bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of isotype specific salivary antibody assays for detecting previous SARS-CoV-2 infection in children and adults
Authors: Thomas Amy C , Oliver Elizabeth , Baum Holly E , Gupta Kapil , Shelley Kathryn L , Long Anna E , Jones Hayley E , Smith Joyce , Hitchings Benjamin , Bartolo Natalie di , Vasileiou Kate , Rabi Fruzsina , Alamir Hanin , Eghleilib Malak , Francis Ore , Oliver Jennifer , Morales-Aza Begonia , Obst Ulrike , Shattock Debbie , Barr Rachael , Collingwood Lucy , Duale Kaltun , Grace Niall , Livera Guillaume Gonnage , Bishop Lindsay , Downing Harriet , Rodrigues Fernanda , Timpson Nicholas , Relton Caroline L , Toye Ashley , Woolfson Derek N , Berger Imre , Goenka Anu , Davidson Andrew D , Gillespie Kathleen M , Williams Alistair JK , Bailey Mick , Brooks-Pollock Ellen , Finn Adam , Halliday Alice ,   the CoMMinS Study Team
Published: April 2022

Saliva is easily obtainable non-invasively and potentially suitable for detecting both current and previous SARS-CoV-2 infection. We established 6 standardised enzyme linked immunosorbent assays (ELISA) capable of detecting IgA and IgG antibodies to whole SARS-CoV-2 spike protein, to its receptor binding domain region and to nucleocapsid protein in saliva. In test accuracy (n=320), we found that spike IgG performed best (ROC AUC: 95.0%, 92.8-97.3%), followed by spike IgA (ROC AUC: 89.9%, 86.5-93.2%) for discriminating between pre-pandemic and post COVID-19 saliva samples. Using machine learning, diagnostic performance was improved when a combination of tests was used. As expected, salivary IgA was poorly correlated with serum, indicating an oral mucosal response whereas salivary IgG responses were predictive of those in serum. When deployed to 20 household outbreaks undergoing Delta and Omicron infection, antibody responses were heterogeneous but remained a reliable indicator of recent infection. Intriguingly, unvaccinated children showed evidence of exposure almost exclusively through specific IgA responses in the absence of evidence of viral infection. We have provided robust standardisation, evaluation, and field-testing of salivary antibody assays as tools for monitoring SARS-CoV-2 immune responses. Future work should focus on investigating salivary antibody responses following infection and vaccination to understand patterns of SARS-CoV-2 transmission and inform ongoing vaccination strategies.
Efficacy of premarital genotype screening and counselling on knowledge toward Sickle Cell disease among university students in Dodoma Tanzania: uncotrolled quasi-experimental study
Authors: Lumbe Arnold Gideon , Kibusi Stephen M
Published: April 2022

Background

Tanzania is experiencing the increase burden of Sickle cell disease, with an estimate of 20.6% prevalence Sickle Cell carriers. However, there is no preventive measure has been put in this area by the government; a great focus has been directed in the diagnosis and management and national guideline emphasis on the care of people affected by Sickle Cell Disease.

Methods

A non-controlled quasi-experimental study was conducted from June to September 2020 among 697 randomly recruited first-years university students from the University of Dodoma. Pre and post-test knowledge information were collected through structured self-administered questionnaires. Data was analyzed using SPSS v20. Simple and multiple linear analysis model was used to test for significant association of variables at 95% CI, at p<0.05. The results were presented using tables and figures.

Results

The mean knowledge score at pretest was 0.009±1.014 which improved to 0.365±0.901 on the posttest, with a statistically significant difference (t=6.965, p<0.01). The results of linear regression showed that knowledge change was not statistically associated with other predictors (p>0.05)

Conclusion

Health education demonstrated to be effective towards change in knowledge on sickle cell disease among University students.
Effects of vitamin D deficiency on blood lipids and bone metabolism: a large cross-sectional study
Authors: Gu Peng , Pu Bin , Chen BaiHang , Zheng XiaoHui , Zeng ZhanPeng , Luo WeiDong
Published: April 2022

Purpose

To investigate the relationship between serum HDL-C and spinal bone mineral density (BMD) under different serum 25-hydroxyvitamin D (25 (OH) D) levels in adults over 40 years old and to explore its mechanism.

Methods

Participants over the age of 40 with data on HDL-C, 25 (OH) D, spinal BMD, and other variables in NHANES 2007–2010 were included in the final analysis. A weighted multiple linear regression model was used to evaluate the association between serum HDL-C and spinal BMD in different gender, ages and serum 25 (OH) D levels.

Results

A total of 3599 subjects aged ≥ 40 years old were included in this study. Univariate analysis of the complete correction model showed a negative correlation between serum HDL-C and spinal BMD. In the two subgroups of serum 25(OH)D, we found that the higher the serum HDL-C in the female with serum 25 (OH) D < 75nmol/L aged 40-59 years old, the lower the total spinal BMD, and a similar relationship was found in the lumbar spine (L1-L4). However, no similar relationship was found in all populations with serum 25 (OH) D ≥ 75nmol/L and males with serum 25 (OH) D < 75nmol/L.

Conclusion

Among Americans over the age of 40, the increase of serum HDL-C is related to decreased BMD of spine only in women aged 40-59 years with vitamin D insufficiency or deficiency.

