bluuebunny/crossref_metadata_2025 huggingface dataset:
The multiple fates of gene duplications: Deletion, hypofunctionalization, subfunctionalization, neofunctionalization, dosage balance constraints, and neutral variation
Authors: Birchler James A , Yang Hua
Published: March 2022

Gene duplications have long been recognized as a contributor to the evolution of genes with new functions. Multiple copies of genes can result from tandem duplication, from transposition to new chromosomes, or from whole-genome duplication (polyploidy). The most common fate is that one member of the pair is deleted to return the gene to the singleton state. Other paths involve the reduced expression of both copies (hypofunctionalization) that are held in duplicate to maintain sufficient quantity of function. The two copies can split functions (subfunctionalization) or can diverge to generate a new function (neofunctionalization). Retention of duplicates resulting from doubling of the whole genome occurs for genes involved with multicomponent interactions such as transcription factors and signal transduction components. In contrast, these classes of genes are underrepresented in small segmental duplications. This complementary pattern suggests that the balance of interactors affects the fate of the duplicate pair. We discuss the different mechanisms that maintain duplicated genes, which may change over time and intersect.
Embryonic reactivation of FLOWERING LOCUS C by ABSCISIC ACID-INSENSITIVE 3 establishes the vernalization requirement in each Arabidopsis generation
Authors: Xu Guokai , Tao Zeng , He Yuehui
Published: March 2022

Many over-wintering plants grown in temperate climate acquire competence to flower upon prolonged cold exposure in winter, through vernalization. In Arabidopsis thaliana, prolonged cold exposure induces the silencing of the potent floral repressor FLOWERING LOCUS C (FLC) through repressive chromatin modifications by Polycomb proteins. This repression is maintained to enable flowering after return to warmth, but is reset during seed development. Here, we show that embryonic FLC reactivation occurs in two phases: resetting of cold-induced FLC silencing during embryogenesis and further FLC activation during embryo maturation. We found that the B3 transcription factor (TF) ABSCISIC ACID-INSENSITIVE 3 (ABI3) mediates both FLC resetting in embryogenesis and further activation of FLC expression in embryo maturation. ABI3 binds to the cis-acting cold memory element at FLC and recruits a scaffold protein with active chromatin modifiers to reset FLC chromatin into an active state in late embryogenesis. Moreover, in response to abscisic acid (ABA) accumulation during embryo maturation, ABI3, together with the basic leucine zipper TF ABI5, binds to an ABA-responsive cis-element to further activate FLC expression to high level. Therefore, we have uncovered the molecular circuitries underlying embryonic FLC reactivation following parental vernalization, which ensures that each generation must experience winter cold prior to flowering.
RiceSTOMATAL CYTOKINESIS DEFECTIVE2regulates cell expansion by affecting vesicular trafficking in rice
Authors: Wang Fan , Cheng Zhijun , Wang Jiachang , Zhang Feng , Zhang Baocai , Luo Sheng , Lei Cailin , Pan Tian , Wang Yongfei , Zhu Yun , Wang Min , Chen Weiwei , Lin Qibing , Zhu Shanshan , Zhou Yihua , Zhao Zhichao , Wang Jie , Guo Xiuping , Zhang Xin , Jiang Ling , Bao Yiqun , Ren Yulong , Wan Jianmin
Published: March 2022

Vesicular trafficking plays critical roles in cell expansion in yeast and mammals, but information linking vesicular trafficking and cell expansion in plants is limited. Here, we isolated and characterized a rice (Oryza sativa) mutant, decreased plant height 1-1 (dph1-1), which exhibited a wide spectrum of developmental phenotypes, including reduced plant height and smaller panicles and grains. Cytological analysis revealed that limited cell expansion was responsible for the dph1-1 mutant phenotype compared to the wild-type. Map-based cloning revealed that DPH1 encodes a plant-specific protein, OsSCD2, which is homologous to Arabidopsis (Arabidopsis thaliana) STOMATAL CYTOKINESIS DEFECTIVE2 (SCD2). Subcellular localization revealed that OsSCD2 is associated with clathrin. Confocal microscopy showed that the dph1-1 mutant has defective endocytosis and post-Golgi trafficking. Biochemical and confocal data indicated that OsSCD2 physically interacts with OsSCD1 and that they are associated with intracellular structures that colocalize with microtubules. Furthermore, we found that cellulose synthesis was affected in the dph1-1 mutant, evidenced by reduced cellulose synthase gene accumulation at the transcript and protein levels, most likely resulting from an impaired localization pattern. Our results suggest that OsSCD2 is involved in clathrin-related vesicular trafficking with an important role in maintaining plant growth in rice.
Patient preferences for the treatment of systemic sclerosis-associated interstitial lung disease: a discrete choice experiment
Authors: Bruni Cosimo , Heidenreich Sebastian , Duenas Ashley , Hoffmann-Vold Anna-Maria , Gabrielli Armando , Allanore Yannick , Chatelus Emmanuel , Distler Jörg H W , Hachulla Eric , Hsu Vivien M , Hunzelmann Nicolas , Khanna Dinesh , Truchetet Marie-Elise , Walker Ulrich A , Alves Margarida , Schoof Nils , Saketkoo Lesley Ann , Distler Oliver
Published: March 2022

Objectives

Treatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes.

