bluuebunny/crossref_metadata_2025 huggingface dataset:
Screen Time and Mental Health Among Adolescents
Authors: Ranjit Karina , Ntlantsana Vuyokazi , Tomita Andrew , Paruk Saeeda
Published: April 2022

The rise in use of digital technology among adolescents is unquestionable, with few studies having explored the effect of screen time on mental or behavior challenges in sub-Saharan Africa. We investigated the extent of screen time and its associations with mental/behavior challenges in South Africa. A multisite study was conducted among adolescents aged 15 to 17 years from three government schools in KwaZulu-Natal Province, South Africa. Measures included depressive symptoms (using Patient Health Questionnaire-9), behavioral problems (using Strengths and Difficulties Questionnaire), and screen time (using Children's Leisure Activities Study Survey). The prevalence of severe depressive symptoms, conduct features, and negative prosocial behavior was 11.2% (n = 20), 13.6% (n = 25), and 4.9% (n = 9), respectively. The mean screen time was 2.1 h/d (SD = 2.4) during weekday and 4.7 h/d (SD = 5.5) during weekend. Weekend screen time was significantly associated with a greater likelihood of severe depression and conduct challenges, based on multivariable regression. We also found that greater weekend cell phone use was significantly associated with lower prosocial behavior. No role of weekday screen time was detected in this study. Parents or legal guardians need to be aware of their children's weekend screen time, including cell phones, as access to digital devices becomes more ubiquitous in resource-limited settings.
Searching for Certainty During a Pandemic
Authors: Negri Ofir , Horesh Danny , Gordon Ilanit , Hasson-Ohayon Ilanit
Published: April 2022

The current study longitudinally examined the moderating effects of consuming different types of media (i.e., formal [news] and informal [social media, WhatsApp]) in the association among COVID-19–related worries, intolerance of uncertainty (IU), and posttraumatic stress symptoms (PTSSs). Data were collected at two time points during July and September 2020, with approximately 60 days between measurements. Results showed that both COVID-19–related worries and IU were found to be positively associated with PTSSs. An interaction with formal media consumption was found, so that when one's formal media consumption was high, he or she were most vulnerable to the aforementioned effects on the development of PTSSs. Our findings point to the interactive effects of both COVID-19 worries and IU with media consumption on the development of PTSSs. Although media consumption might provide information during uncertainty, it may also intensify PTSSs during times of crisis. Implications and limitations are discussed.
Preliminary Exploration on the Value of Shear Wave Elastography in Evaluating the Effectiveness of Microwave Ablation on Hepatic Malignancies
Authors: Luo Chunyue , Lin Jianying , Liu Guancheng , He Guangmin , Zuo Yanling , Dai Lu , Li Tao
Published: April 2022

Shear wave elastography (SWE) is a new type of ultrasonic elastography that can quantitatively assess the elasticity and stiffness of tissues. This study aimed to investigate the value of SWE in evaluating the effectiveness of microwave ablation in hepatic malignancies. A total of 24 patients (including 30 lesions) with liver malignancies receiving microwave ablation treatment at the Cancer Hospital of Guangzhou Medical University from April 2018 to January 2019 were enrolled. The elastography was performed within 1 week before and after ablation. The SWE values in the central zone, the marginal zone of the lesion, and peripheral liver parenchyma were collected and analyzed. Before ablation, the mean of SWE value was 65.80 ± 13.37 kPa for the central zone of the tumor and 39.93 ± 7.87 kPa for the marginal zone, both of which were significantly greater than that for the perinatal liver parenchyma (12.85 ± 2.67 kPa, both P < 0.05). In the central and marginal zone of the lesions, the SWE value was significantly elevated after ablation (both P < 0.001) but not in the peripheral liver parenchyma (P = 0.444). Receiver operating characteristic curve analysis showed that the cutoff value for ablation in the marginal zone was 53.87 kPa, suggesting that an SWE exceeding 53.87 kPa is an index guaranteeing the ablation effectiveness. These results suggested that SWE has the potential to be used in evaluating the effectiveness of microwave ablation in liver cancers.
Combinatorial language parent-report score differs significantly between typically developing children and those with Autism Spectrum Disorders
Authors: Arnold Matthew , Vyshedskiy Andrey
Published: April 2022

Prefrontal synthesis (PFS) is a component of constructive imagination. It is defined as the process of mentally juxtaposing objects into novel combinations. For example, to comprehend the instruction “put the cat under the dog and above the monkey,” it is necessary to use PFS in order to correctly determine the spatial arrangement of the cat, dog, and monkey with relation to one another. The acquisition of PFS hinges on the use of combinatorial language during early development in childhood. Accordingly, children with developmental delays exhibit a deficit in PFS, and frequent assessments are recommended for these individuals. In 2018, we developed the Mental Synthesis Evaluation Checklist (MSEC), a parent-reported evaluation designed to assess PFS and combinatorial language comprehension. In this manuscript we use MSEC to identify differences in combinatorial language acquisition between ASD (N=29138) and neurotypical (N=111) children. Results confirm the utility of the MSEC in distinguishing language deficits in ASD from typical development as early as 2 years of age (p<0.0001).
Effectiveness of mHEALTH Application at Primary Health Care to Improve Maternal and New-born Health Services in Rural Ethiopia: Comparative study
Authors: Kassa Aragie , Matlakala Mokgadi C.
Published: April 2022

Ethiopia has recently implemented mHealth technology on a limited scale to help increase the uptake of health services, including intervention for maternal and new-born health service utilisation. In this study, the effectiveness of the mHealth intervention was assessed by measuring the level of maternal health service utilization in 4 Health Centers in Ethiopia.

