bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of stigma and associated characteristics in people with tuberculosis in Medellín, Colombia: a cross-sectional study
Authors: Rodríguez-Márquez Iader , Montes Fernando , Upegui-Arango Luz D , Montoya Nilton , Vargas Nelly E , Rojas Abelardo , Valencia Gloria C , Álvarez Claudia M , Marceló-Díaz Catalina , Ochoa Jesus
Published: March 2022

Background

Stigma towards tuberculosis (TB) delays diagnosis and compromises adherence to treatment. We measured the degree of stigma and identified the sociodemographic and clinical characteristics that were associated with a higher degree of stigma in patients with pulmonary and extrapulmonary TB in Colombia.

Methods

We conducted a cross-sectional study with 232 participants included in the TB control program in 2017. Sociodemographic and clinical variables were measured. The stigma component was measured through a validated scale and a multiple linear regression was used.

Results

The study analysed 232 patients, of which 52.2% were men, 53.5% were between 27 and 59 y of age and 66.8% had a basic–medium education level. Two characteristics were significantly related to a higher stigma score: the basic–medium education level and homeless status. Homeless status increased the stigma score by 0.27. In contrast, the adjusted stigma score decreased by 0.07 if the patient's health status was perceived as ‘healthy’.

Conclusion

Stigma is maximized in homeless patients and patients with a low education level. It is minimized in patients who perceive their state of health as ‘healthy’.
Time-Specific Differences in Stated Preferences for Health in the United States
Authors: Law Ernest H. , Pickard Alan Simon , Walton Surrey M. , Xie Feng , Lee Todd A. , Schwartz Alan
Published: March 2022

Background:

Changes over time in health state values from a societal perspective may be an important reason to consider updating societal value sets for preference-based measures of health.

Objective:

The aim was to examine whether stated health preferences are different between 2002 and 2017, controlling for demographic changes in the United States.

Methods:

Data from 2002 and 2017 US EQ-5D-3L valuation studies were combined. The primary analysis compared valuations of better-than-dead (BTD) states only, as both studies used the same time trade-off (TTO) method for these states. For worse-than-dead (WTD) states, the 2017 study used the lead-time TTO and the 2002 study used the conventional TTO, which necessitated transformation. Regression models were fitted to BTD values to estimate time-specific differences, adjusting for respondent characteristics. Secondary analyses examined models that fitted WTD values (using linear and nonlinear transformations of the 2002 data) and all values.

Results:

The adjusted BTD-only model showed mean values were higher for 2017 compared with 2002 (βY2017=0.05, P<0.001). WTD-only models showed negative changes over time but that were dependent on the transformation method (linear βY2017=−0.72; nonlinear βY2017=−0.35; both P<0.001). Using all values, 2017 mean valuations were lower using a linear transformation (βY2017=−0.11; P<0.001) but did not differ with the nonlinear transformation.

Conclusions:

Individuals in 2017 are generally less willing to trade quantity for quality of life compared with 2002. This study provides evidence of time-specific differences in a society’s preferences, suggesting that the era in which values were elicited may be an important reason to consider updating societal value sets.
Quality of life in lower limb amputees: a cross-sectional study from a tertiary care center of South India
Authors: Priyadharshan K. P. , Kumar Navin , Shanmugam D. , Kadambari D. , Kar Sitanshu Sekhar
Published: March 2022

Background:

Various literature have dealt with the physical aspect of amputation and the functional outcome after amputation. There are a few studies that give focused attention to the quality of life (QOL) of amputees. These studies are mostly from the developed countries. This study analyzed amputation as a whole and how it affects an individual physically, psychologically, emotionally, and socially, which would enable the health care providers to help the amputees to attain a better QOL.

Study Design:

Cross-sectional study

Materials and Methods:

This cross-sectional study was conducted on lower limb amputees. Data were collected using a proforma for demographic details and two pretested questionnaires—the World Health Organization QOL-Bref and prostheses-specific Trinity Amputation and Prosthesis Experience Scales-Revised questionnaires. The data were analyzed using SPSS software, version 20.

Results:

Amputation significantly affects all domains of the QOL. Age was a significant determinant of QOL of amputees, and it was found that the QOL decreased with an increase in age. 48.1% of the amputees were using a prosthetic device, and they were found to have a significantly better QOL. The prevalence of residual limb pain and phantom limb pain was 52.9% and 37%, respectively.

