterative feedback was collected and implemented on these recommendations from study participants and chairs participating in a national AACEM webinar.

Results

In findings from 53 interviews of chairs, vice‐chairs, and faculty leaders from across the United States, we noted heterogeneity in the faculty development and promotion processes across institutions. Four main themes were identified from the interviews: the need for a directed, structured promotion process; provision of structured mentorship; clarity on requirements for promotion within tracks; and transparency in salary structure. Recommendations were developed to address gaps in structured mentorship and equitable promotion and compensation.

Conclusions

These recommendations for AEM departments have the potential to increase structured mentorship programs, improve equity in promotion and advancement, and reduce disparities in the AEM workforce. These recommendations have been endorsed by SAEM, AACEM, AWAEM, ADIEM, and AAAEM.
Immunomodulator FTY720 improves glucose homeostasis and diabetic complications by rejuvenation of β‐cell function in nonhuman primate model of diabetes
Authors: Wang Yixin (Jim) , Wang Xiaoli , An Annie , Zang Mingfa , Xu Ling , Gong Kefeng , Song Weihua , Li Qing , Lu Xiaojun , Xiao Yong‐Fu , Yu Guoliang , Ma Zhongmin A.
Published: January 2022

Inadequate β‐cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1‐phosphate (S1P) receptor modulator, sustainably normalized hyperglycemia by stimulating β‐cell in vivo regeneration in db/db mice. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes. The male diabetic cynomolgus macaques of 18–19 year old were randomly divided into Vehicle (Purified water, n = 5) and FTY720 (5 mg/kg, n = 7) groups with oral gavage once daily for 10 weeks followed by 10 weeks drug free period. Compared with the Vehicle group, FTY720 effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA‐IR); ameliorated glucose intolerance and restored glucose‐stimulated insulin release, indicating rejuvenation of β‐cell function in diabetic NHPs. Importantly, after withdrawal of FTY720, FBG, and HbA1c remained at low level in the drug free period. Echocardiography revealed that FTY720 significantly reduced proteinuria and improved cardiac left ventricular systolic function measured by increased ejection fraction and fractional shortening in the diabetic NHPs. Finally, flow cytometry analysis (FACS) detected that FTY720 significantly reduced CD4 + and CD8 + T lymphocytes as well as increased DC cells in the circulation. Immunomodulator FTY720 improves glucose homeostasis via rejuvenation of β‐cell function, which can be mediated by suppression of cytotoxic CD8 + T lymphocytes to β‐cells, thus, may be a novel immunotherapy to reverse T2D progression and ameliorate the diabetic complications.