Methods

Seven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated.

Results

Overall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6–12 monthly infusions. Patients’ choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions’ frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections.

Conclusions

This is the first study to quantitatively elicit patients’ preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice.
Comparison of the toxic effects of organic and inorganic arsenic in Caenorhabditis elegans using a multigenerational approach
Authors: Müller Larissa , Soares Gabriela Corrêa , Josende Marcelo Estrella , Monserrat José Maria , Ventura-Lima Juliane
Published: March 2022

Although arsenic (As) is a persistent contaminant in the environment, few studies have assessed its effects over generations, as it requires an animal model with a short lifespan and rapid development, such as the nematode Caenorhabditis elegans. Furthermore, few studies have evaluated the effects of As metabolites such as dimethylarsinic acid (DMAV), and several authors have considered DMA as a moderately toxic intermediate of As, although recent studies have shown that this chemical form can be more toxic than inorganic arsenic (iAs) even at low concentrations. In the present study, we compared the toxic effects of arsenate (AsV) and DMAV in C. elegans over 5 subsequent generations. We evaluated biochemical parameters such as reactive oxygen species (ROS) concentration, the activity of antioxidant defense system (ADS) enzymes such as catalase (CAT) and glutathione-S-transferase (GST), and nonenzymatic components of ADS such as reduced glutathione (GSH) and protein-sulfhydryl groups (P-SH). Exposure to 50 μg L−1 of AsV led to an increase in ROS generation and GSH levels together with a decrease in GST activity, while exposure to DMAV led to an increase in ROS levels, with an increase in lipid peroxidation, CAT activity, and a decrease in GSH levels. In addition, both treatments reduced animal growth from the third generation onward and caused disturbances in their reproduction throughout all 5 generations. This study shows that the accumulated effects of DMA need to be considered; it highlights the importance of this type of multigenerational approach for evaluating the effects of organic contaminants considered low or nontoxic.
Radon-222 Brain Dosimetry
Authors: Harley Naomi H. , Robbins Edith S.
Published: March 2022

The human brain dose from radon-222 (222Rn) exposure is calculated here using 222Rn tissue solubility data. A fraction of 222Rn inhaled dissolves in blood and cellular fluids and circulates to brain and all organs. Radon-222 has a relatively high solubility in blood and body fluids based on human inhalation experiments. The brain dose uses calculated concentrations of 222Rn in blood and cellular fluids from exhaled breath measurements following human exposure in a 222Rn chamber. The annual brain dose from continuous inhalation of a concentration of 100 Bq m−3 is about 450 times less than the dose to bronchial epithelium from inhalation of the same 222Rn concentration. Based on the 222Rn dosimetry here, it is highly unlikely that brain cancer is related to even high 222Rn exposures. Any functional or neurodegenerative issues from exposure to very small doses of 222Rn alpha particles are, at present, unknown.
Improving the Discharge Experience of Hospital Patients Through Standard Tools and Methods of Education
Authors: Thum Andrew , Ackermann Lily , Edger Mary Beth , Riggio Jeffrey
Published: March 2022

Discharge education is essential to patient health and care coordination. Patient satisfaction with discharge education reveals a hospital's ability to provide reliable, quality experiences that engage and prepare patients for recovery in the community. The purpose of this study was to examine and improve patient satisfaction with discharge preparation by providing timely, standardized methods of educating patients about their medical condition, discharge needs, and follow-up care. This project provided nursing and the care team with training in effective techniques such as the teach-back method as well as new tools like a discharge folder to be successful. Provider workflows were redesigned, and the discharge education document was changed to ensure appropriate information was provided to patients. Patient perspective and satisfaction with their degree of preparedness for discharge were measured using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. After intervention, an improvement in the HCAHPS survey top box percent score for the domains of Care Transitions, 52.41%–54.49% (p < .0001) and Discharge Information, 87.38–90.12% (p < .0001), was noted. Increasing scores for HCAHPS questions pertinent to discharge suggest the intervention improved patient satisfaction with discharge information and preparation for recovery outside the hospital.
Fluidized Positioner to Prevent Occipital Pressure Injury
Authors: Byfield Donna
Published: March 2022

PURPOSE:

The purpose of this quality improvement project was to determine if head immobilization, pressure redistribution for the occiput, and offloading of pressure from craniotomy incisions could be improved by utilizing fluidized positioners instead of pillows previously used as the standard of care. The second purpose was to determine cost savings for the organization.

PARTICIPANTS AND SETTING:

Eight patients with head trauma and craniotomy in a surgical intensive care unit (SICU) and cardiovascular intensive care unit (CVICU) from a level 1 trauma center in the Southeast region of the United States participated over a 6-month period.

APPROACH:

The project comprised educating staff including nurses, nursing assistants, supervisors, and care managers, and implementation of the head positioner from July 2018 to December 2018. Staff from the SICU and CVICU, a step-down unit, and a neurological ICU were also educated on the fluidized positioner, because patients were transferred to these units when stable. All patients who underwent craniotomy surgery were placed on the fluidized positioner postoperatively until immobilization and offloading were no longer required.