Conclusion:

Nearly half of the population perceived that their QOL was neither poor nor good. The QOL of the physical domain was better than the other domains. The most important factors that were found to be associated with QOL of amputees were age, duration since amputation, and use of prosthesis.
Fulvivirga marina sp. nov. and Fulvivirga sediminis sp. nov., two novel Bacteroidetes isolated from the marine sediment
Authors: Zhao Li-Hua , Wang Zong-Jie , Song Cui , Xing Xiang , Liu Ying-Ying , Shi Li-Fang , Yu Tong-Tong , Zhang You-Ming , Zhu Qian , Du Zong-Jun
Published: March 2022

Two novel, designated strains 29W222T and 2943T, were isolated from the marine sediment from Aoshan Bay, Jimo, PR China. Growth was observed at pH 6.0–8.5 (optimum, pH 7.5) for strain 29W222T, and pH 5.5–8.5 (pH 7.0) for strain 2943T. Both strains displayed growth in 0.5–6 % NaCl with an optimum at 1 % for 29W222T; 0.5 % for 2943T. Both strains grew optimally at 33 °C. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that 29W222T and 2943T represented members of the genus

Fulvivirga

and strain 29W222T was most closely related to

Fulvivirga kasyanovii

KMM 6220T (97.9 % sequence similarity) and

Fulvivirga imtechensis

AK7T (95.0 %), and 2943T to

Fulvivirga imtechensis

AK7T (95.7 %) and

Fulvivirga kasyanovii

KMM 6220T (94.8 %). The genomic DNA G+C contents of 29W222T and 2943T were 39.9 and 37.7 mol%, respectively. The results of chemotaxonomic analysis indicated that the sole respiratory quinone was menaquinone 7 (MK-7), and the major fatty acid was iso-C15 : 0 for both strains. Average nucleotide identity and average amino acid identity values between strain 29W222T and

Fulvivirga kasyanovii

KMM 6220T were 78.9 and 83.6 %, respectively; the corresponding values between 2943T and

Fulvivirga imtechensis

AK7T were 69.8 and 63.6 %, respectively. Therefore, strains 29W222T and 2943T represent to two novel species of the genus

Fulvivirga

, for which the names Fulvivirga marina sp. nov. (29W222T=KCTC 62848T=MCCC 1K05194T) and Fulvivirga sediminis sp. nov. (2943T=KCTC 62847T= MCCC 1K05144T) are proposed, respectively.
Using Machine Learning Algorithms to predict sepsis and its stages in ICU patients
Authors: Ghias Nimrah , Haq Shan Ul , Arshad Huzifa , Sultan Haseeb , Bashir Farhan , Ghaznavi Syed Ameer , Shabbir Maria , Badshah Yasmin , Rafiq Mehak
Published: March 2022

Sepsis is blood poisoning disease that occurs when body shows dysregulated host response to an infection and cause organ failure or tissue damage which may increase the mortality rate in ICU patients. As it becomes major health problem, the hospital cost for treatment of sepsis is increasing every year. Different methods have been developed to monitor sepsis electronically, but it is necessary to predict sepsis as soon as possible before clinical reports or traditional methods, because delayed in treatment can increase the risk of mortality with every single hour. For the early detection of sepsis, specifically in ICU patients, different machine learning models i.e Linear learner, Multilayer perceptron neural networks, Random Forest, lightgbm and Xgboost has trained on the data set proposed by Physio Net/ Computing in Cardiology Challenge in 2019. This study shows that Machine learning algorithms can accurately predict sepsis at the admission time of patient in ICU by using six vitals signs extracted from patient records over the age of 18 years. After comparative analysis of machine learning models, Xgboost model achieved a highest accuracy of 0.98, precision of 0.97, and recall 0.98 under the precision-recall curve on the publicly available data. Early prediction of sepsis can help clinicians to implement supportive treatments and reduce the mortality rate as well as healthcare expenses.
Variants in Interferon Lambda are Associated with Very Early Onset Inflammatory Bowel Disease
Authors: Ouahed Jodie D. , Broggi Achille , Glick Abigail , Haring Robin T. , Field Michael , Chinnapen Daniel , Grey Michael J. , Lencer Wayne , Steiner Steven J. , Dennis-Heyward Evida , Shroyer Noah , Criss Zachary , Lin Shih-Ching , Zeng Xi-Lei , Crawford Sue E. , Estes Mary K. , Thiagarajah Jay R. , Capilla Amalia , Scoon Whitney , Mostoslavsky Gustavo , Spence Jason , Klein Christoph , Muise Aleixo M. , Horwitz Bruce , Zanoni Ivan , Snapper Scott B.
Published: March 2022

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the intestine that affect children and adults. The etiology is multifactorial with the contribution of genetic, immune, microbial, and environmental risk factors with a substantial involvement of host:microbial cross-talk in the lumen. Whether and how antiviral responses contribute to IBD pathogenesis is under intense investigation. Here, we identified two unrelated patients diagnosed with very early onset IBD (VEOIBD) with rare variants in type III Interferons (IFNs), also known as interferon lambdas (IFNλs), a group of IFNs that play key roles in the protection against enteric viruses. The first patient was found to have homozygous variants in both IFNL2 and IFNL3, the genes encoding, IFN-λ2 and IFN-λ3, respectively. The second patient was found to have inherited compound heterozygous variants in IFNL3, with one of the two alleles bearing the same variant as the first patient. Functional analyses revealed that the proteins coded for by these variant IFN-λ genes exhibited defects in the induction of IFN signaling. More detailed assessment of the variants identified in Patient 1 demonstrated defects in their ability to bind to IFN-λ receptor 1 (IFNLR1), as well as their ability to induce heterodimerization of IFNLR1 and IL10RB, which together compromise the functional receptor for IFN-λ (IFNLR). These patient-encoded IFN-λ variants also exhibit defects in the ability to induce robust downstream IFN-stimulated genes (ISGs) in patient-derived intestinal organoids. All in all, we demonstrate that VEOIBD is associated with variants in IFN-λs and defective induction of downstream IFN signaling.
Predictors of HIV Testing among Youth 15-24 Years in urban Ethiopia, 2017-2018 Ethiopia Population-based HIV Impact Assessment
Authors: Ajiboye Aderonke S. , Eshetu Frehywot , Lulseged Sileshi , Getaneh Yimam , Tademe Nadew , Kifle Tsigereda , Bray Rachel , Eshete Hailegnaw , Demissie Yohannes , Dykewicz Clare A. , Hoos David ,   EPHIA Study Group
Published: March 2022