Author summary

We performed a cross-sectional study using the National Health Examination and Nutrition Survey (NHANES) data. We found that increased serum high-density lipoprotein cholesterol (HDL-C) during vitamin D deficiency is a potential risk factor for osteopenia or osteoporosis in middle-aged and elderly American women.
The acute effects of knee extension exercises with different contraction durations on the subsequent maximal knee extension torque for athletes with different strength levels
Authors: Nakata Kaito , Mishima Takaaki
Published: April 2022

Individuals with high fatigue resistance against a high-intensity conditioning activity (CA) may be able to avoid experiencing significant fatigue and enhance their voluntary performance. We examined whether the optimal contraction duration of dynamic knee extension exercises to maximize subsequent voluntary performance varies depending on the strength level of an individual. The study participants were 22 male American college football players. Initially, all participants performed a 10-s maximal isometric knee extension exercise and were classified as stronger individuals (n = 8) and weaker individuals (n = 8) based on their relative muscle strength. Each group then performed three types of dynamic CA with different contraction durations (6 s [6-CA], 12 s [12-CA], and 18 s [18-CA]) in random order. To observe the time-course changes in post-activation potentiation and performance enhancement, the twitch torques induced by electrical stimulation and isokinetic knee extension torques at 180°/s were recorded before and after each CA. The twitch torque increased at 10 s (29.5% ± 9.3%) and 1 min (18.5% ± 6.8%) after 6-CA for the stronger individuals (p < 0.05). However, no post-activation potentiation was induced in the weaker individuals in either protocol. Voluntary performance increased at 4 (7.0% ± 4.5%) and 7 (8.2% ± 4.3%) min after 18-CA for stronger individuals (p < 0.05). However, there was no post-activation performance enhancement in either protocol for weaker individuals. Thus, CA with a relatively long contraction duration was optimal to maximize the subsequent voluntary performance for stronger individuals. It remains unknown whether CAs performed with relatively short or long contraction durations were optimal for weaker individuals.
Time to Recovery from Diabetic Ketoacidosis and its Predictors among Adult Diabetic Ketoacidosis Patients in DEBRE MARKOS Referral Hospital, North West Ethiopia, 2021: Retrospective Cohort Study
Authors: Temesgen Dessie , Miskir Yihun , Dessie Getenet , Nuru Ahmed , Tesema Berihun Bantie , Azmeraw Molla , Teym Abraham , Dagne Melesew
Published: April 2022

Introduction

Diabetic ketoacidosis is an acute life-threatening complication of diabetes mellitus. With appropriate treatments, diabetic ketoacidosis patients are expected to make a full recovery within 24 hours. Previous studies did not address variables such as duration of diabetic ketoacidosis symptoms, and blood glucose level. In addition, the recovery time and its predictors of diabetic ketoacidosis in adult patients are not well known in Ethiopia.

Objective

To assess time to recovery from diabetic ketoacidosis and its predictors among adult diabetic ketoacidosis patients in Debre Markos referral hospital, North West Ethiopia, 2021

Methods

A retrospective cohort study was employed among 452 records of adult diabetic ketoacidosis patients who were admitted starting from January 1, 2016 to January 1, 2021 using their medical registration number. Data were entered into Epi-data version 4.6 and analyzed using Stata version 14. A Kaplan Meier survival curve was used to estimate diabetic ketoacidosis-free survival time. In addition, a generalized log-rank test was utilized to compare diabetic ketoacidosis-free survival time between different categorical explanatory variables. Cox proportional hazards model was used to identify predictors of time to diabetic ketoacidosis recovery time. Variables with a P-value < 0.25 in the bivariable analysis were entered into a multivariable Cox proportional hazards model to identify predictors of recovery time at p≤ 0.05.

Result

The median time to recovery from diabetic ketoacidosis for all observations was 24 hours. Severity of diabetic ketoacidosis (AHR=0.24, 95%CI=0.16-0.35), duration of diabetic ketoacidosis (AHR=0.46, 95%CI 0.33-0.64), diabetes duration (AHR=1.74, 95%CI 1.35-2.25), and random blood sugar level (AHR=0.64, 95%CI= (0.51-0.79) were significant predictors of recovery time.

Conclusion and recommendation

The median time to recovery from diabetic ketoacidosis was relatively prolonged. The hospital shall give special attention to patients with the identified predictors. Further study using a prospective design by including admission pH and admission serum potassium level is advised.
Prevalence of diabetic macular edema and risk factors among diabetic patients at the University of Gondar Tertiary Eye Care and Training Center, North West Ethiopia
Authors: Kabtu Endale , Tsegaw Asamere
Published: April 2022

BACKGROUND

Diabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes mellitus. The prevalence of DME globally is around 6.8 % and in Ethiopia range from 5.7% to 11%.Different factors are associated with DME including poor glycemic control, longer duration, hypertension, dyslipidemia

OBJECTIVE

To determine the prevalence and associated factors of diabetic macular edema among diabetic patients attending University of Gondar (UOG) hospital, tertiary eye care and training center, NW Ethiopia

METHODS

A hospital based cross-sectional study was conducted from March 2021 to October 2021. Socio-demographic, clinical and laboratory data of patients was gathered. The collected data was entered into epi-data 4.6 version, exported to SPSS version 20 and analyzed.