OUTCOME:

During the initial 6-month evaluation period, no new pressure injuries or incisional trauma occurred in the 8 patients. The economic impact to treat one hospital-acquired unstageable pressure injury was estimated at $78,722. Because no new occipital pressure injuries occurred in the 8 patients placed on the fluidized head positioner, the hospital potentially saved $629,776.

IMPLICATION FOR PRACTICE:

Findings from the project suggest that implementation of a fluidized positioner can redistribute pressure to the occiput, offload craniotomy incision sites, and prevent pressure injuries.
A high-quality reference genome for the fish pathogen Streptococcus iniae
Authors: Alsheikh-Hussain Areej S. , Ben Zakour Nouri L. , Forde Brian M. , Rudenko Oleksandra , Barnes Andrew C. , Beatson Scott A.
Published: March 2022

Fish mortality caused by

Streptococcus iniae

is a major economic problem in aquaculture in warm and temperate regions globally. There is also risk of zoonotic infection by

S. iniae

through handling of contaminated fish. In this study, we present the complete genome sequence of

S. iniae

strain QMA0248, isolated from farmed barramundi in South Australia. The 2.12 Mb genome of

S. iniae

QMA0248 carries a 32 kb prophage, a 12 kb genomic island and 92 discrete insertion sequence (IS) elements. These include nine novel IS types that belong mostly to the IS3 family. Comparative and phylogenetic analysis between

S. iniae

QMA0248 and publicly available complete

S. iniae

genomes revealed discrepancies that are probably due to misassembly in the genomes of isolates ISET0901 and ISNO. Long-range PCR confirmed five rRNA loci in the PacBio assembly of QMA0248, and, unlike

S. iniae

89353, no tandemly repeated rRNA loci in the consensus genome. However, we found sequence read evidence that the tandem rRNA repeat existed within a subpopulation of the original QMA0248 culture. Subsequent nanopore sequencing revealed that the tandem rRNA repeat was the most prevalent genotype, suggesting that there is selective pressure to maintain fewer rRNA copies under uncertain laboratory conditions. Our study not only highlights assembly problems in existing genomes, but provides a high-quality reference genome for

S. iniae

QMA0248, including manually curated mobile genetic elements, that will assist future

S. iniae

comparative genomic and evolutionary studies.
BA.2 evasion of vaccine induced binding and functional non-neutralizing antibodies
Authors: Bartsch Yannic C , Cizmeci Deniz , Kang Jaewon , Gao Hailong , Shi Wei , Chandrashekar Abishek , Collier Ai-ris Y , Chen Bing , Barouch Dan H , Alter Galit
Published: March 2022

The number of mutations in the omicron (B1.1.529) BA.1 variant of concern (VOC) led to an unprecedented evasion of vaccine induced immunity. However, despite the remarkable rise in global infections, severe disease and death did not increase proportionally, linked to persistent recognition of BA.1 by T cells and non-neutralizing opsonophagocytic antibodies. Yet, the emergence of a new sublineage, BA.2, that is more transmissible compared to BA.1, despite relatively preserved neutralizing antibody responses, has raised the possibility that BA.2 may evade other vaccine induced responses that may be key to protection against infection and disease. Here we comprehensively profiled the BNT162b2 vaccine induced response to several VOCs including the omicron BA.1 and BA.2, after the primary vaccine series, 8 months following vaccination, and after a boost. While vaccine induced immune responses were compromised against both Omicron sublineages, vaccine induced antibody isotype titers, FcγR3a- and FcγR3b-receptor binding levels, and non-neutralizing opsonophagocytic functions were significantly attenuated to the omicron BA.2 Spike compared to the BA.1 lineage. Conversely, FcγR2a and FcγR2b binding was elevated to BA.2 potentially contributing to persistent protection against severity of disease. These data point to an attenuation of particular non-neutralizing antibody properties that may be key to protection against transmission, but the maintenance of others that may continue to confer protection against disease.
Memory Consolidation with Orthogonal Gradients for avoiding Catastrophic Forgetting
Authors: Kanagamani Tamizharasan , Krishnamurthy Rupak , Chakravarthy V. Srinivasa , Ravindran Balaraman , Menon Ramshekhar N.
Published: March 2022

The memory consolidation process enables the accumulation of recent and remote memories in the long-term memory store. In general, the deep network models of memory suffer from forgetting old information while learning new information, called catastrophic forgetting/interference. The human brain overcomes this problem quite effectively, a problem that continues to challenge current deep neural network models.

We propose a regularization-based model to solve the problem of catastrophic forgetting. According to the proposed training mechanism, the network parameters are constrained to vary in a direction orthogonal to the average of the error gradients corresponding to the previous tasks. We also ensure that the constraint used in parameter updating satisfies the locality principle.

The proposed model’s performance is compared with Elastic Weight Consolidation on standard datasets such as permuted MNIST and split MNIST on classification tasks using fully connected networks, and Convolution-based networks. The model performance is also compared to an autoencoder on split MNIST dataset, and to complex core50 dataset on two types of classification tasks with EWC.