Introduction

Youth (adolescents and young adults) aged 15-24 years comprise approximately 22% of Ethiopia’s total population and make up 0.73% of HIV cases in urban Ethiopia. However, only 63% of HIV-positive youth are aware of their HIV status. We described the HIV testing behaviors of youth 15-24 years and determined the characteristics of those who were most likely to be tested for HIV within the past year.

Methods

Using data from the 2017-2018 Ethiopia Population-based HIV Impact Assessment, we provide survey-weighted estimates and prevalence risk ratios for engagement in HIV testing in the 12 months preceding the survey. We model the likelihood of HIV testing one year or more before the survey compared to never testing, using a multinomial logistic regression model.

Results

Among HIV-negative and unaware HIV-positive youth 15-24 years old (N=7,508), 21.8% [95% Confidence Interval (CI): 20.4-23.3%] reported testing for HIV in the last 12 months. Female youth [Prevalence Ratio (PR)=1.6, 95% CI: 1.4-1.8], those aged 20-24 years (PR=2.6, 95% CI:2.3-2.9), and those ever married (PR=2.8, 95% CI: 2.5-3.1) were more likely to have tested for HIV within the last year. Adjusting for select demographic characteristics, sex with a non-spousal or non-live-in partner [Relative Risk (RR)=0.3, 95% CI:0.1-0.8] among males did not increase their likelihood to test for HIV in the prior 12 months. Female youth engaged in antenatal care (RR=3.0, 95% CI: 1.7-5.3) were more likely to test for HIV in the past year.

Conclusion

The Ethiopian HIV case finding strategy may consider approaches for reaching untested youth, with a specific focus on adolescent males. This is critical towards achieving the UNAIDS HIV testing goal of 95% of all individuals living with HIV aware of their status by 2030.
Evaluation of a throat spray with lactobacilli in COVID-19 outpatients in a randomized, double-blind, placebo-controlled trial for symptom and viral load reduction
Authors: De Boeck Ilke , Cauwenberghs Eline , Spacova Irina , Gehrmann Thies , Eilers Tom , Delanghe Lize , Wittouck Stijn , Bron Peter A. , Henkens Tim , Gamgami Imane , Simons Alix , Claes Ingmar , Mariën Joachim , Ariën Kevin K. , Bakokimi Diana , Loens Katherine , Jacobs Kevin , Ieven Margareta , Bruijning-Verhagen Patricia , Delputte Peter , Coenen Samuel , Verhoeven Veronique , Lebeer Sarah
Published: March 2022

Objectives

Primary care urgently needs treatments for COVID-19 patients because current options are limited, while these patients account for more than 90% of the people infected with SARS-CoV-2.

Methods

We evaluated a throat spray containing three Lactobacillaceae strains with broad antiviral properties in a randomized double-blind placebo-controlled trial. Seventy-eight eligible COVID-19 patients were randomized to verum (n=41) and placebo (n=37) within 96 hours of positive PCR-based SARS-CoV-2 diagnosis and per-protocol analysis was performed. Symptoms and severity were reported daily via an online diary. Combined nose-throat swabs and dried blood spots were collected at regular time points in the study.

Results

The daily reported symptoms were highly variable, with no added benefit for symptom resolution in the verum group. Specific monitoring of the applied lactobacilli strains showed that they were detectable via microbiome (27%) and qPCR analysis (82%) of the verum group. Their relative abundances were also negatively correlated with the acute symptom score. At the end of the trial, a trend towards lower SARS-CoV-2 viral loads was observed for the verum group (2/30, 6.7% positive) compared to the placebo group (7/27, 26% positive) (p = 0.07).

Conclusions

Despite a trend towards lower SARS-CoV-2 viral loads at the end of the trial and a negative correlation between relative abundances of the applied lactobacilli in the microbiome and acute symptoms, we did not observe a significant effect on overall symptom score for the verum group. This suggests that studies with earlier application of the spray in larger study populations are needed to further assess application potential.
Effectiveness of a positive deviant intervention to improve appropriate feeding practices and nutritional outcomes in West Omo Zone, Maji District: South West Region, Ethiopia: A study protocol for a cluster randomized control trial
Authors: Gizaw Abraham Tamirat , Sopory Pradeep , Sudhakar Morankar
Published: March 2022

Background

Non-optimal infant and young child feeding practices (IYCFP) are linked to malnutrition and infant mortality in poor countries, notably in Ethiopia. The majority of growth stalls occur within the first two years of life; hence, there is a need to discover interventions that enhance appropriate IYCFP for improving nutritional outcomes during this critical period. Using the experience of mothers who have come up with solutions to their IYCFP problems to educate others is is a potential pathway to initiate and sustain behavioral changes in resource-limited areas. However, such interventions are not widely implemented in Ethiopia.