RESULTS

A total of 165 diabetic patients were enrolled with mean age of 54.71 ±13.66 years, 50.9% male, 85.5% urban dwellers, 79.9% type 2 DM, 49.7% on oral hypoglycemic agents and the mean duration of diabetes was 7.93 years. Cataract was the commonest ocular morbidity and 42% of patients had at least mild vision impairment. The overall prevalence of DME was 17% and 5.5% of patients had clinically significant macular edema (CSME). The presence of proteinuria was 8.04 times more likely to have DME.

CONCLUSION

The prevalence of DME among our patients was high. The presence of proteinuria was significantly associated with DME. Screening of diabetic patients for sight threatening retinopathy early and appropriate treatment is recommended.
Systems Biology Approach of Understanding Insulin Resistance: Linkage between Type 2 Diabetes & Alzheimer’s Disease
Authors: Villasis Osbert Bryan , Tan Daniel Stanley , Mendoza Eduardo , Lao Angelyn
Published: April 2022

Insulin resistance (IR) is a physiological condition in which cells in the body become resistant to insulin. It is a known risk factor associated to type 2 diabetes (T2D). Recently, the idea that IR plays an important role in the progression of Alzheimer’s disease (AD) has been gaining a lot of attention. Comparing the components of the insulin signalling pathway in relation to T2D and AD, there seems to be a lot of commonality. However, on what role IR plays in linking T2D and AD remains unknown. Through systems biology approach, we extended an existing mathematical model (i.e. ODE based) to study and understand the role IR plays in linking T2D and AD. The simulations, together with the experimental data collected from the literature, show that the common components in T2D and AD express the same dynamical behaviors. This result provides the bases for further modelling of the insulin signaling pathway in determining the link between T2D and AD.
The Main Themes and Experiences Shared with the Hashtag #BlackintheIvory: A Qualitative Analysis
Authors: Adewumi Mopileola Tomi , Delgado Paul , Carr Marvin , Sowah Emily , Vassar Matt
Published: April 2022

Background

The movement #BlackintheIvory gave Black academics an opportunity to connect through a social media platform allowing them to share common experiences in the pursuit of higher education. Through the analysis of Twitter posts, using the hashtag #BlackintheIvory, this study investigates the main themes identified among Black scholars in academia and their shared experiences with teaching, mentoring, collegiality, identity, service, and racism.

Methods

Using the Twitter API, we isolated all publicly available tweets, which can include text, images, and links to websites, posted with the hashtag #BlackintheIvory on the Twitter website (www.twitter.com) from the inception of the hashtag in June 2020 to the end of December 2020. To evaluate the tweets, we categorized the tweets inductively. Based on the content of the posts, we identified 6 themes: Teaching, Mentoring, Collegiality, Identity, Service, and Racism.

Results

Our search yielded a total of 12,538 original posts, including tweets between inception in June 2020 to December 2020 from profiles made public (excluding modified tweets and duplicate tweets). We selected and analyzed the top retweeted 2500 tweets, which is 20% (2500/12538) of the total number of downloaded tweets. The greatest percentage of posts were about Teaching (881; 35%), followed by Service (441; 18%) and Racism (414; 17%). The remaining tweets were categorized as Collegiality (388; 15%), Identity (210; 8%), and Mentoring (166; 7%) of the total number of tweets from June-December 2020.

Conclusion

The experiences, perspectives, and narratives among the Black diaspora within #BlackintheIvory are not uniform. The commonality exists within the structural systemic racism which impacts Black academics within the ivory tower, this study is a resounding wake-up call for action.

Funding

This study was not subject to any funding
Genetic admixture history and forensic characteristics of Tibeto-Burman-speaking Qiang people explored via the newly developed Y-STR panel and genome-wide SNP data
Authors: He Guanglin , Adnan Atif , Wang Mengge , Al-Qahtani Wedad Saeed , Safhi Fatmah Ahmed , Yeh Hui-Yuan , Hadi Sibte , Wanag Chuan-Chao , Liu Chao , Yao Jun
Published: April 2022

Fine-scale patterns of population genetic structure and diversity of ethnolinguistically diverse populations are important for biogeographical ancestry inference, kinship testing and also for the development and validation of new kits focused on forensic personal identification. Analyses focused on forensic markers and genome-wide SNP data can provide new insights into the origin, admixture processes and forensic characteristics of targeted populations. Qiang people with a large sample size among Tibeto-Burman-speaking populations widely reside in the middle latitude of the Tibetan Plateau. However, their genetic structure and forensic features have remained uncharacterized due to the paucity of comprehensive genetic analyses. Here, we first developed and validated the AGCU-Y30 Y-STR panel, which contains slowly and moderately mutating Y-STRs, and then we conducted comprehensive population genetic analyses based on Y-STRs and genome-wide SNPs to explore the admixture history of Qiang people and their neighbours. The validated results of this panel showed that the new Y-STR kit was sensitive and robust enough for forensic applications. Haplotype diversity (HD) ranging from 0.9932 to 0.9996 and allelic frequencies ranging from 0.001946 to 0.8326 in 514 Qiang people demonstrated that all included markers were highly polymorphic in Tibeto-Burman people. Population genetic analyses based on Y-STRs (RST, FST, MDS, NJ, PCA and MJNs) revealed that the Qiang people harboured a paternally close relationship with lowland Tibetan-Yi corridor populations. Furthermore, we made a comprehensive population admixture analysis among Eurasian modern and ancient populations based on the shared alleles. We determined that the Qiang people were a genetically admixed population and showed the closest relationship with Tibetan and Neolithic Yellow River farmers. Admixture modelling showed that Qiang people shared the primary ancestry with Tibetan and was derived from North China, supporting the hypothesis of common origin between Tibetan and Qiang people.
The effect of calcium supplementation in people under 35 years old: A systematic review and meta-analysis of randomized controlled trials
Authors: Liu Yupeng , Le Siyu , Liu Yi , Jiang Huinan , Ruan Binye , Huang Yufeng , Ao Xuemei , Shi Xudong , Fu Xiaoyi , Wang Shuran
Published: April 2022

Background and objective

The effect of calcium supplementation on bone mineral accretion in people under 35 years old is inconclusive. To comprehensively summarize the evidence for the effect of calcium supplementation on bone mineral accretion in young populations (≤35 years).