The proposed model gives a new view on plasticity at the neuronal level. In the proposed model, the parameter updating is controlled by the neuronal level plasticity rather than synapse level plasticity as in other standard models. The biological plausibility of the proposed model is discussed by linking the extra parameters to synaptic tagging, which represents the state of the synapse involved in Long Term Potentiation (LTP).
Fast and functionally specific cortical thickness changes induced by visual stimulation
Authors: Zaretskaya Natalia , Fink Erik , Arsenovic Ana , Ischebeck Anja
Published: March 2022

Structural characteristics of the human brain serve as important markers of brain development, aging, disease progression and neural plasticity. They are considered stable properties, changing slowly over time. Multiple recent studies reported that structural brain changes measured with MRI may occur much faster than previously thought, within hours or even minutes. The mechanisms behind such fast changes remain unclear, with hemodynamics as one possible explanation. Here we investigated the functional specificity of cortical thickness changes induced by a flickering checkerboard and compared the them to BOLD fMRI activity. We found that checkerboard stimulation led to a significant thickness increase, which was driven by an expansion at the gray-white matter boundary, functionally specific to V1, confined to the retinotopic representation of the checkerboard stimulus, and amounted to 1.3 % or 0.022 mm. Although functional specificity and the effect size of these changes were comparable to those of the BOLD signal in V1, thickness effects were substantially weaker in V3. Furthermore, a comparison of predicted and measured thickness changes for different stimulus timings suggested a slow increase of thickness over time, speaking against a hemodynamic explanation. Altogether, our findings suggest that visual stimulation can induce structural gray matter enlargement measurable with MRI.
Optimization of Neuroprosthetic Vision via End-to-end Deep Reinforcement Learning
Authors: Küçükoğlu Burcu , Rueckauer Bodo , Ahmad Nasir , de Ruyter van Steveninck Jaap , Güçlü Umut , van Gerven Marcel
Published: March 2022

Visual neuroprostheses are a promising approach to restore basic sight in visually impaired people. A major challenge is to condense the sensory information contained in a complex environment into meaningful stimulation patterns at low spatial and temporal resolution. Previous approaches considered task-agnostic feature extractors such as edge detectors or semantic segmentation, which are likely suboptimal for specific tasks in complex dynamic environments. As an alternative approach, we propose to optimize stimulation patterns by end-to-end training of a feature extractor using deep reinforcement learning agents in virtual environments. We present a task-oriented evaluation framework to compare different stimulus generation mechanisms, such as static edge-based and adaptive end-to-end approaches like the one introduced here. Our experiments in Atari games show that stimulation patterns obtained via task-dependent end-to-end optimized reinforcement learning result in equivalent or improved performance compared to fixed feature extractors on high difficulty levels. These findings signify the relevance of adaptive reinforcement learning for neuroprosthetic vision in complex environments.
Efficient Neutralization of SARS-CoV-2 Omicron and Other VOCs by a Broad Spectrum Antibody 8G3
Authors: Ma Hang , Tseng Chien-Te K. , Zong Huifang , Liao Yunji , Ke Yong , Tang Haoneng , Wang Lei , Wang Zhenyu , He Yang , Chang Yunsong , Wang Shusheng , Drelich Aleksandra , Hsu Jason , Tat Vivian , Yuan Yunsheng , Wu Mingyuan , Liu Junjun , Yue Yali , Xu Wenbo , Zhang Xiaoju , Wang Ziqi , Yang Li , Chen Hua , Bian Yanlin , Zhang Baohong , Yin Haiyang , Chen Yi , Zhang En , Zhang Xiaoxiao , Gilly John , Sun Tao , Han Lei , Xie Yueqing , Jiang Hua , Zhu Jianwei
Published: March 2022

Numerous mutations in the spike protein of SARS-CoV-2 B.1.1.529 Omicron variant pose a crisis for antibody-based immunotherapies. The efficacy of emergency use authorized (EUA) antibodies that developed in early SARS-CoV-2 pandemic seems to be in flounder. We tested the Omicron neutralization efficacy of an early B cell antibody repertoire as well as several EUA antibodies in pseudovirus and authentic virus systems. More than half of the antibodies in the repertoire that showed good activity against WA1/2020 previously had completely lost neutralizing activity against Omicron, while antibody 8G3 displayed non-regressive activity. EUA antibodies Etesevimab, Casirivimab, Imdevimab and Bamlanivimab were entirely desensitized by Omicron. Only Sotrovimab targeting the non-ACE2 overlap epitope showed a dramatic decrease activity. Antibody 8G3 efficiently neutralized Omicron in pseudovirus and authentic virus systems. The in vivo results showed that Omicron virus was less virulent than the WA1/2020 strain, but still caused deterioration of health and even death in mice. Treatment with 8G3 quickly cleared virus load of mice. Antibody 8G3 also showed excellent activity against other variants of concern (VOCs), especially more efficient against authentic Delta plus virus. Collectively, our results suggest that neutralizing antibodies with breadth remains broad neutralizing activity in tackling SARS-CoV-2 infection despite the universal evasion from EUA antibodies by Omicron variant.
Pan-cancer proteomic map of 949 human cell lines reveals principles of cancer vulnerabilities
Authors: Gonçalves Emanuel , Poulos Rebecca C , Cai Zhaoxiang , Barthorpe Syd , Manda Srikanth S , Lucas Natasha , Beck Alexandra , Bucio-Noble Daniel , Dausmann Michael , Hall Caitlin , Hecker Michael , Koh Jennifer , Mahboob Sadia , Mali Iman , Morris James , Richardson Laura , Seneviratne Akila J , Sykes Erin , Thomas Frances , Valentini Sara , Williams Steven G , Wu Yangxiu , Xavier Dylan , MacKenzie Karen L , Hains Peter G , Tully Brett , Robinson Phillip J , Zhong Qing , Garnett Mathew J , Reddel Roger R
Published: March 2022