Objective

This study aims to assess the effectiveness of a positive deviant (hearth nutrition education) intervention to improve appropriate feeding practices and nutritional outcomes in West Omo Zone, Maji District: South West region, Ethiopia.

Methods

A cluster randomized controlled trial will be conducted to compare the effect of positive deviant intervention versus routine health educationa. The intervention will be provided by positive deviant mothers who are members of the community using WHO infant and young child feeding guidelines, and “training of the trainers manual on counseling and supporting non-positive deviant mothers, infant and young child feeding” in the local language. Culturally appropriate and scientifically acceptable operational packages of information will be developed. Using preset criteria, 516 mothers will be recruited from 36 zones. The intervention arm will receive 12 demonstration (hearth) session in groups and every 15th day home visit by positive deviant mothers. Data will be entered into epi-data version 3.1 and analyzed using STATA version 13.0. All analyses will be done as intention-to-treat. We will fit mixed effects linear regression models for the continuous outcomes and mixed effects linear probability models for the binary outcomes with the study zone as random intercept to estimate study arm difference (intervention vs. routine health education) adjusted for baseline value of the outcome and additional relevant covariates.

The protocol was developed in collaboration with the West Omo Zone and Maji Woreda Health Office. Ethical approval (Ref no: IHRPG/938/2020) was obtained from Jimma University, Institute of Health Research and Postgraduate Office. This study is funded by Jimma University research and postgraduate office.

Discussion

We expect that the trial will generate findings informing IYCFP and nutritional policies and practices in Ethiopia.

Trial registration

Registry: PACTR202108880303760 (30/08/2021); www.pactr.org, URL : https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=16081
Remote virtual reality assessment elucidates self-blame-related action tendencies in depression
Authors: Duan Suqian , Valmaggia Lucia , Fennema Diede , Moll Jorge , Zahn Roland
Published: March 2022

Darwin stated that humans have a strong and involuntary tendency to perform certain actions when a specific state of mind is induced. Such “action tendencies” are key to understanding the maladaptive impact of self-blame-related feelings in depression. For example, feeling like “hiding” and “creating a distance from oneself” in a text-based task were previously associated with recurrence risk in remitted depression. Despite their functional importance, action tendencies have not been systematically investigated in current depression, which was the aim of this pre-registered study. To this end, we developed the first virtual reality (VR) assessment of blame-related action tendencies and compared current depression (n=98) with control participants (n=40). The immersive VR-task, pre-programmed on devices sent to participants’ homes, used hypothetical social interactions, in which either participants (self-agency) or their friend (other-agency) were described to have acted inappropriately. Good concurrent validity was demonstrated for VR-versus the text-based task. As predicted, compared with controls, people with depression showed a maladaptive profile: Particularly in the other-agency condition, rather than feeling like verbally attacking their friend, they were prone to feeling like hiding, and punishing themselves. The depression group showed a more pronounced slowing of response times in the other-versus the self-agency condition, which may reflect a stronger ambivalence about externalising blame in depression. Interestingly, feeling like punishing oneself was associated with a history of self-harm but not suicide attempts. Current depression and self-harm history were thus linked with distinctive motivational signatures, paving the way for remote VR-based stratification and treatment.

General Scientific Summary

As precursors of social actions, action tendencies, such as feeling like hiding when experiencing shame or guilt, provide the key link between depressive emotions and behaviour. Here, we developed a novel virtual reality task and used it in a large sample of people with depression to unveil a distinctive pattern of such action tendencies. As predicted, we found a maladaptive pattern of action tendencies in people with depression that were specifically associated with self-harm. Our findings thereby elucidate a so far unexplored key aspect of psychopathology in depression and provide important targets for the development of novel future psychological interventions tackling self-harm-related motivations and depression.
Spatio-temporal clusters and patterns of spread of dengue, chikungunya, and Zika in Colombia
Authors: Freitas Laís Picinini , Carabali Mabel , Yuan Mengru , Jaramillo-Ramirez Gloria I. , Balaguera Cesar Garcia , Restrepo Berta N. , Zinszer Kate
Published: March 2022

Background

Colombia has one of the highest burdens of arboviruses in South America. The country was in a state of hyperendemicity between 2014 and 2016, with co-circulation of severalAedes-borne viruses, including a syndemic of dengue, chikungunya, and Zika in 2015.