Design

This is a systematic review and meta-analysis.

Data sources

The Pubmed, Embase, ProQuest and CENTRAL databases were systematically searched from database inception to April 25, 2021.

Eligibility

Randomized clinical trials assessing the effects of calcium supplementation on bone mineral density (BMD) or bone mineral content (BMC) in people under 35 years old.

Results

This systematic review and meta-analysis identified 43 studies involving 7382 subjects. Moderate certainty of evidence showed that calcium supplementation was associated with the accretion of BMD and BMC, especially on femoral neck (SMD 0.627, 95% CI 0.338 to 0.915; SMD 0.364, 95% CI 0.134 to 0.595; respectively) and total body (SMD 0.330, 95% CI 0.163 to 0.496; SMD 0.149, 95% CI 0.006 to 0.291), also with a slight improvement effect on lumbar spine BMC (SMD 0.163, 95% CI 0.008 to 0.317), no effects on total hip BMD and BMC and lumbar spine BMD were observed. Very interestingly, subgroup analyses suggested that the improvement of bone at femoral neck was more pronounced in the peri-PBM population (20-35 years) than the pre-PBM population (<20 years).

Conclusion

Our findings provided novel insights and evidence in calcium supplementation, which showed that calcium supplementation significantly improves bone mass, implying that preventive calcium supplementation before or around achieving PBM may be a shift in the window of intervention for osteoporosis.

Funding

This work was supported by Wenzhou Medical University grant [89219029].
Post-operative pain management practice and associated factors among nurses working at public hospitals, in Oromia region, Ethiopia
Authors: Dechasa Abebe , Kurke Abdo , Abdisa Desalegn , Gurmu Yonas
Published: April 2022

Background

Management of postoperative pain leads to positive patient progress and shortens the duration of hospital stay. Nurses, who are the majority in almost all hospitals and spend most of their time with the patients, are expected to play big role in the postoperative pain management practice. However, there is paucity of information regarding postoperative pain management practice and its associated factors among nurses.

Objective

To assess postoperative pain management practice and associated factors among nurses working at public hospitals, in Oromia Region, Ethiopia, 2020.

Methods

Institutional based cross sectional study was employed among randomly selected 377 nurses working at public hospitals in Oromia region, Ethiopia. Data was collected by distributing structured self-administered questionnaires that adapted from different literatures. The data were entered into Epi data version 3.1 and exported to SPSS version 22 for analysis. Variables with significant association in the bivariate analyses were entered into a multivariable regression analysis to identify the independent factors associated with nurses’ postoperative pain management practice. Significant factors were declared at P<0.05.

Result

The result showed that, 66% of nurses had good pain management practice. Nurses favorable attitude towards post-operative pain management [AOR: 4.698, 95% CI: (2.725-8.100)], having access to read pain management guideline [AOR: 3.112, 95% CI: (1.652-5.862)], adequate knowledge of post-operative pain management [AOR: 2.939, 95% CI: (1.652-5.227)], working at Operation Room [AOR: 2.934, 95% CI: (1.27-6.795)] and received training on pain management [AOR: 3.289, 95% CI: (1.461-7.403)] were significantly associated with the practices of postoperative pain management.

Conclusion and recommendation

Sixty six percent of participants (nurses) have a good level of practice of postoperative pain management. Training on post-operative pain management (POPM), access to pain management guidelines, knowledge and attitude are significant factors in post-operative pain management practice. Governmental and other bodies concerned to post-operative care quality needs to show commitment on availing infrastructures like pain management guideline and improving nurses knowledge and attitude.
Association between breastfeeding, host genetic factors, and calicivirus gastroenteritis in a Nicaraguan birth cohort
Authors: Vielot Nadja A. , François Ruthly , González Fredman , Reyes Yaoska , Huseynova Emilya , Gutierrez Lester , Nordgren Johan , Toval-Ruiz Christian , Vilchez Samuel , Vinjé Jan , Becker-Dreps Sylvia , Bucardo Filemon
Published: April 2022

Background

Norovirus and sapovirus are important causes of childhood acute gastroenteritis (AGE). Breastfeeding prevents AGE generally; however, it is unknown if breastfeeding prevents AGE caused specifically by norovirus and sapovirus.

Methods

We investigated the association between breastfeeding and norovirus or sapovirus AGE episodes in a birth cohort. Weekly data on breastfeeding and AGE episodes were captured during the first year of life. Stools were collected from children with AGE and tested by RT-qPCR for norovirus and sapovirus. Time-dependent Cox models estimated associations between weekly breastfeeding and time to first norovirus or sapovirus AGE.