The proteome provides unique insights into biology and disease beyond the genome and transcriptome. Lack of large proteomic datasets has restricted identification of new cancer biomarkers. Here, proteomes of 949 cancer cell lines across 28 tissue types were analyzed by mass spectrometry. Deploying a clinically-relevant workflow to quantify 8,498 proteins, these data capture evidence of cell type and post-transcriptional modifications. Integrating multi-omics, drug response and CRISPR-Cas9 gene essentiality screens with a deep learning-based pipeline revealed thousands of protein-specific biomarkers of cancer vulnerabilities. Proteomic data had greater power to predict drug response than the equivalent portion of the transcriptome. Further, random downsampling to only 1,500 proteins had limited impact on predictive power, consistent with protein networks being highly connected and co-regulated. This pan-cancer proteomic map (ProCan-DepMapSanger), available at https://cellmodelpassports.sanger.ac.uk, is a comprehensive resource revealing principles of protein regulation with important implications for future clinical studies.
Real-world Effectiveness of Casirivimab and Imdevimab in Patients With COVID-19 in the Ambulatory Setting: An Analysis of Two Large US National Claims Databases
Authors: Wei Wenhui , Murdock Dana , Jalbert Jessica J. , Mastey Vera , Sanchez Robert J. , Hirshberg Boaz , Weinreich David M. , Hussein Mohamed
Published: March 2022

Background

In a phase III clinical trial, casirivimab and imdevimab (CAS+IMD) reduced the composite endpoint of COVID-19-related hospitalizations or all-cause mortality in outpatients at risk of severe disease. This study assessed real-world effectiveness of CAS+IMD.

Methods

Data from Optum® Clinformatics® Data Mart (CDM) and IQVIA Pharmetrics Plus (PMTX+) were used to identify patients diagnosed with COVID-19 in ambulatory settings between December 2020 and March 2021 (PMTX+) and June 2021 (CDM), and either treated with CAS+IMD or untreated but treatment-eligible under Emergency Use Authorization. CAS+IMD-treated patients were matched to untreated patients and followed up to 30 days for the outcome of all-cause mortality or COVID-19-related hospitalizations (CDM) and COVID-19-related hospitalizations (PMTX+). Kaplan-Meier estimators were used to calculate outcome risks; Cox proportional-hazard models estimated adjusted hazard ratios (aHR) with 95% confidence intervals (CI).

Results

For CDM, 1116 CAS+IMD-treated patients were matched to 5294 untreated patients; for PMTX+, 3280 CAS+IMD-treated patients were matched to 16,284 untreated patients. The 30-day outcome risk was 2.1% and 5.3% in treated and untreated cohorts, respectively (CDM), and the 30-day risk of COVID-19-related hospitalization was 1.9% and 4.8%, respectively (PMTX+); translating to a 61% lower adjusted outcome risk (CDM aHR 0.39 (95% CI 0.26–0.60; PMTX+ aHR 0.39 (95% CI 0.30–0.51). The benefit of treatment was maintained across multiple subgroups of high-risk patients; earlier intervention was associated with improved outcomes.

Conclusions

This real-world study further supports randomized clinical trial findings that treatment with CAS+IMD reduces the risk of hospitalization and mortality in patients infected with susceptible variants.
Hereditary haemochromatosis beyond liver cancer: increased risk of prostate cancer during an 11-year follow-up
Authors: Atkins Janice L , Pilling Luke C , Torti Suzy V , Torti Frank M , Kuchel George A , Melzer David
Published: March 2022

In European ancestry populations, the iron overload disorder Hereditary Haemochromatosis (HH) is predominantly caused by the HFE p.C282Y mutation. Male p.C282Y homozygotes have markedly increased hepatic malignancy risks but risks for other cancers in both male and female homozygotes are unclear. We studied data from 451,143 UK Biobank European ancestry community participants (aged 40-70 years; 54.3% female) followed for a mean 11.6 years via hospital admission and national cancer registry data. We estimated risks of incident bladder, blood (with sub-analyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, oesophageal, ovarian, pancreatic, prostate and stomach cancers in the 2,890 p.C282Y homozygotes, compared to participants without HFE mutations. Male p.C282Y homozygotes (12.1% with baseline diagnosed HH) had increased risks of prostate cancer (6.8% versus 5.4% without mutations, hazard ratio HR=1.32, 95% CI=1.07-1.63, p=0.01,). In lifetable estimates from ages 40-75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%, 95% CI = 1.3-6.8). There was no excess of studied cancers in female p.C282Y homozygotes, or in p.C282Y/p.H63D compound heterozygotes of either sex. In a large community sample of male p.C282Y homozygotes, there was a 32% increase in prostate cancer risk, in addition to the known increased liver cancer risk. Those reporting HFE genotype status or monitoring p.C282Y homozygous males may need to ensure clinical monitoring for both liver and prostate cancers.