Methodology/Principal Findings

We analyzed the cases of dengue, chikungunya, and Zika notified in Colombia from January 2014 to December 2018 by municipality and week. The trajectory and velocity of spread was studied using trend surface analysis, and spatio-temporal high-risk clusters for each disease in separate and for the three diseases simultaneously (multivariate) were identified using Kulldorff’s scan statistics. During the study period, there were 66,628, 77,345 and 74,793 cases of dengue, chikungunya, and Zika, respectively, in Colombia. The spread patterns for chikungunya and Zika were similar, although Zika’s spread was accelerated. Both chikungunya and Zika mainly spread from the regions on the Atlantic coast and the south-west to the rest of the country. We identified 21, 16, and 13 spatio-temporal clusters of dengue, chikungunya and Zika, respectively, and, from the multivariate analysis, 20 spatio-temporal clusters, among which 7 were simultaneous for the three diseases. For all disease-specific analyses and the multivariate analysis, the most-likely cluster was identified in the south-western region of Colombia, including the Valle del Cauca department.

Conclusions/Significance

The results further our understanding of emergingAedes-borne diseases’ trajectory in Colombia and provide useful information on the identified spatio-temporal disease-specific and multivariate clusters of dengue, chikungunya, and Zika, that can be used to target interventions. To our knowledge, this is the first time that the co-occurrence of all three diseases in Colombia was explored using multivariate scan statistics.
Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals
Authors: Richardson Victorya , Zhang Kai , Engel Nora , Kulathinal Rob J
Published: March 2022

Mammalian gonadal sex is determined by the presence or absence of a Y chromosome. In males, the Y chromosome initiates male gonadogenesis and the subsequent production of male-specific hormones defines the male state of each cell in the organism. In females, the lack of a Y chromosome and the presence of two X chromosomes triggers the development of female gonads, hormones, and cellular identity. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression. Here, we apply a comparative bioinformatics analysis on published single-cell datasets from mouse and human during very early embryogenesis–from two-cell to preimplantation stages–to characterize sex-specific signals and to assess the degree of conservation among early-acting sex-specific genes and pathways. Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis. In addition, gene expression signals from male and female gametes during fertilization may still be present. Although these transcriptional sex effects rapidly diminish, the sex-biased expression of epigenetic enzymes has the potential to establish sex-specific patterns that persist beyond preimplantation. Sex-biased genes appear to form sex-specific protein-protein interaction networks across preimplantation stages in both mammals. While the distribution of sex-differentially expressed genes (sexDEGs) in early embryonic stages are similar in mice and humans, the genes involved are generally different. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages including post-fertilization, epigenetic, and preimplantation ontologies conserved between mouse and human. This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease.
Symbolic quantitative cognition in wild zebrafish (Danio rerio)
Authors: Majeed Nawaf Abdul , Singh Dhairrya , Gopal Akshita Baiju , Battiwala Tanya , Kulshreshtha Ninaad , Mishra Rahulraj , Sabharwal Shagun , Behera Madhusmita , Sahu Manisha , Menon Ameya , Bungsut Lalchhanhimi , Walia Amiya , Saraf Raksha , Mathew Susan , Shah Ashumi , Kochhar Suhaavi , Salar Nivedita , Thakuri Sushmita , Sharma Yashant , Rampuria Nishtha , Bhattacharjee Anubhab , Wagh Niharika , Hegde Sahana , Bulhan Indira , Singh Gurasheesh , Rajaraman Bittu Kaveri
Published: March 2022

Zebrafish (Danio rerio) constitute an excellent model system to investigate the neural and genetic basis of quantitative cognition because of the single neuron resolution of calcium imaging of awake, behaving fish. While nonsymbolic numerical cognition has been investigated across many taxa, symbolic numerical cognition has not been investigated among fish. We developed a novel quantitative symbolic test for zebrafish using an operant conditioning paradigm in which the number of horizontal lines zebrafish approached in a 2-alternative forced choice task predicted the number of food reward pellets they would receive. Zebrafish did not at the population level learn a preference for the 2-line stimulus predictive of receiving 2 food pellets. However, they performed significantly above chance in a nonsymbolic discrimination task with the same apparatus, in which the 2-line stimulus was associated with the same reward but the choice of the 1-line stimulus was not rewarded. We also explored the explanatory value of alternative spatial learning hypotheses such as a Win-Stay, Lose-Shift (WSLS) strategy at the individual level for fish in navigating these spatially randomised tasks. The implications of this for symbolic versus nonsymbolic quantitative cognition in this model system are discussed relative to reward type and stimulus modality.
Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1 mediated HSR
Authors: Miles Jay , Townend Sarah , Smith William , Westhead David R. , van Oosten-Hawle Patricija
Published: March 2022

Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the C. elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress-signaling from the intestine to the muscle is regulated. We find that the TCS-mediated “gut-to-muscle” induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of “inter-tissue” stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated HSR is switched off upon TCS activation, in favor of an intercellular stress-signaling-route to safeguard survival.
DENVIS: scalable and high-throughput virtual screening using graph neural networks with atomic and surface protein pocket features
Authors: Krasoulis Agamemnon , Antonopoulos Nick , Pitsikalis Vassilis , Theodorakis Stavros
Published: March 2022