Findings

From June 2017 to July 2018, 444 newborns were enrolled in the study. In the first year of life, 69 and 34 children experienced a norovirus and a sapovirus episode, respectively. Exclusive breastfeeding lasted a median of 2 weeks, and any breastfeeding lasted a median of 42 weeks. Breastfeeding in the last week did not prevent norovirus (HR: 1.09, 95% CI: 0.62, 1.92) or sapovirus (HR: 1.00, 95% CI: 0.82, 1.21) AGE in a given week, adjusting for household sanitation, consumption of high-risk foods, and mother’s and child’s histo-blood group phenotypes. Maternal secretor-positive phenotype was protective against norovirus AGE, whereas child’s secretor-positive phenotype was a risk factor for norovirus AGE.

Interpretation

Exclusive breastfeeding in this population was short-lived, and no conclusions could be drawn about its potential to prevent norovirus or sapovirus AGE. Non-exclusive breastfeeding did not prevent norovirus or sapovirus AGE in the first year of life. However, maternal secretor-positive phenotype was associated with a reduced hazard of norovirus AGE.

WHAT IS KNOWN

–

Breastfeeding prevents acute gastroenteritis (AGE) in nursing infants.

–

It is unknown if breastfeeding prevents AGE caused by norovirus or sapovirus, which are leading causes of childhood AGE worldwide.

–

Host genetic factors can influence AGE risk, and the mediating effects of breastfeeding are unclear.

WHAT IS NEW

–

Exclusive breastfeeding was rare, and breastfeeding did not prevent norovirus (hazard ratio 1.09, 95% CI: 0.62, 1.92) or sapovirus (hazard ratio 1.00, 95% CI: 0.82, 1.21) AGE.

–

Secretor-positive phenotype of the child and the mother may be more important than breastfeeding in determining norovirus and sapovirus AGE risk in this setting.
Neural network approach to somatic SNP calling in WGS samples without a matched control
Authors: Vilov Sergey , Heinig Matthias
Published: April 2022

Somatic variants are usually called by analysing the DNA sequences of a tumor sample in conjunction with a matched normal. However, a matched normal is not always available for instance in diagnostic settings. To unlock such data for basic research single-sample somatic variant calling is required. Previous approaches can not easily be applied in the case of typical whole genome sequencing (WGS) samples.We present a neural network-based approach for calling somatic single nucleotide polymorphism (SNP) variants in tumor WGS samples without a matched normal. The method does not require any manual tuning of filtering parameters and can be applied under the conditions of a typical WGS experiment. We demonstrate the effectiveness of the proposed approach by reporting its performance on 5 SNP datasets corresponding to 5 different cancer types.

The proposed method is implemented in Python 3.6 and available as a GitHub repository at https://github.com/heiniglab/deepSNP.
Epigenetics and island-mainland divergence in an insectivorous small mammal
Authors: Cossette Marie-Laurence , Stewart Donald T. , Haghani Amin , Zoller Joseph A. , Shafer Aaron B.A. , Horvath Steve
Published: April 2022

Geographically isolated populations, specifically island-mainland counterparts, tend to exhibit phenotypic variation in many species. The so-called island syndrome occurs when different environmental pressures lead to insular divergence from mainland populations. This phenomenon can be seen in an island population of Nova Scotia masked shrews (Sorex cinereus), which have developed a specialized feeding habit and digestive enzyme compared to their mainland counterparts. Epigenetic modifications, such as DNA methylation (DNAm), can impact phenotypes by altering gene expression without changing the DNA sequence. Here, we used ade novomasked shrew genome assembly and a mammalian methylation array profiling 37 thousand conserved CpGs to investigate morphological and DNA methylation patterns between island and mainland populations. Island shrews were morphologically and epigenetically different than their mainland counterparts, exhibiting a smaller body size. A gene ontology enrichment analyses of differentially methylated CpGs implicated developmental and digestive system related pathways. Based on our shrew epigenetic clock, island shrews might also be aging faster than their mainland counterparts. This study provides novel insight on phenotypic and epigenetic divergence in island-mainland mammal populations and suggests an underlying role of methylation in island-mainland divergence.
Effect of Chlonisol (2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol) on Overall Survival in Laboratory Rodents with Intracranial Tumors: A Meta-analysis of Preclinical Studies
Authors: Murazov Iaroslav G. , Stukov Alexander N. , Zmitrichenko Iuliia G.
Published: April 2022

Background

The need for new, effective, and affordable drugs for the treatment of primary and metastatic brain tumors remains unsatisfactory. Preclinical studies of chlonisol (2-[3-(2-chloroethyl)-3-nitrosoureido]-1,3-propanediol) showed promising results in the treatment of experimental intracranial tumors.

Objectives

To apply a meta-analytical approach to estimate the combined effect size of chlonisol on overall survival (OS) in rodents with brain tumor transplants.

Search strategy

Data for the meta-analysis were obtained from the laboratory’s internal database from reports of preclinical studies of chlonisol.

Selection criteria

Eligible studies were parallel preclinical trials in rodents (mice, rats) with intracranially transplanted tumors. Chlonisol was compared with active control treatment (lomustine or temozolomide). All cytostatics were administered at the maximum tolerated dose (MTD). The duration of the studies was at least 90 days. The main outcome was OS-HR (hazard ratio).

Data analysis

We applied the inverse variance technique for the meta-analysis of HRs. In HR analysis we adopted a random-effect model.