Novelty and impact of the work

Male HFE p.C282Y homozygotes, at risk of iron overload disorder hereditary haemochromatosis, have known increased liver cancer risks. We have shown, for the first time, that the male p.C282Y homozygotes also have a 32% increased risk of prostate cancer; with an excess proportion of 3.8% by age 75 compared to those without mutations. Those reporting HFE genotype status or monitoring p.C282Y homozygous males need to ensure vigilance for both excess liver and prostate cancers.
Knowledge-guided deep learning models of drug toxicity improve interpretation
Authors: Hao Yun , Romano Joseph D. , Moore Jason H.
Published: March 2022

In drug development, a major reason for attrition is the lack of understanding of cellular mechanisms governing drug toxicity. The black-box nature of conventional classification models has limited their utility in identifying toxicity pathways. Here we developed DTox (Deep learning forToxicology), an interpretation framework for knowledge-guided neural networks, which can predict compound response to toxicity assays and infer toxicity pathways of individual compounds. We demonstrate that DTox can achieve the same level of predictive performance as conventional models with a significant improvement in interpretability. Using DTox, we were able to rediscover mechanisms of transcription activation by three nuclear receptors, recapitulate cellular activities induced by aromatase inhibitors and PXR agonists, and differentiate distinctive mechanisms leading to HepG2 cytotoxicity. Virtual screening by DTox revealed that compounds with predicted cytotoxicity are at higher risk for clinical hepatic phenotypes. In summary, DTox provides a framework for deciphering cellular mechanisms of toxicityin silico.
Generating publication ready visualizations for Single Cell transcriptomics using SCpubr
Authors: Blanco-Carmona Enrique
Published: March 2022

Single Cell transcriptomic analysis has become a widespread technology of choice when it comes to understanding the differences at a transcriptomic level in heterogeneous samples. As a consequence, a plethora of analysis tools have been published to tackle the different analysis steps from count matrix generation to downstream analysis. Many of them provide ways to generate visualizations of the data. While some design choices are made, it is a common practice to provide the user with visualizations as raw as possible so that they can be customized to the user needs. However, in many cases these final customization steps are either time consuming or demand a very specific set of skills. This problem is addressed by SCpubr, which sacrifices some of this initial freedom of choice in aesthetics to provide the user a more streamlined way of generating high quality Single Cell transcriptomic visualizations.
Connexin 43-mediated Neurovascular Interactions Regulate Neurogenesis in the Adult Brain Subventricular Zone
Authors: Genet Nafiisha , Genet Gael , Fang Jennifer S. , Chavkin Nicholas W. , Vasavada Hema H. , Goldberg Joshua S. , Acharya Bipul R. , Bhatt Neha , Baker Kasey , McDonnell Stephanie , Huba Mahalia R. , Ma Gerry , Eichmann Anne , Thomas Jean Leon , ffrench-Constant Charles , Hirschi Karen K.
Published: March 2022

The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the SVZ control NSC behavior are unclear. We found Cx43 to be highly expressed by both NSCs and ECs in the SVZ, and its deletion in either cell type leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by in vitro studies showing co-culture with ECs decreases NSC proliferation and increases their expression of genes associated with quiescence in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights further advance our understanding of NSC regulation in vivo and may inform NSC maintenance ex vivo for stem cell therapies for neurodegenerative disorders.
A nepenthesin insert allosterically controls catalysis in the malaria parasite protease plasmepsin V
Authors: Polino Alexander J. , Miller Justin J. , Bhakat Soumendranath , Bobba Suhas , Bowman Gregory R. , Goldberg Daniel E.
Published: March 2022

Plasmepsin V (PM V) is a pepsin-like aspartic protease essential for growth of the malaria parasite Plasmodium falciparum. Previous work has shown PM V to be an ER-resident protease that processes parasite proteins destined for export into the host cell. Depletion or inhibition of the enzyme is lethal during asexual replication within red blood cells, as well as during the formation of sexual stage gametocytes. The structure of the P. vivax PM V has been characterized by x-ray crystallography, revealing a canonical pepsin fold punctuated by structural features uncommon to secretory aspartic proteases. Here we use parasite genetics to probe these structural features by attempting to rescue lethal PM V depletion with various mutant enzymes. We find an unusual nepenthesin 1-type insert to be essential for parasite growth and PM V activity. Mutagenesis of the nepenthesin insert suggests that both its amino acid sequence and one of the two disulfide bonds that undergird its structure are required for the nepenthesin insert’s role in PM V function. Molecular dynamics simulations paired with Markov state modelling suggest that the nepenthesin insert allosterically controls PM V catalysis through multiple mechanisms.
Model Selection in Occupancy Models: Inference versus Prediction
Authors: Stewart Peter S. , Stephens Philip A. , Hill Russell A. , Whittingham Mark J. , Dawson Wayne
Published: March 2022