Computational methods for virtual screening can dramatically accelerate early-stage drug discovery by identifying potential hits for a specified target. Docking algorithms traditionally use physics-based simulations to address this challenge by estimating the binding orientation of a query protein-ligand pair and a corresponding binding affinity score. Over the recent years, classical and modern machine learning architectures have shown potential for outperforming traditional docking algorithms. Nevertheless, most learning-based algorithms still rely on the availability of the protein-ligand complex binding pose, typically estimated via docking simulations, which leads to a severe slowdown of the overall virtual screening process. A family of algorithms processing target information at the amino acid sequence level avoid this requirement, however at the cost of processing protein data at a higher representation level. We introduce deep neural virtual screening (DENVIS), an end-to-end pipeline for virtual screening using graph neural networks (GNNs). By performing experiments on two benchmark databases, we show that our method performs competitively to several docking-based, machine learning-based, and hybrid docking/machine learning-based algorithms. By avoiding the intermediate docking step, DENVIS exhibits several orders of magnitude faster screening times (i.e., higher throughput) than both docking-based and hybrid models. When compared to an amino acid sequence-based machine learning model with comparable screening times, DENVIS achieves dramatically better performance. Some key elements of our approach include protein pocket modelling using a combination of atomic and surface features, the use of model ensembles, and data augmentation via artificial negative sampling during model training. In summary, DENVIS achieves competitive to state-of-the-art virtual screening performance, while offering the potential to scale to billions of molecules using minimal computational resources.

Graphical TOC Entry
EXONIZATION BY THE EMERGENCE OF A CLEAVAGE-POLYADENYLATION SITE
Authors: Méreau Agnès , Lerivray Hubert , Viet Justine , Hardy Serge , Paillard Luc , Audic Yann
Published: March 2022

Exonization is the evolutionary process of recruitment of new exonic regions from previously intronic regions. It is a major contributor to the increased complexity of alternative splicing. Here, we explore exonization mediated by the emergence of a novel cleavage-polyadenylation site in an intron. In Xenopus laevis, the tpm1 gene, which encodes muscular tropomyosin, contains alternative terminal exons. In adult muscles and embryonic hearts, exon 9A is joined to the terminal exon 9B. In embryonic somites, it is joined to the exonic region 9’, which is transcribed from the intron immediately downstream of exon 9A. Consequently, exon 9A is either an internal exon when ligated to exon 9B, or a part of a terminal exon along with region 9’. We show here that region 9’ is present only in amphibians and coelacanths. This suggests that it emerged in sarcopterygians and was lost in amniotes. We used antisense morpholino oligonucleotides to mask the regions of tpm1 pre-mRNA that potentially regulate the inclusion of exon 9A9’. This revealed that the definition of exon 9A9’ relies on a weak cleavage-polyadenylation site and an intronic enhancer, but is independent of the 3’ splice site. We demonstrate that RNAs containing exon 9B are toxic in somites. This may have contributed to the evolutionary pressure that led to the exonization of region 9’ in sarcopterygians. These findings reveal the emergence of a novel cleavage-polyadenylation site that avoids the accumulation of a toxic RNA as a novel mechanism for exonization-mediated diversification of terminal exons.
Fate mapping melanoma persister cells through regression and into recurrent disease in adult zebrafish
Authors: Travnickova Jana , Muise Sarah , Wojciechowska Sonia , Brombin Alessandro , Zeng Zhiqiang , Young Adelaide I.J. , Wyatt Cameron , Patton E. Elizabeth
Published: March 2022

Melanoma heterogeneity and plasticity underlie therapy resistance. Some tumour cells possess innate resistance, while others reprogramme during drug exposure and survive to form persister cells, a source of potential cancer cells for recurrent disease. Tracing individual melanoma cell populations through tumour regression and into recurrent disease remains largely unexplored, in part, because complex animal models are required for live imaging of cell populations over time. Here, we apply tamoxifen-inducible creERt2/loxP lineage tracing to a zebrafish model of MITF-dependent melanoma regression and recurrence to image and trace cell populations in vivo through disease stages. Using this strategy, we show that melanoma persister cells at the minimal residual disease site originate from the primary tumour. Next, we fate mapped rare MITF-independent persister cells and demonstrate that these cells directly contribute to progressive disease. Multiplex immunohistochemistry confirmed MITF-independent persister cells give rise to Mitfa+ cells in recurrent disease. Taken together, our work reveals a direct contribution of persister cell populations to recurrent disease, and provides a resource for lineage tracing methodology in adult zebrafish cancer models.

Summary statement

We fate map melanoma cells from the primary tumour into a persister cell state and show that persister cells directly contribute to recurrent disease.
Identification of minor alleles associated with reduced lodging in tef (Eragrostis tef)
Authors: Ben-Zeev Shiran , Hellwig Timo , Demeile Muluken , Barak Vered , Vorobyova Sasha , Hübner Sariel , Saranga Yehoshua
Published: March 2022

Rational

Underutilized species that are not widely cultivated (known as orphan crops) present opportunities to increase crop diversity and food security. Tef [Eragrostis tef (Zucc.) Trotter] is known for its high-quality grain and forage. Root-borne lodging is a major devastating problem in tef cultivation, leading to large economic losses and limiting its widespread adoption.