Results

The analysis included seven trials with 132 rodents. Studies were conducted between 2016 and 2022. As a murine intracranial grafts we used Ehrlich’s carcinoma, Sarcoma 180 and the HER2-positive mammary tumor derived from a female FVB/N HER-2/neu transgenic mouse. Glioma 35 was transplanted into rats. Compared with active control, oral or intraperitoneal administration of chlonisol at MTD of 20 mg/kg, significantly reduced the risk of death by 63% (HR=0.37; 95% CI: 0.24-0.56; P<0.00001) in animals with intracranial tumors. The direction in favor of chlonisol was stable across studies despite the use of different animals and transplants, the routes of administration of chlonisol, and control treatment. No significant heterogeneity was observed between the studies (Tau2 = 0.03; Chi2 = 6.52; df = 6; P = 0.33; I2 = 8%).

Conclusion

Compared with lomustine and temozolomide, chlonisol treatment in MTD provides an important advantage in OS in animals with intracranial tumors. Our results may serve as a basis for further study of chlonisol as a chemotherapy agent for primary and metastatic brain tumors.
3D pose estimation enables virtual head-fixation in freely moving rats
Authors: Schneider Artur , Zimmermann Christian , Alyahyay Mansour , Steenbergen Florian , Brox Thomas , Diester Ilka
Published: April 2022

The impact of spontaneous movements on neuronal activity has created the need to quantify behavior. We present a versatile framework to directly capture the 3D motion of freely definable body points in a marker-free manner with high precision and reliability. Combining the tracking with neural recordings revealed multiplexing of information in the motor cortex neurons of freely moving rats. By integrating multiple behavioral variables into a model of the neural response, we derived a virtual head-fixation for which the influence of specific body movements was removed. This strategy enabled us to analyze the behavior of interest (e.g., front paw movements). Thus, we unveiled an unexpectedly large fraction of neurons in the motor cortex with tuning to the paw movements, which was previously masked by body posture tuning. Once established, our framework can be efficiently applied to large datasets while minimizing the experimental workload caused by animal training and manual labeling.
MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Unique Proteomic Networks and Variable Clinical Significance
Authors: Hacking Sean M. , Chou Charissa , Baykara Yigit , Wang Yihong , Uzun Alper , Uzun Ece D. Gamsiz
Published: April 2022

Mismatch repair (MMR) alterations are important prognostic and predictive biomarkers in a variety of cancer subtypes including colorectal and endometrial. However, in breast cancer (BC), the distinction and clinical significance of MMR is largely unknown. This may be due in part to the fact that genetic alterations in MMR genes are rare, and only seen to occur in around 3% of BCs. In the present study we analyzed TCGA data using a multi-sample protein-protein interactions (PPI) analysis tool, Proteinarium, and showed a distinct separation in the MMR deficient and intact specific networks. MMR deficient tumor specific networks have a highly connected cluster of histone genes, identified by unique PPI. We also found that distribution of MMR deficient breast cancer is more prevalent in HER2-enriched and triple-negative (TN) BC subtypes compared to luminal BCs. Poorer survival was seen in patients with HER2-enriched BCs with MMR deficiency, whereas an improved survival was seen in TNBCs with MMR deficiency. We recommend defining MMR deficient breast cancer by next generation sequencing (NGS) when any somatic mutation is detected in one of the 7 MMR genes found in our study. Our recommendations include labeling patients with variants of undetermined significance (VUS) as MMR deficient supported by findings from distinct clusters of patients based on our network analysis. MMR may have a role in guiding the use of immunotherapy for both TN as well as HER2-enriched BC.
Covert attention to obstacles biases zebrafish escape direction
Authors: Zwaka Hanna , McGinnis Olivia J , Pflitsch Paula , Prabha Srishti , Mansinghka Vikash , Engert Florian , Bolton Andrew D
Published: April 2022

To study the evolutionary origins of object perception, we investigated whether a primitive vertebrate, the larval zebrafish, is sensitive to the presence of obstacles. The zebrafish, which has become a useful model to study brain-wide circuit dynamics, executes fast escape swims when in danger of predation. We posited that collisions with solid objects during escape would be maladaptive to the zebrafish, and therefore the direction of escape swims should be informed by the locations of barriers. To answer this question, we developed a novel closed-loop high-speed imaging rig outfitted with barriers of various qualities. Using this system, we show that when larval zebrafish escape in response to a non-directional vibrational stimulus, they use visual scene information to avoid collisions with obstacles. Our study demonstrates that fish compute absolute distance to obstacles, as distant barriers outside of collision range elicit less bias than nearby collidable barriers that occupy the same visual field. The computation of barrier features is covert, as the fish’s reaction to barriers during routine swimming does not predict that they will avoid barriers when escaping. Finally, through two-photon laser ablations, we suggest the presence of an excitatory input from the visual system to Mauthner cells in the brainstem escape network that is responsible for escape direction bias. We propose that zebrafish construct “object solidity” via an integrative visual computation that is more complex than retinal occupancy alone, suggesting a primitive understanding of object features and possibly the origins of a structured model of the physical world.
Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes
Authors: Ban Ivana , Tomašić Lucija , Trakala Marianna , Tolić Iva M. , Pavin Nenad
Published: April 2022

Most tumors have abnormal karyotypes, which arise from mistakes during mitotic division of healthy euploid cells and evolve through numerous complex mechanisms. In a recent mouse model with high levels of chromosome missegregation, chromosome gains dominate over losses both in pretumor and tumor tissues, whereas tumors are characterized by gains of chromosomes 14 and 15. However, the mechanisms driving clonal selection leading to tumor karyotype evolution remain unclear. Here we show, by introducing a mathematical model based on a concept of a macro-karyotype, that tumor karyotypes can be explained by proliferation-driven evolution of aneuploid cells. In pretumor cells, increased apoptosis and slower proliferation of cells with monosomies lead to predominant chromosome gains over losses. Tumor karyotypes with gain of one chromosome can be explained by karyotype-dependent proliferation, while for those with two chromosomes an interplay with karyotype-dependent apoptosis is an additional possible pathway. Thus, evolution of tumor-specific karyotypes requires proliferative advantage of specific aneuploid karyotypes.