The study was comparative by design employing comparison of maternal and newborn health service utilization before and after initiation of mHealth implementation. Follow-up data of 800 clients were randomly selected and included in the study, to determine the magnitude of maternal and new-born health service utilization. Data analysis included comparison of pre-mHealth (baseline) with mHealth follow-up data, using independent t-test to compare magnitude of maternal and new-born health service utilization.

The mean of antenatal care follow-up during their recent pregnancy was 2.21(SD±1.02) and 3.43(SD±0.88) for baseline and intervention, respectively. Antenatal visit of four or more was reached for 55(13.8%) of the baseline and 256(64%) of pregnant women in the mHealth intervention group. Pregnant women’s timeliness to start ANC follow-up at baseline and intervention groups was 44.5% and 77.3%, respectively. Institutional delivery at baseline and intervention groups were 35.0% and was 71.2%, respectively. Of women who gave birth, 23.8% at baseline received first postnatal care within 6 hours, 11.3% within 6 days, and 6.8% within 6 weeks. In the intervention group, 84% delivered women received first postpartum within 6 hours after delivery, 70.8% after 6 hours, and 46% made their third postpartum visit within 6 weeks after delivery. Penta-3 vaccination coverage at baseline and mHealth intervention groups was 61.5% and 70.4%, respectively.

The study result suggest that the introduction of a low-cost mHealth technologies contributed to the observed improvement of maternal and new-born health service utilization. This intervention shows promise for scale up as well as to be applied to other health interventions beyond maternal and newborn health services.
Prevalence and Factors Associated with Chronic Kidney Disease among Patients Admitted to Medical Ward in a Tertiary Hospital, Northern Ethiopia, a Cross Sectional Study
Authors: Weldetensae Meskelu Kidu , Geberemedhin Migbnesh , Gebreselassie Measho , Berhe Ephrem
Published: April 2022

Introduction

Chronic Kidney Disease (CKD) is being recognized as a global public health problem. CKD is a major non-communicable disease with the global prevalence varying between 10.5% and 13.1%. Diabetes and hypertension appear to be the leading causes of CKD and End Stage Renal Disease worldwide. The aim of this study is to determine the prevalence of CKD and its associated factors among patients admitted to medical ward in a tertiary hospital, Northern Ethiopia.

Methodology

An institution based cross-sectional study was undertaken using systematic random sampling technique to select study participants. Sample sizes of 450 patients were included in the study. Data was collected using a pre-tested semi-structured questionnaire designed to meet the study objective. The data collection period was from October 20, 2017 to March 20, 2018 G.C. Data was analyzed using SPSS version 21.The odds ratio with their 95% confidence interval and P value were calculated. Statistical significance was declared if P value < 0.05.

Result

Of the 450 patients, 260(57.8%) were males. More than half (54.2%) were between ages of 25 to 40 years. The overall prevalence of CKD among patients admitted to medical ward was 17.3% (95% CI 13 - 29.9) and 14.4% (95 % CI 6.2 – 12.3) by Cockcroft Gault and MDRD equations respectively. Prevalence of stage 5 CKD was 61.5% by Cockcroft Gault equation. Hypertension AOR 3(95%CI 1.28, 4.1), history of recurrent urinary tract infection AOR 3.5 (95% CI 1.1, 7.3) and history of using nephrotoxic drugs AOR 3.4 (95% CI 2, 9.3) were significantly associated with CKD.

Conclusion

The prevalence of CKD among adult patients admitted to medical ward in tertiary hospital, Northern Ethiopia was high and majority of patients with CKD were stage 5. Hypertension, use of nephrotoxic agents and recurrent urinary tract infections were significantly associated with CKD.
Detection of Dugbe virus from ticks in Ghana
Authors: Addae Charlotte Adwoa , Wiley Michael , Pratt Catherine , Koehler Jeffrey W. , Addo Seth Offei , Mosore Mba , Yeboah Clara , Agbodzi Bright , Ladzekpo Danielle , Tagoe Janice A. , Behene Eric , Adrah Isaac , Defeamekpor Courage , Quaye Osbourne , Letizia Andrew , Nimo-Paintsil Shirley , Arimoto Hanayo , Diclaro Joseph W. , Dadzie Samuel
Published: April 2022

Vector-borne pathogens historically have impacted U.S. warfighters and active-duty personnel stationed both domestically and globally during deployments or forward operations. Tick-borne diseases continue to spread to new geographical regions affecting both animal and human health. In Ghana, there is limited information on the circulating tick-borne pathogens and their risk of infections. This military-to-military vector surveillance study focused on seven sites in Ghana: Navrongo, Airforce Base, 6th Battalion Infantry, Air Borne Force, Army Recruit Training School, 1st Battalion Infantry and 5th Battalion Infantry for detection of tick-borne pathogens. Ticks from these sites were collected by hand-picking with a pair of forceps from domesticated animals including cattle, sheep, goats and dogs. A total of 2,016 ticks were collected from two main ecological zones; the northern Sahel savannah and the coastal savannah. Amblyomma variegatum was the predominant species, accounting for 59.5% of the collected ticks. Next-generation sequencing allowed for Dugbe virus whole genome detection. This study reports the second detection of Dugbe virus in Ghana, which is closely related to Dugbe virus strains from Kenya and Nigeria. This study (sponsored by the Armed Forces Health Surveillance Branch-Global Emerg-ing Infections Surveillance Section) aimed to better inform Force Health Protection (FHP) decisions within the U.S. AFRICOM area of responsibility, the Ghana Armed Forces, and enhance global health security countermeasures. Further surveillance needs to be conducted within the country to determine the distribution of tick-borne pathogens to formulate effective control measures.