Occupancy models are a vital tool for applied ecologists studying the patterns and drivers of species occurrence, but their use requires a method for selecting between models with different sets of occupancy and detection covariates. The information-theoretic approach, which employs information criteria such as Akaike’s Information Criterion (AIC) is arguably the most popular approach for model selection in ecology and is often used for selecting occupancy models. However, the information-theoretic approach risks selecting models which produce inaccurate parameter estimates, due to a phenomenon called collider bias. Using simulations, we investigated the consequences of collider bias (using an illustrative example called M-bias) in the occupancy and detection processes of an occupancy model, and explored the implications for model selection using AIC and a common alternative, the Schwarz Criterion (or Bayesian Information Criterion, BIC). We found that when M-bias was present in the occupancy process, AIC and BIC selected models which inaccurately estimated the effect of the focal occupancy covariate, while simultaneously producing more accurate predictions of the site-level occupancy probability. In contrast, M-bias in the detection process did not impact the focal estimate; all models made accurate inferences, while the site-level predictions of the AIC/BIC-best model were slightly more accurate. Our results demonstrate that information criteria can be used to select occupancy covariates if the sole purpose of the model is prediction, but must be treated with more caution if the purpose is to understand how environmental variables affect occupancy. By contrast, detection covariates can usually be selected using information criteria regardless of the model’s purpose. These findings illustrate the importance of distinguishing between the tasks of parameter inference and prediction in ecological modelling. Furthermore, our results underline concerns about the use of information criteria to compare different biological hypotheses in observational studies.

Open Research Statement

Code to fully reproduce our simulations and analyses is available at:https://zenodo.org/badge/latestdoi/462801230
CRISPR–Cas9 Mutagenesis in Xenopus tropicalis for Phenotypic Analyses in the F0 Generation and Beyond
Authors: Blitz Ira L. , Nakayama Takuya
Published: March 2022

CRISPR–Cas9 mutagenesis is being widely used to create targeted loss-of-function mutations in the diploid frog Xenopus tropicalis. Here we describe a simple mutagenesis protocol using microinjection of Cas9 protein or mRNA, together with synthetic guide RNAs (sgRNAs) targeting specific DNA sequences, into the early embryo. Cas9-catalyzed double-strand breaks undergo error-prone repair, resulting in production of short insertions and/or deletions. Thus, careful selection of target sites can lead to mutations that impair normal function of the protein product. CRISPR–Cas9 can be used to create either mosaic loss-of-function Xenopus embryos that display F0 generation phenotypes or mutant lines for downstream analysis. In addition to describing how to mutagenize genes using CRISPR–Cas9, we also discuss a simple method to determine the mutagenesis efficiency, some potential problems that can arise, and possible solutions to overcome them. The protocol described here should be applicable to other amphibians and, in principle, many other organisms.
Modeling Human Genetic Disorders with CRISPR Technologies in Xenopus
Authors: Willsey Helen Rankin , Guille Matthew , Grainger Robert M.
Published: March 2022

Combining the power of Xenopus developmental biology with CRISPR-based technologies promises great discoveries in understanding and treating human genetic disorders. Here we provide a practical pipeline for how to go from known disease gene(s) or risk gene(s) of interest to methods for gaining functional insight into the contribution of these genes to disorder etiology in humans.
Crystal structure of racemic (R/S,E)-2-(4-hydroxyphenyl)-4-(2-phenylhydrazin-1-ylidene)chromane-5,7-diol ethanol monosolvate
Authors: Yennawar Hemant P. , Sigmon Anna
Published: March 2022

The crystal structure of racemic (R/S,E)-2-(4-hydroxyphenyl)-4-(2-phenylhydrazin-1-ylidene)chromane-5,7-diol ethanol monosolvate, C21H18N2O4·C2H6O, in a centrosymmetric lattice is reported. The two racemates occupy the same position in the asymmetric unit – a disordered mixed enantiomeric structure. Hydrogen bonds of the type O—H...C(π) in addition to typical C—H...O, O—H...O and O—H...N are identified. A positional disorder is seen in the solvent molecule (ethanol) as well. The phenylhydrazone group is nearly coplanar with the chromane ring system [dihedral angle = 15.5 (1)°], while the the 4-hydroxyphenyl ring is perpendicular [dihedral angle = 87.2 (1)°] to the chromane. The pyran ring has an envelope pucker [Q = 0.363 (3) Å, θ = 57.6 (3)°; and for the enantiomer: Q = 0.364 (3) Å, θ = 127.4 (4)°].
A systematic and critical review of leadership styles in contemporary hospitality: a roadmap and a call for future research
Authors: Elkhwesky Zakaria , Salem Islam Elbayoumi , Ramkissoon Haywantee , Castañeda-García José-Alberto
Published: March 2022

Purpose

The purpose of this paper is to provide an overview of leadership styles in the hospitality industry. It also demonstrates theories used in hospitality leadership styles research, identifies the main outcomes and highlights gaps for future research.

Design/methodology/approach

This paper presents a comprehensive review of the 79 articles on leadership styles in the hospitality context spanning over 13 years (2008–2020) and extends the scope in distinctive means.

Findings

This review has demonstrated that leadership styles research in hospitality has made progress in the past 13 years; however, there are conceptual and empirical overlaps among different leadership styles in hospitality. There is a lack of research on antecedents and integrating theories in studies. This review has revealed that several leadership styles have not been rigorously examined in hospitality research with their outcomes.