Significance

Most tumors have an erroneous number of chromosomes, which arise from mistakes during division of healthy cells and evolve through numerous complex mechanisms, including chromosome missegregation, cell proliferation and cell death. However, understanding the mechanisms leading to tumor evolution from healthy cells is a hot topic. Here we show, by introducing a “macro-karyotype model”, that perturbed number of chromosomes in tumor cells arises predominantly from faster division of cells characterized by a specific combination of chromosomes, or together with irregular cell death. This finding, strengthened by comparison of our theory with experimentally observed combination of chromosomes in different stages of tumor development, gives a direction for future experiments in identifying the key processes underlying tumor development.
Evidence for a Single Rather than a Triple Dissociation in the Medial Temporal Lobe: an fMRI Recognition Memory Replication Study
Authors: Van Julie , Nielsen Sam E. , Kirwan C. Brock
Published: April 2022

Common research practices in neuroimaging studies using functional magnetic resonance imaging may produce outcomes that are difficult to replicate. Results that cannot be replicated have contributed to a replication crisis in psychology, neuroscience, and other disciplines over the years. Here we replicate two previous papers in which the authors present two analysis paths for a dataset in which participants underwent fMRI while performing a recognition memory test for old and new words. Both studies found activation in the medial temporal lobe including the hippocampus, with the first demonstrating a distinction in activation corresponding to true and perceived oldness of stimuli and the second demonstrating that activation reflects the subjective experience of the participant. We replicated the behavioral and MRI acquisition parameters reported in the two target articles (Daselaar, Fleck, & Cabeza, 2006; Daselaar, Fleck, Prince, et al., 2006) with N=53 participants. We focused fMRI analyses on regions of interest reported in the target articles examining fMRI activation for differences corresponding with true and perceived oldness and those associated with the subjective memory experiences of recollection, familiarity, and novelty. Comparisons between true and perceived oldness revealed main effects not only for true, but also perceived oldness along with significant interaction effects. We replicate the findings of recollection and familiarity signals in the hippocampus and medial temporal lobe cortex, respectively, but failed to replicate a novelty signal in the anterior medial temporal lobe. These results remained when we analyzed only correct trials, indicating that the effects were not due to selectively averaging correct and incorrect trials. Taken together, our findings demonstrate that activation in the hippocampus corresponds to the subjective experience associated with correct recognition memory retrieval.

Highlights

We replicated the methods of two influential papers using fMRI to examine recognition memory.

The hippocampus consistently signals the subjective experience of remembering but not the objective old/new status of stimuli.

Hippocampal response was consistent with recollection while the medial temporal lobe (MTL) cortex response was consistent with familiarity.

We did not observe any regions in the MTL that signaled novelty, indicating recognition memory does not involve a triple dissociation of recollection, familiarity, and novelty in the MTL.
Generative power of a protein language model trained on multiple sequence alignments
Authors: Sgarbossa Damiano , Lupo Umberto , Bitbol Anne-Florence
Published: April 2022

Computational models starting from large ensembles of evolutionarily related protein sequences capture a representation of protein families and learn constraints associated to protein structure and function. They thus open the possibility for generating novel sequences belonging to protein families. Protein language models trained on multiple sequence alignments, such as MSA Transformer, are highly attractive candidates to this end. We propose and test an iterative method that directly employs the masked language modeling objective to generate sequences using MSA Transformer. We demonstrate that the resulting sequences score as well as natural sequences, for homology, coevolution and structure-based measures. For large protein families, our synthetic sequences have similar or better properties compared to sequences generated by Potts models, including experimentally-validated ones. Moreover, for small protein families, our generation method based on MSA Transformer outperforms Potts models. Our method also more accurately reproduces the higher-order statistics and the distribution of sequences in sequence space of natural data than Potts models. MSA Transformer is thus a strong candidate for protein sequence generation and protein design.
Snake Fungal Disease Caused by the Fungal Pathogen Ophidiomyces ophidiicola in Texas
Authors: Lizarraga Alan , Hart Lezley , Nolen Michele , Williams Lance , Glavy Joseph
Published: April 2022

The pathogen Ophidiomyces ophidiicola (O.o.), widely known as the primary cause of snake fungal disease (SFD) has been detected in Texas’s naïve snakes. Our team set out to begin to characterize O. ophidiicola’s spread in east Texas. From July 2019 until October 2021, we sampled 176 snakes across east Texas and detected 27 positives cases (qPCR confirmed 27/176). From a ribbon snake with clear clinical display, we isolated and cultured what we believe to be the Texas isolate of O. ophidiicola. With over 1/10 snakes that may be infected in East Texas, gives credence to the onset of SFD in Texas.
A combinatorial anticancer drug screen identifies off-target effects of epigenetic chemical probes
Authors: Barghout Samir H. , Mann Mandeep K. , Yu Yifan , Schimmer Aaron D. , Schapira Matthieu , Arrowsmith Cheryl H. , Barsyte-Lovejoy Dalia
Published: April 2022