Author summary

The prevalence of Dugbe virus in tick species within Ghana was investigated. This study involved seven sampling sites that covered two ecological zones, the northern Sahel savannah and the coastal savannah. About 2,000 ticks were collected from cattle, sheep, goats and dogs and identified using a dissecting microscope. The most predominant tick species was Amblyomma variegatum (59.5%) also known as the tropical bont tick. Using Next-generation sequencing, the full genome of Dugbe virus was for the first time in Ghana identified in A. variegatum. This positive Amblyomma variegatum was collected from the Greater Accra region of Ghana within a military site. The virus was found to be related to Dugbe virus strains from Kenya and Nigeria. Findings from this study show that the trade of livestock across borders facilitates the spread of tick-borne pathogens hence there is a need to enforce measures that prevent the importation of potentially harmful ticks and tick-borne pathogens.
Built environment’s impact on COVID-19 transmission and mental health revealed by COVID-19 Participant Experience data from the All of Us Research Program
Authors: Luo Wenting , Baldwin Edwin , Jiang Anna Yi , Li Shujuan , Yang Bo , Li Haiquan
Published: April 2022

Objectives

The coronavirus disease 2019 (COVID-19) pandemic has led to millions of deaths. Effectively cutting the transmission of COVID-19 is essential to reduce the impact. Previous studies have observed the potential relationship between the built environment and COVID-19 transmission; however, to date, stringent studies investigating these relationships at the individual level are still insufficient. Here, we aim to examine the relationship between household types and COVID-19 infection (or mental health) during the early stages of the pandemic by using the All of Us Research Program COVID-19 Participant Experience (COPE) survey data.

Design

Based on 62,664 participants’ responses to COPE from May to July 2020, we matched the cases of self-reported COVID-19 status, anxiety, or stress, with controls of the same race, sex, age group, and survey version. We conducted multiple logistic regressions between one of the outcomes and household type under the adjustment of other related covariates, such as ethnicity, age, social distancing behavior, and house occupancy.

Results

Household type with a shared component was significantly associated with COVID-19 infection (OR=1.19, 95% CI 1.1 to 1.3; p=2×10−4), anxiety (OR=1.26, 95% CI 1.1 to 1.4; p=1.1×10−6), and stress (OR=1.29, 95% CI 1.2 to 1.4, p=4.3×10−10) as compared to free-standing houses after adjusting for the abovementioned confounding factors. Further, frequent nonessential shopping or outings, another indicator of the built environment, was also associated with COVID-19 infection (OR=1.36, 95% CI 1.1 to 1.8; p=0.02), but not associated with elevated mental health conditions.

Conclusion

Our study demonstrated that the built environment of houses with a shared component tends to increase the risk of COVID-19 transmission, which consequently led to more anxiety and stress for their dwellers. It also suggested the necessity to improve the quality of the built environment through planning, design, and management toward a more resilient society in coping with future pandemics.
Effect of common pregnancy and perinatal complications on offspring metabolic traits across the life course: a multi-cohort study
Authors: Elhakeem Ahmed , Ronkainen Justiina , Mansell Toby , Lange Katherine , Mikkola Tuija , Mishra Binisha H , Wahab Rama , Cadman Tim , Yang Tiffany , Burgner David , Eriksson Johan G , Järvelin Marjo-Riitta , Gaillard Romy , Jaddoe Vincent WV , Lehtimäki Terho , Raitakari Olli T , Saffery Richard , Wake Melissa , Wright John , Sebert Sylvain , Lawlor Deborah A
Published: April 2022

Backgroun

Common pregnancy and perinatal complications are associated with offspring cardiometabolic risk factors. These complications may influence multiple metabolic traits in offspring and these associations might differ with offspring age.

Methods

We used data from eight population-based cohort studies to examine and compare associations of pre-eclampsia (PE), gestational hypertension (GH), gestational diabetes (GD), preterm birth (PTB), small (SGA) and large (LGA) for gestational age (vs. appropriate size for gestational age (AGA)) with up to 167 plasma/serum-based nuclear magnetic resonance-derived metabolic traits encompassing lipids, lipoproteins, fatty acids, amino acids, ketones, glycerides/phospholipids, glycolysis, fluid balance, and inflammation. Confounder-adjusted regression models were used to examine associations (adjusted for maternal education, parity age at pregnancy, ethnicity, pre/early pregnancy body mass index and smoking, and offspring sex and age at metabolic trait assessment), and results were combined using meta-analysis by five age categories representing different periods of the offspring life course: neonates (cord blood), infancy (mean ages: 1.1-1.6y), childhood (4.2-7.5y); adolescence (12.0-16.0y), and adulthood (22.0-67.8y).