Objective

The aim of this study was to identify genomic regions that are associated with tef lodging.

Methods

A tef diversity panel (TDP-300) comprised of 297 lines was assembled, genotyped, and phenotyped across 4 field environments. This unique panel, the first of its kind in tef, has the potential to facilitate tef research and breeding.

Results

Genome-wide association study identified 29 sites associated with lodging; in all cases with a minor allele conferring reduced lodging. The eleven sites of prime interest were located in or near genes, 5 of them with a putative role, of which 3 were found to be involved root development.

Conclusions

The identification of lodging-related sites in the current study may advance understanding of the mechanisms underlying tef lodging and crop improvement. The identification of genes related to root development support the importance of root traits in tef lodging, which should be targeted in future breeding.
Reproducible Tract Profiles (RTP2): from diffusion MRI acquisition to clinical practice and research
Authors: Lerma-Usabiaga Garikoitz , Liu Mengxing , Paz-Alonso Pedro M. , Wandell Brian A.
Published: March 2022

Diffusion MRI is a complex technique, where new discoveries and implementations occur at a fast pace. The expertise needed for data analyses and accurate and reproducible results is increasingly demanding and requires multidisciplinary collaborations. In the present work we introduce Reproducible Tract Profiles (RTP2): a set of flexible and automated methods to analyze anatomical MRI and diffusion weighted imaging (DWI) data for reproducible tractography. The tools read structural MRI data and process them through a succession of serialized containerized analyses. We describe the DWI algorithms used to identify white-matter tracts and their summary metrics, the flexible architecture of the platform, and the tools to programmatically access and control the computations. The combination of these three components provides an easy-to-use automatized tool developed and tested over 20 years, to obtain usable and reliable state-of-the-art diffusion metrics at the individual and group levels for basic research and clinical practice.

Highlights

Automated, flexible and reproducible protocol for white-matter tractography and tractometry.

High computational (same data, different computations) and test-retest reproducibility (data from different sessions, different computations).

Open-source code and publicly available containers.
Using a combination of CRISPR/Cas9, behavioural experiments and functional analysis to characterise taste receptors in honeybees
Authors: Değirmenci Laura , Ferreira Fábio Luiz Rogé , Vukosavljevic Adrian , Heindl Cornelia , Keller Alexander , Geiger Dietmar , Scheiner Ricarda
Published: March 2022

Honeybees (Apis mellifera) need their fine sense of taste to evaluate nectar and pollen sources. Gustatory receptors (Grs) translate taste signals into electrical responses. In vivo experiments primarily demonstrate collective responses of the whole Gr-set, but little is known about the individual impact of receptors. Here, we disentangle for the first time the contributions of three gustatory receptors (AmGr1-3) in sugar sensing of honeybees by combining CRISPR/Cas9 mediated genetic knock-out, electrophysiology and behaviour. AmGr1 responds to multiple sugars. Bees lacking this receptor have a reduced response to sucrose and glucose but not to fructose. AmGr2 acts as co-receptor of AmGr1 in a heterologous expression system, but honeybee knock-out mutants perform normally. Eliminating AmGr3 while preserving AmGr1 and AmGr2 abolishes the perception of fructose but not of sucrose. We thus dissociate the roles of AmGr1, AmGr2 and AmGr3 in honeybee taste perception.
Ratiometric Sensing of Redox Environments Inside Individual Carboxysomes Trapped in Solution
Authors: Carpenter William B. , Lavania Abhijit A. , Borden Julia S. , Oltrogge Luke M. , Perez Davis D. , Dahlberg Peter D. , Savage David F. , Moerner W. E.
Published: March 2022

Diffusion of biological nanoparticles in solution impedes our ability to continuously monitor individuals and measure their physical and chemical properties. To overcome this, we previously developed the Interferometric Scattering Anti-Brownian ELectrokinetic (ISABEL) trap, which uses scattering to localize a particle and applies electrokinetic forces which counteract Brownian motion, thus enabling extended observation. Here, we present an improved ISABEL trap that incorporates a near-infrared scatter illumination beam and rapidly interleaves 405 and 488 nm fluorescence excitation reporter beams. With the ISABEL trap, we monitor the internal redox environment of individual carboxysomes labeled with the ratiometric redox reporter roGFP2. Carboxysomes widely vary in scattering contrast (reporting on size) and redox-dependent ratiometric fluorescence. Further, we used redox sensing to explore the chemical kinetics within intact carboxysomes, where bulk measurements may contain unwanted contributions from aggregates or interfering fluorescent proteins. Overall, we demonstrate the ISABEL trap’s ability to sensitively monitor nanoscale biological objects, enabling new experiments on these systems.