Research limitations/implications

The search strategy used to find articles published in Web of Science about leadership styles in hospitality was restricted to title to boost the accuracy of the subsequent literature.

Practical implications

By following the guidance presented in this review, the authors expect to advance and maintain hospitality leadership research to provide substantive insights into the context of hospitality leadership over the coming years.

Originality/value

To the best of the authors’ knowledge, this study is one of the first to undertake a comprehensive understanding of various leadership styles in the hospitality context. This study provides a comprehensive projected research agenda to demonstrate theoretical discourses and empirical research. Overall, this critical review presents a holistic idea of the focus of the prior studies and what should be highlighted in future studies.
Determinants of the intellectual capital efficiency of listed banks in Nigeria: a DEA approach
Authors: Olohunlana Aminat Olayinka , Odeleye Anthonia Taye , Isola Wakeel Atanda
Published: March 2022

Purpose

This study empirically investigates the level of intellectual capital efficiency amongst the listed commercial banks in Nigeria and the factors influencing its efficient utilisation.

Design/methodology/approach

The paper employs the data envelopment analysis (DEA) to determine intellectual capital efficiency for the listed banks in Nigeria using data obtained from their annual financial reports from 2013 to 2019. After obtaining the efficiency scores, the Tobit regression technique was used to analyse the impact of firm-specific factors on intellectual capital efficiency.

Findings

The study found that only 8.33% of the sampled Nigerian commercial banks are at optimum capacity in utilising their intellectual capital, while 91.67% are inefficient. It also finds that bank size and directors' shareholdings positively impact intellectual capital efficiency, while market and ownership concentration debar the attainment of optimum intellectual capital efficiency.

Research limitations/implications

This study contributes to very scare literature on intellectual capital efficiency measurements by using the non-parametric analysis (DEA) to measure intellectual capital efficiency for listed banks in Nigeria.

Practical implications

This study showcases the importance of measuring intellectual capital efficiency amongst listed banks in Nigeria. It provides more information to the regulators and stakeholders on the need to enforce the disclosure of the value created from intellectual capital investment.

Originality/value

This study contributes to the scarce literature on measuring intellectual capital efficiency using a non-parametric analysis (DEA). It also provides new insights into the factors that influence intellectual capital efficiency amongst listed commercial banks in Nigeria.
“What is going on in the ‘big tent’?” Current developments in (new) institutional theory and performance measurement and management research
Authors: Polzer Tobias
Published: March 2022

Purpose

In a recent paper that was published inJournal of Public Budgeting, Accounting and Financial Management, Modell (2021) takes stock of the institutional research on performance measurement and management (PMM) in the public sector and proposes a number of avenues for further inquiry in the area. The aim of this comment is to contextualise some of his observations against the backdrop of current developments in (new) institutional theory.

Design/methodology/approach

The recent scholarly debate about whether institutional theory needs any redirecting is the point of departure for this comment. Three of the themes from this debate are revisited and implications for research on PMM in the public sector are outlined.

Findings

First, against the backdrop of an emerging plethora of organisational forms in the public sector, this comment focusses on the locus or “where” PMM can be analysed and how organisational forms affect PMM. The second point addresses the “what” of analysis, where it is argued that PMM instruments are embedded in an ecology of concepts and a relational perspective on diffusion is introduced. A third observation is related to methodological issues and discusses the “how”: how best to study manifestations of PMM systems.

Originality/value

The comment illustrates a number of implications of the current developments in (new) institutional theory for research on PMM. In so doing, the wider ambition is to stimulate an exchange between public-sector accounting and organisation studies.
Personal thermal comfort models: a deep learning approach for predicting older people’s thermal preference
Authors: Arakawa Martins Larissa , Soebarto Veronica , Williamson Terence , Pisaniello Dino
Published: March 2022

Purpose

This paper presents the development of personal thermal comfort models for older adults and assesses the models’ performance compared to aggregate approaches. This is necessary as individual thermal preferences can vary widely between older adults, and the use of aggregate thermal comfort models can result in thermal dissatisfaction for a significant number of older occupants. Personalised thermal comfort models hold the promise of a more targeted and accurate approach.

Design/methodology/approach

Twenty-eight personal comfort models have been developed, using deep learning and environmental and personal parameters. The data were collected through a nine-month monitoring study of people aged 65 and over in South Australia, who lived independently. Modelling comprised dataset balancing and normalisation, followed by model tuning to test and select the best hyperparameters’ sets. Finally, models were evaluated with an unseen dataset. Accuracy, Cohen’s Kappa Coefficient and Area Under the Receiver Operating Characteristic Curve (AUC) were used to measure models’ performance.

Findings

On average, the individualised models present an accuracy of 74%, a Cohen’s Kappa Coefficient of 0.61 and an AUC of 0.83, representing a significant improvement in predictive performance when compared to similar studies and the “Converted” Predicted Mean Vote (PMVc) model.

Originality/value

While current literature on personal comfort models have focussed solely on younger adults and offices, this study explored a methodology for older people and their dwellings. Additionally, it introduced health perception as a predictor of thermal preference – a variable often overseen by architectural sciences and building engineering. The study also provided insights on the use of deep learning for future studies.