Results

Offspring numbers for each age category/analysis varied from 8,925 adults (441 PTB) to 1,181 infants (135 GD); 48.4% to 60.0% were females. Pregnancy complications (PE, GH, GD) were each associated with up to three metabolic traits in neonates (P≤0.001) with some limited evidence of persistence to older ages. PTB and SGA were associated with 32 and 12 metabolic traits in neonates respectively, which included an adjusted standardised mean difference of -0.89 standard deviation (SD) units for albumin with PTB (95%CI: -1.10 to -0.69, P=1.3×10−17) and -0.41SD for total lipids in medium HDL with SGA (95%CI: -0.56 to -0.25, P=2.6×10−7), with limited evidence of persistence to older ages. LGA was inversely associated with 19 metabolic traits including lower levels of cholesterol, lipoproteins, fatty acids, and amino acids, with associations emerging in adolescence, (e.g., -0.11SD total fatty acids, 95%CI: -0.18 to -0.05, P=0.0009), and attenuating with older age across adulthood.

Conclusions

These reassuring findings suggest little evidence of wide-spread and long-term impact of common pregnancy and perinatal complications on offspring metabolic traits, with most associations only observed for new-borns rather than older ages, and for perinatal rather than pregnancy complications.
Pre-Diagnostic Cognitive and Functional Impairment in Multiple Sporadic Neurodegenerative Diseases
Authors: Swaddiwudhipong Nol , Whiteside David J. , Hezemans Frank H. , Street Duncan , Rowe James B. , Rittman Timothy
Published: April 2022

INTRODUCTION

The pathophysiological processes of neurodegenerative diseases begin years before diagnosis. However, pre-diagnostic changes in cognition and physical function are poorly understood, especially in sporadic neurodegenerative disease.

METHODS

UK Biobank data was extracted. Cognitive and functional measures in individuals who subsequently developed Alzheimer’s Disease, Parkinson’s Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, or Multiple System Atrophy, were compared against those without neurodegenerative diagnoses. The same measures were regressed against time to diagnosis, after adjusting for the effects of age.

RESULTS

There was evidence for pre-diagnostic cognitive impairment and decline with time, particularly in Alzheimer’s. Pre-diagnostic functional impairment and decline was observed in multiple diseases.

DISCUSSION

The scale and longitudinal follow-up of UK Biobank participants provides evidence for cognitive and functional decline years before symptoms become obvious in multiple neurodegenerative diseases. Identifying pre-diagnostic functional and cognitive changes could improve selection for preventive and early disease-modifying treatment trials.

Research in Context

Systematic review

Studies of genetic dementia cohorts provide evidence for pre-diagnostic changes in disease biomarkers and cognitive function in several genetic neurode-generative diseases. The pre-diagnostic phase of sporadic neurodegenerative disease has been less well-studied. It is unclear whether early functional or cognitive changes are detectable in sporadic neurodegenerative disease.

Interpretation

We have established an approach to identify cognitive and functional pre-diagnostic markers of neurodegenerative disease years before diagnosis. We found disease-relevant patterns of pre-diagnostic cognitive and functional impairment, and observed a pre-diagnostic linear decline in a number of cognitive and functional measures.

Future Directions

Our approach can form the basis for pre-diagnostic cognitive and functional screening to recruit into trials of disease prevention and disease modifying therapies for neurodegenerative diseases. A screening panel based on cognition and function could be followed by disease-specific biomarkers to further improve risk stratification.
SARS-CoV-2 Omicron sublineage BA.2 replaces BA.1.1: genomic surveillance in Japan from September 2021 to March 2022
Authors: Hirotsu Yosuke , Maejima Makoto , Shibusawa Masahiro , Natori Yume , Nagakubo Yuki , Hosaka Kazuhiro , Sueki Hitomi , Mochizuki Hitoshi , Tsutsui Toshiharu , Kakizaki Yumiko , Miyashita Yoshihiro , Omata Masao
Published: April 2022

Objective

The new emerging Omicron strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently spreading worldwide. We aimed to analyze the genomic evolution of the shifting Omicron virus subtypes.

Methods

The study included 1,297 individuals diagnosed as SARS-CoV-2 positive by PCR test or antigen quantification test from September 2021 to March 2022. Samples were analyzed by whole genome sequencing analysis (n=489) or TaqMan assay (n=808).

Results

After the outbreak of the SARS-CoV-2 Delta strain, the Omicron strain spread rapidly in Yamanashi, Japan. BA.1.1 was the predominant sublineage of the Omicron strain from January to mid-February 2022, but the number of cases of sublineage BA.2 began to increase after mid-February, and this sublineage was shown to have replaced BA.1.1 by the end of March 2022. We observed higher viral and antigen levels of sublineage BA.2 than of sublineage BA.1.1 in nasopharyngeal swab samples. However, no difference in viral load by patient age was apparent between sublineages BA.1.1 and BA.2.