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What Happens After an Error?
Authors: Adkins Tyler J , Zhang Han , Lee Taraz G
Published: March 2022

Humans tend to slow down after making an error. A longstanding account of this post-error slowing is that people are simply more cautious. However, accuracy typically does not improve following an error leading some researchers to suggest that an initial ‘orienting’ response may initially impair performance immediately following error. Unfortunately, characterizing the nature of this error-based impairment remains a challenge in standard tasks that use free response times. Using a new experimental approach, we exert tight control over the timing of responses to reveal the time course of stimulus-response processing. Participants are less accurate after an error even when given ample time to make a response. A computational model of response preparation rules out the possibility that errors lead to slower cognitive processing. Instead, we find that the “efficacy” of cognitive processing in producing an intended response is impaired following errors. Participants commit more perseverative slips of action following an error. Rather than a strategic shift along a single speed-accuracy tradeoff function, post-error slowing observed in free response time tasks may be an adaptive response to impaired cognitive processing that reflects a fundamentally altered relationship between the speed and accuracy of responses.
Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis
Authors: Choi Jiahn , Zhang Xusheng , Li Wenge , Houston Michele , Peregrina Karina , Dubin Robert , Ye Kenny , Augenlicht Leonard H.
Published: March 2022

NWD1, a purified rodent diet establishing mouse exposure to key nutrients recapitulating levels that increase risk for intestinal cancer, reproducibly causessporadicintestinal and colonic tumors in the mouse, reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 reprogramming of stem cells and lineages was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly reprogrammed Lgr5histem cells, epigenetically down-regulatingPpargc1aexpression, altering mitochondrial structure and function. This suppressed Lgr5histem cell functions and developmental maturation of Lgr5hicell progeny as cells progressed through progenitor cell compartments, recapitulated byPpargc1agenetic inactivation in Lgr5hicellsin vivo. MobilizedBmi1+, Ascl2hicells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lg5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Thus, although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.
Emotional intensity can enrich or degrade memories: impact of the amygdalar pathway on hippocampus through inhibitory neurons
Authors: John Yohan J. , Wang Jingyi , Bullock Daniel , Barbas Helen
Published: March 2022

The brain’s emotional system powerfully modulates processing of context and episodic memory. A key pathway that mediates these effects is the projection from the amygdala to the hippocampus. Wang and Barbas (1) uncovered a distinctive pattern in the pathways from amygdala to hippocampus in primates. In hippocampal CA3, a pathway from the amygdala innervated excitatory pyramidal neurons as well as parvalbumin (PV) and calretinin (CR) inhibitory neurons. In hippocampal CA1, amygdalar projections also innervated pyramidal neurons and CR interneurons, but not PV interneurons. The effects of these complex circuits can best be probed using computational simulations. We developed a model of spiking neurons to investigate the implications and significance of these amygdala-hippocampal circuits for affective influence on processing mnemonic context, and to test their effects as input from the amygdala gradually increased. Our simulations revealed that moderate input from the amygdala can enhance detail in CA3 representations that can correctly sort out contexts and episodes from memory. However, high amygdalar input suppressed CA3 responses to non-amygdalar inputs through powerful inhibitory neurons, leading to memory representations that lack detail. Moreover, high amygdalar input prematurely hastened the timing of responses in CA1 occurring when the current situation broadly and non-specifically matched a remembered context. Amygdalar pathways to hippocampus enable a mechanism whereby affective signaling appropriately enhances hippocampal representations of remembered context. However, when amygdalar input is excessive in high emotional arousal, there is loss of memory detail and overgeneralization, as seen in post-traumatic stress disorder or pathologic phobias.
The DC1 domain protein BINUCLEATE POLLEN is required for pollen development in Arabidopsis thaliana
Authors: Arias Leonardo A. , D’Ippolito Sebastián , Frik Jésica , Amigo Natalia L. , Marchetti Fernanda , Casalongué Claudia A. , Pagnussat Gabriela C. , Fiol Diego F.
Published: March 2022

Development of the male gametophyte is a tightly regulated process that requires precise control of cell division and gene expression. A relevant aspect to understand the events underlying pollen development regulation constitutes the identification and characterization of the genes required for this process. In this work we showed that the DC1 domain protein BINUCLEATE POLLEN (BNP) is essential for pollen development and germination. Pollen grains carrying the defective BNP allele failed to complete mitosis II and are impaired in pollen germination. By yeast two-hybrid analysis and bimolecular fluorescence complementation assays, we identified a set of BNP-interacting proteins. Among confirmed interactors we found NAC family transcriptional regulators Vascular Plant One-Zinc Finger 1 (VOZ1) and VOZ2. VOZ1 localization changes during pollen development, moving to the vegetative nucleus at the tricellular stage. We observed that this relocalization requires BNP, as in the absence of BNP in pollen from bnp/BNP plants, VOZ1 nuclear localization is impaired. As voz1voz2 double mutants showed the same developmental defect observed in bnp pollen grains, we propose that BNP requirement to complete microgametogenesis could be linked to its interaction with VOZ1/2 proteins. BNP could have a role of scaffold protein, recruiting VOZ1/2 to the endosomal system into assemblies that are required for their further translocation to the nucleus, where they act as transcriptional regulators.