Anticancer drug response is determined by genetic and epigenetic mechanisms. To identify the epigenetic regulators of anticancer drug response, we conducted a chemical epigenetics screen using chemical probes that target different epigenetic modulators. In this screen, we tested 31 epigenetic probes in combination with 14 mechanistically diverse anticancer agents and identified 8 epigenetic probes that significantly potentiate the cytotoxicity of TAK-243, a first-in-class ubiquitin-activating enzyme (UBA1) inhibitor evaluated in several solid and hematologic malignancies. These probes are TP-472, GSK-864, A-196, UNC1999, SGC-CBP30 and PFI-4 (and its related analogs GSK6853 and GSK5959), and they target BRD9/7, mutant IDH1, SUV420H1/2, EZH2/1, p300/CBP and BRPF1B, respectively. In contrast to epigenetic probes, negative control compounds did not have a significant impact on TAK-243 cytotoxicity. Potentiation of TAK-243 cytotoxicity was associated with reduced ubiquitylation and induction of apoptosis. Mechanistically, epigenetic probes exerted their potentiation by inhibiting the efflux transporter ABCG2 without inducing significant changes in the ubiquitylation pathways or ABCG2 expression levels. The identified probes shared chemical scaffold similarities with TAK-243 and could potentially interact with ABCG2 as assessed by docking analysis. Based on these data, we have developed a cell-based assay that can quantitatively evaluate ABCG2 inhibition by drug candidates. In conclusion, our study identifies epigenetic chemical probes that profoundly potentiate TAK-243 cytotoxicity through off-target ABCG2 inhibition. We also provide experimental evidence that several negative control compounds cannot exclude a subset of off-target effects of chemical probes. Finally, potentiation of TAK-243 cytotoxicity can serve as a quantitative measure of ABCG2-inhibitory activity.
Ganglioside enriched phospholipid vesicles induce cooperative Aβ oligomerization and membrane disruption
Authors: Saha Jhinuk , Bose Priyankar , Dhakal Shailendra , Ghosh Preetam , Rangachari Vijayaraghavan
Published: April 2022

A major hallmark of Alzheimer disease (AD) is the accumulation of extracellular aggregates of amyloid-β (Aβ). Structural polymorphism observed among Aβ fibrils in AD brains seem to correlate with the clinical sub-types suggesting a link between fibril polymorphism and pathology. Since fibrils emerge from a templated growth of low-molecular weight oligomers, understanding the factors affecting oligomer generation is important. The membrane lipids are key factors that influence early stages of Aβ aggregation and oligomer generation, and cause membrane disruption. We have previously demonstrated that conformationally discrete Aβ oligomers can be generated by modulating the charge, composition, chain length of lipids and surfactants. Here, we extend our studies into liposomal models by investigating Aβ oligomerization on large unilamellar vesicles (LUVs) of total brain extracts (TBE), reconstituted lipid rafts (LRs) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Specifically, we varied the vesicle composition by varying the amount of GM1 gangliosides added as a constituent. We found that liposomes enriched in GM1 induce the formation of toxic, low-molecular weight oligomers that are isolable in a lipid-complexed form. Importantly, the data indicate that oligomer formation and membrane disruption are highly cooperative processes. Numerical simulations on the experimental data confirm cooperativity and reveal that GM1-enriched liposomes form twice as many numbers of pores as those without GM1. Overall, this study uncovers mechanisms of cooperativity between oligomerization and membrane disruption under controlled lipid compositional bias, and refocuses the significance of the early stages of Aβ aggregation in polymorphism, propagation, and toxicity in AD.

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BioAct: Biomedical Knowledge Base Construction using Active Learning
Authors: Wright Dustin , Gentile Anna Lisa , Faux Noel , Beck Kristen L.
Published: April 2022

Creating and curating knowledge resources has been a paramount activity in the biomedical domain. In recent years, automated methods for knowledge base construction have flourished and have enabled large scale construction and curation of such resources. In the biological domain, techniques such as next generation sequencing produce new data at exponential rate, making mere manual curation of knowledge resources simply unfeasible. The major technology to automate knowledge base construction is Information Extraction — specifically tasks such as Named Entity Recognition or Relation Extraction. The major hurdle for IE methods is the availability of labelled data for training, which can be prohibitively expensive and challenging to obtain due to the need of domain experts. Active learning aims at minimizing the cost of manual labelling by only requiring it for smaller and more useful portions of the data. With this motivation, we devised a method to quickly construct highly curated datasets to enable biomedical knowledge base construction. The method, named BioAct, is based on a partnership between automatic annotation methods (leveraging SciBERT with other machine learning models) and subject matter experts and uses active learning to create training datasets in the biological domain. The main contribution of this work is twofold; in addition to the BioAct method itself, we publicly release an annotated dataset on antimicrobial resistance, produced by a team of subject matter experts using BioAct. Additionally, we simulate a knowledge base construction task using the MegaRes and CARD knowledge bases to provide insight and lessons learned about the usefulness of the annotated dataset for this task.