Conclusions

A transition from sublineage BA.1.1 to sublineage BA.2 was clearly observed over approximately one month. Omicron sublineage BA.2 was found to be more transmissible owing to its higher viral load regardless of patient age.
Impact of energy limitations on function and resilience in long-wavelength Photosystem II
Authors: Viola Stefania , Roseby William , Santabarabara Stefano , Nürnberg Dennis , Assunção Ricardo , Dau Holger , Sellés Julien , Boussac Alain , Fantuzzi Andrea , Rutherford A William
Published: April 2022

Photosystem II (PSII) uses the energy from red light to split water and reduce quinone, an energy-demanding process based on chlorophyll a (Chl-a) photochemistry. Two kinds of cyanobacterial PSII can use Chl-d and Chl-f to perform the same reactions using lower energy, far-red light. PSII from Acaryochloris marina has Chl-d replacing all but one of its 35 Chl-a, while PSII from Chroococcidiopsis thermalis, a facultative far-red species, has just 4 Chl-f and 1 Chl-d and 30 Chl-a. From bioenergetic considerations, the far-red PSII were predicted to lose photochemical efficiency and/or resilience to photodamage. Here, we compare enzyme turnover efficiency, forward electron transfer, back-reactions and photodamage in Chl-f-PSII, Chl-d-PSII and Chl-a-PSII. We show that: i) all types of PSII have a comparable efficiency in enzyme turnover; ii) the modified energy gaps on the acceptor side of Chl-d-PSII favor recombination via PD1+Phe- repopulation, leading to increased singlet oxygen production and greater sensitivity to high-light damage compared to Chl-a-PSII and Chl-f-PSII; ii) the acceptor-side energy gaps in Chl-f-PSII are tuned to avoid harmful back reactions, favoring resilience to photodamage over efficiency of light usage. The results are explained by the differences in the redox tuning of the electron transfer cofactors Phe and QA and in the number and layout of the chlorophylls that share the excitation energy with the primary electron donor. PSII has adapted to lower energy in two distinct ways, each appropriate for its specific environment but with different functional penalties.
Intraspecific diversity based on low temperature induced arrhythmia in embryonic heart of medaka (Oryzias latipes)
Authors: Yoshimura Wataru , Oda Shoji , Katsumura Takafumi , Mitani Hiroshi , Watanabe-Asaka Tomomi
Published: April 2022

Background

Cold tolerance during embryonic development, especially blood circulation is important for growth in poikilothermic animals. Medaka (Oryzias latipes), has cold tolerance and is distributed in the highest latitudes occupied by the genus Oryzias. Regarding cold tolerance in embryogenesis, Hd-rR strain belonging to the southern Japanese (S.JPN) group showed arrhythmia when the embryo was exposed to 15 °C in the heartbeat initiation period (st. 24), whereas the embryo of Odate medaka, which belongs to the northern Japanese (N.JPN) group, showed stable heartbeats.

Results

In this study, to verify the sensitivity to low temperature in the medaka wild populations, heartbeat intervals of st. 24 embryos derived from three N.JPN, eight S.JPN, and two western Korean/Chinese (W.KOR) populations were investigated at an arbitrary temperature range of 12–15 °C. There was no significant difference in the mean values of the heart rates and the coefficient of variation (CV) of interbeat intervals in the N.JPN, S.JPN, and W.KOR groups. A temperature dependency of the CV within 12–15 °C was observed only in five S.JPN specimens, whereas three S.JPN, the N.JPN and the W.KOR specimens showed no alteration in CV with temperature. Temperature dependency of the heart rate was also varied in the S.JPN specimens.

Conclusions

These results suggest that the temperature dependency of the CV under 12–15 °C during the heartbeat initiation period is a variation within the S.JPN after the divergence from the N.JPN.
Deep Local Analysis evaluates protein docking conformations with Locally oriented Cubes
Authors: Behbahani Yasser Mohseni , Crouzet Simon , Laine Elodie , Carbone Alessandra
Published: April 2022

Abstract

With the recent advances in protein 3D structure prediction, protein interactions are becoming more central than ever before. Here, we address the problem of determining how proteins interact with one another. More specifically, we investigate the possibility of discriminating near-native protein complex conformations from incorrect ones by exploiting local environments around interfacial residues. Deep Local Analysis (DLA)-Ranker is a deep learning framework applying 3D convolutions to a set of locally oriented cubes representing the protein interface. It explicitly considers the local geometry of the interfacial residues along with their neighboring atoms and the regions of the interface with different solvent accessibility. We assessed its performance on three docking benchmarks made of half a million acceptable and incorrect conformations. We show that DLA-Ranker successfully identifies near-native conformations from ensembles generated by molecular docking. It surpasses or competes with other deep learning-based scoring functions. We also showcase its usefulness to discover alternative interfaces.

Availability

http://gitlab.lcqb.upmc.fr/dla-ranker/DLA-Ranker.git
Auditory Language Comprehension During Saccadic Eye Movements: An Investigation Using the N400 Event-Related Brain Potential
Authors: Dimigen Olaf , Schild Ulrike , Hohlfeld Annette , Sommer Werner
Published: April 2022

In many situations of everyday life, it is important to quickly understand a spoken message despite distraction by an already ongoing activity. Previous dual-task studies recording the N400 component of the event-related potential (ERP) have shown that auditory language comprehension can be strongly delayed by temporally overlapping additional tasks. In the current study, we investigated whether this interference is aggravated by the need for saccadic eye movements and visuospatial attention shifts in the overlapping task. In two dual-task experiments, a synonymy judgment task for spoken words was combined with a visual discrimination task at different stimulus onset asynchronies. In half of the trials, the primary visual task required a 10° exogenous saccade towards a peripheral stimulus. The timing of semantic processing in the secondary task was assessed by recording the N400. We replicated that with increasing temporal overlap between the tasks, the N400 component was strongly delayed. However, additional saccade-related processes in the primary task had no detrimental effects on concurrent spoken language processing on their own. Unexpectedly, we also observed that a preceding saccade consistently facilitated subsequent motoric processing in the visual task (as indexed by manual reaction times and the lateralized readiness potential), suggesting that saccade execution as such can significantly enhance subsequent processing.
Novel Bruton’s Tyrosine Kinase (BTK) substrates for time-resolved luminescence assays
Authors: Widstrom Naomi E. , Perez Minervo , Pratt Erica D. , Heier Jason L. , Blankenhorn John F. , Breidenbach Lindsay , Peterson Hannah , Parker Laurie L.
Published: April 2022

Bruton’s tyrosine kinase (BTK) is a well-documented target for cancer therapeutics due to its role in B-cell signaling pathways. However, inhibitor design is hindered by lack of tools to assess kinase activity. We used in vitro phosphoproteomics to determine BTK’s substrate preferences and applied this information to our updated data processing pipeline, KINATEST-ID 2.1.0. This pipeline generates a position-specific scoring matrix for BTK and a list of candidate synthetic substrates, each given a score. Characterization of selected synthetic substrates demonstrated a correlation between KINATEST-ID 2.1.0 score and biochemical performance in in vitro kinase assays. Additionally, by incorporating a known terbium-chelation motif, we adapted synthetic substrates for use in an antibody-free time-resolved terbium luminescence assay. This assay has applications in high-throughput inhibitor screening.
Introducing CELLBLOKS®: a novel organ-on-a-chip platform allowing a plug-and-play approach towards building organotypic models
Authors: Llabjani Valon , Siddique M.R. , Makos Anaïs , Abozoid Afaf , Hoti Valmira , Martin Francis L , Patel Imran I. , Raza Ahtasham
Published: April 2022

Human organs are structurally and functionally complex systems. Their function is driven by interactions between many specialised cell types, which is difficult to unravel on a standard petri-dish format. Conventional “petri-dish” approaches to culturing cells are static and self-limiting. However, current organ-on-a-chip technologies are difficult to use, have a limited throughput and lack compatibility with standard workflow conditions. We developed CELLBLOKS® as a novel “plug & play” organ-on-a-chip platform that enables straightforward creation of multiple-cell type organ specific microenvironments and demonstrate its advantages by building a liver model representative of live tissue function. CELLBLOKS® allows one to systematically test and identify various cell combinations that replicate optimal hepatic relevance. The combined interactions of fibroblasts, endothelial cells and hepatocytes were analysed using hepatic biochemistry (CYP3A4 and urea), cellular proliferation and transporter activities (albumin). The results demonstrate that optimal liver functional can be achieved in cross talk co-culture combinations compared to conventional mono-culture. The optimised CELLBLOKS® liver model was tested to analyse drug-induced liver toxicity using tamoxifen. The data suggests that our CELLBLOKS® liver model is highly sensitive to toxic insult compared to mono-culture liver model. In summary, CELLBLOKS® provides a novel cell culture technology for creating human relevant organotypic models that are easy and straightforward to establish in laboratory settings.
Sexual dimorphism and biomechanical loading in occipital bone morphological variation
Authors: Hoover Kara C. , Thomas Geoffrey P.
Published: April 2022

We explore the contribution of biological sex and biomechanical activity from subsistence to occipital bone variation. Previous studies have used occipital bone traits to determine biological sex and identify ancestry to differing degrees of success. Biomechanical stress from variation in subsistence and gender-based divisions of labor could perhaps explain some of the noise in the signal for these grouping variables. To explore this possibility, we used metric (foramen magnum length and breadth, external occipital protuberance depth, lambda-inion length, bicondylar breadth) and nonmetric traits (general occipital form, presence of a nuchal crest, and nuchal line count). We collected original data and mined published data for our analysis using skeletal collections of Native American hunter-gatherers and horticulturalists, a historic military site, and contemporary study collections. We find that the foramen magnum area exhibits sexual dimorphism and is not influenced by subsistence but the accuracy of sex estimation is only 71%, suggesting the chance of being correct at slightly more than two-thirds. All traits exhibited sex-based variation but only bicondylar breadth and lambda-inion exhibited subsistence-based variation. Given the limited amount of variance explained by either sex or sex and subsistence, biomechanics may still play a role but not from the influence of subsistence practices. Additional data from a wider array of skeletal samples, perhaps with known occupation, is warranted if we are to understand how occipital variation is shaped.

PRACTITIONER POINTS

The study examines the role of biological sex and biomechanical stress in shaping occipital morphology.

We introduce an area variable to describe the foramen magnum and apply ectocranial metric and nonmetric states for the first time to sex estimation.

We share methods and R code for cleaning data, testing assumptions, and analysis of research questions.
Transcriptional targets of senataxin and E2 promoter binding factors are associated with neuro-degenerative pathways during increased autophagic flux
Authors: Casey Aaron E. , Liu Wenjun , Hein Leanne K. , Sargeant Timothy J. , Pederson Stephen M. , Mäkinen Ville-Petteri
Published: April 2022

Autophagy is an intracellular recycling process that degrades harmful molecules, maintains optimal composition of cellular organelles and enables survival during starvation. Previous studies have demonstrated how transcription factors (TFs) can increase autophagy with therapeutic potential (impaired autophagy in the ageing brain, in particular, may be an important risk factor for dementia). To investigate the transcriptional regulation of autophagy from a systems perspective, we induced autophagy by amino acid starvation and mTOR inhibition in HeLa, HEK 293 and SH-SY5Y cells and used RNA-seq to measure gene expression at three time points. We observed 453 differentially expressed (DE) genes due to starvation and 284 genes due to mTOR inhibition (PFDR < 0.05 in every cell line). Pathway analyses confirmed enrichment of genes implicated in Alzheimer’s (PFDR < 0.001 in SH-SY5Y and HeLa) and Parkinson’s (PFDR ≤ 0.024 in SH-SY5Y and HeLa) diseases and amyotrophic lateral sclerosis (ALS, PFDR < 0.05 in 4 of 6 experiments). We then integrated Signaling Pathway Impact Analysis and TF target enrichment testing to predict which TF target genes were contributing to pathway perturbation. Differential expression of the Senataxin (SETX) target gene set was predicted to activate multiple neurodegenerative pathways (PFDR ≤ 0.04). Notably, SETX is a causal gene for a rare form of ALS. In the SH-SY5Y cells of neuronal origin, the E2F transcription family was predicted to activate Alzheimer’s disease pathway (PFDR ≤ 0.0065). SETX and E2F may be important mediators of transcriptional regulation of autophagy and may provide new therapeutic opportunities for neuro-degenerative conditions.
A positive feedback loop controls Toxoplasma chronic differentiation
Authors: Licon M. Haley , Giuliano Christopher J. , Chakladar Sundeep , Shallberg Lindsey , Waldman Benjamin S. , Hunter Christopher A. , Lourido Sebastian
Published: April 2022

Successful infection strategies must balance pathogen amplification and persistence. In Toxoplasma gondii, this is accomplished through differentiation into dedicated cyst-forming chronic stages that avoid clearance by the host immune system. The transcription factor BFD1 is both necessary and sufficient for stage conversion; however, its regulation is not understood. We examine five factors transcriptionally activated by BFD1. One of these is a cytosolic RNA-binding protein of the CCCH-type zinc finger family, which we name BFD2. Parasites lacking BFD2 fail to induce BFD1 and are consequently unable to fully differentiate in culture or in mice. BFD2 interacts with the BFD1 transcript in a stress-dependent manner. Deletion of BFD2 reduces BFD1 protein levels, but not mRNA abundance. The reciprocal effects on BFD2 transcription and BFD1 translation outline a positive feedback loop that enforces commitment to differentiation. BFD2 helps explain how parasites commit to the chronic gene-expression program and elucidates how the balance between proliferation and persistence is achieved over the course of infection.
The cytolethal distending toxin modulates cell differentiation and elicits epithelial to mesenchymal transition
Authors: Azzi-Martin Lamia , Touffait-Calvez Valentin , Everaert Maude , Jia Ruxue , Sifré Elodie , Seeneevassen Lornella , Varon Christine , Dubus Pierre , Ménard Armelle
Published: April 2022

We are frequently exposed to bacterial genotoxins, such as cytolethal distending toxin (CDT), a prevalent heterotrimeric toxin whose active moiety is its CdtB subunit. CdtB triggers potent DNA damage, predisposing factors in the development of cancers, in host cells. CDT fromHelicobacter hepaticus, a mouse pathogen, was shown to be directly involved in the development of murine hepatocarcinoma. Preliminary studies have shown that CDT induces certain phenotypes reminiscent of epithelial to mesenchymal transition (EMT), a process by which cells lose their epithelial characteristics in favor of mesenchymal ones, conducive to cell motility. In the present study, we investigated the different steps of EMT using liver tissues of mice infected withH. hepaticus, as well as human epithelial cell lines and xenograft mouse models followingH. hepaticusCdtB expression. Most of the different steps of the EMT process were reproduced throughout the studied models. Indeed, microarray data showed a CdtB- dependent regulation of EMT-related transcripts. The key transcriptional regulators of EMT (SNAIL1 and ZEB1) and EMT markers (Vimentin, Fibronectin and α5β1 integrin) were upregulated both at RNA and protein levels in response to CdtB. It also induced cell-cell junctions’ disassembly, causing individualization of cells and acquisition of a spindle-like morphology. CdtB activated the expression and activity of matrix metalloproteases and increased cell motility. This study demonstrated that CDT/CdtB elicits EMT process activation, supporting the idea that infection with genotoxin-producing bacteria can promote malignant transformation.

Author Summary

We are frequently exposed to infection with genotoxin--producing bacterial from the gut microbiota, such as cytolethal distending toxin (CDT). CDT,viaits active CdtB subunit, causes severe DNA damage in host cells, well-known risk factor of cancer development and progression. Chronic infection with CDT-producing bacteria is thus involved in cancer development. CDT is widespread among many bacteria and its impact in human cancer seems likely underestimated. Despite its major significance, CDT remains little studied. Here, we showed that cells exposed to CdtB are no longer cohesive, become individualized and acquire a spindle-shaped morphology known to be conducive to migration. These cells also express increased level of mesenchymal markers, as well as increased level of SNAIL1 and ZEB1, two key transcription factors orchestrating a crucial mechanism for cancer initiation and progression: epithelial to mesenchymal transition. These effects induced by CdtB were associated with increased matrix metalloproteinases degrading activity and emergence of cellular motility. Collectively, these data showed that CdB activates epithelial to mesenchymal transition, supporting the role of CDT in tumorigenesis.
Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site
Authors: Rennie ML , Arkinson C , Chaugule V , Walden H
Published: April 2022

Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. USP1, a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase I clinical trials, have been established, their binding mode is unknown. Here we use cryo-Electron Microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5 Å resolution, we discover an unusual binding mode in which the inhibitor displaces part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1.

One Sentence Summary

USP1, a cancer target, is inhibited by ML323 displacing part of the protein fold, allosterically disrupting the active site.
Conserved degronome features governing quality control associated proteolysis
Authors: Mashahreh Bayan , Armony Shir , Johansson Kristoffer Enøe , Chappleboim Alon , Friedman Nir , Gardner Richard G. , Hartmann-Petersen Rasmus , Lindorff-Larsen Kresten , Ravid Tommer
Published: April 2022

The eukaryotic proteome undergoes constant surveillance by quality control systems that either sequester, refold, or eliminate aberrant proteins by ubiquitin-dependent mechanisms. Ubiquitin-conjugation necessitates the recognition of degradation determinants, termed degrons, by their cognate E3 ubiquitin-protein ligases. To learn about the distinctive properties of quality control degrons, we performed an unbiased peptidome stability screen in yeast. The search identified a large cohort of proteome-derived degrons, some of which exhibited broad E3 ligase specificity. Consequent application of a machine-learning algorithm established constraints governing degron potency, including the amino acid composition and secondary structure propensities. According to the set criteria, degrons with transmembrane domain-like characteristics are the most probable sequences to act as degrons. Similar quality control degrons were identified in viral and human proteins, suggesting conserved degradation mechanisms. Altogether, the emerging data indicate that transmembrane domain-like degron features have been preserved in evolution as key quality control determinants of proteins’ half-life.
Identification and calibration of ultrabright localizations to eliminate quantification error in SMLM
Authors: Cao Bo , Ni Jielei , Niu Gang , Chen Danni , Liu Gang , Zhou Lingxiao , Xia Tingying , Feng Fu , Wei Shibiao , Yuan Xiaocong , Ni Yanxiang
Published: April 2022

Single molecule localization microscopy (SMLM) is irreplaceable among super-resolution microscopies in revealing biological ultra-structures, given its unmatched high resolution. However, its sub-optimal quantitative capability, which is critical for characterizing true biomolecular organization of ultra-structures in cells, has hindered its widest application in biomedical research. Here, in SMLM imaging of cellular structures such as lipid rafts and microtubules with saturation labelling, we identified ultra-bright localizations, each of which is contributed by simultaneous emission of multiple molecules within a diffraction-limit region and has been regarded before as a regular localization from single molecule. Consistently, ultra-bright localizations are also observed in simulated SMLM imaging of endoplasmic reticulum or microtubules from public resource. Furthermore, after calibrating each ultrabright localization into multiple single-molecule localizations using the photon-number-based models, the density of total localizations shows linear correlation with the true molecule density, presenting SMLM with new reconstruction method as a quantitative analysis approach. Therefore, identification and dissection of ultra-bright localizations in SMLM enable the close and quantitative estimate of the true biomolecular organization.
Delta-Omicron recombinant escapes therapeutic antibody neutralization
Authors: Duerr Ralf , Zhou Hao , Tada Takuya , Dimartino Dacia , Marier Christian , Zappile Paul , Wang Guiqing , Plitnick Jonathan , Griesemer Sara B. , Girardin Roxanne , Machowski Jessica , Bialosuknia Sean , Lasek-Nesselquist Erica , Hong Samuel L. , Baele Guy , Dittmann Meike , Ortigoza Mila B. , Prasad Prithiv J. , McDonough Kathleen , Landau Nathaniel R. , George Kirsten St. , Heguy Adriana
Published: April 2022

Background

The emergence of recombinant viruses is a threat to public health. Recombination of viral variants may combine variant-specific features that together catalyze viral escape from treatment or immunity. The selective advantages of recombinant SARS-CoV-2 isolates over their parental lineages remain unknown.

Methods

Multi-method amplicon and metagenomic sequencing of a clinical swab and the in vitro grown virus allowed for high-confidence detection of a novel recombinant variant. Mutational, phylogeographic, and structural analyses determined features of the recombinant genome and spike protein. Neutralization assays using infectious as well as pseudotyped viruses and point mutants thereof defined the recombinant’s sensitivity to a panel of monoclonal antibodies and sera from vaccinated and/or convalescent individuals.

Results

A novel Delta-Omicron SARS-CoV-2 recombinant was identified in an unvaccinated, immunosuppressed kidney transplant recipient treated with monoclonal antibody Sotrovimab. The recombination breakpoint is located in the spike N-terminal domain, adjacent to the Sotrovimab quaternary binding site, and results in a 5’-Delta AY.45 and a 3’-Omicron BA.1 mosaic spike protein. Delta and BA.1 are sensitive to Sotrovimab neutralization, whereas the Delta-Omicron recombinant is highly resistant to Sotrovimab, both with and without the RBD resistance mutation E340D.

Conclusions

Recombination between circulating SARS-CoV-2 variants can functionally contribute to immune escape. It is critical to validate phenotypes of mosaic viruses and monitor immunosuppressed COVID-19 patients treated with monoclonal antibodies for the selection of recombinant and immune escape variants. (Funded by NYU, the National Institutes of Health, and others)