bluuebunny/crossref_metadata_2025 huggingface dataset:
DoubleHelix: nucleic acid sequence identification, assignment and validation tool for cryo-EM and crystal structure models
Authors: Chojnowski Grzegorz
Published: July 2023

Sequence assignment is a key step of the model building process in both cryogenic electron microscopy (cryo-EM) and macromolecular crystallography (MX). If the assignment fails, it can result in difficult to identify errors affecting the interpretation of a model. There are many model validation strategies that help experimentalists in this step of protein model building, but they are virtually non-existent for nucleic acids. Here, I present doubleHelix—a comprehensive method for assignment, identification, and validation of nucleic acid sequences in structures determined using cryo-EM and MX. The method combines a neural network classifier of nucleobase identities and a sequence-independent secondary structure assignment approach. I show that the presented method can successfully assist sequence-assignment step in nucleic-acid model building at lower resolutions, where visual map interpretation is very difficult. Moreover, I present examples of sequence assignment errors detected using doubleHelix in cryo-EM and MX structures of ribosomes deposited in the Protein Data Bank, which escaped the scrutiny of available model-validation approaches. The doubleHelix program source code is available under BSD-3 license at https://gitlab.com/gchojnowski/doublehelix.
Large-scale analysis of mRNA sequences localized near the start and amber codons and their impact on the diversity of mRNA display libraries
Authors: Umemoto Shun , Kondo Taishi , Fujino Tomoshige , Hayashi Gosuke , Murakami Hiroshi
Published: July 2023

Extremely diverse libraries are essential for effectively selecting functional peptides or proteins, and mRNA display technology is a powerful tool for generating such libraries with over 1012–1013 diversity. Particularly, the protein-puromycin linker (PuL)/mRNA complex formation yield is determining for preparing the libraries. However, how mRNA sequences affect the complex formation yield remains unclear. To study the effects of N-terminal and C-terminal coding sequences on the complex formation yield, puromycin-attached mRNAs containing three random codons after the start codon (32768 sequences) or seven random bases next to the amber codon (6480 sequences) were translated. Enrichment scores were calculated by dividing the appearance rate of every sequence in protein-PuL/mRNA complexes by that in total mRNAs. The wide range of enrichment scores (0.09–2.10 for N-terminal and 0.30–4.23 for C-terminal coding sequences) indicated that the N-terminal and C-terminal coding sequences strongly affected the complex formation yield. Using C-terminal GGC-CGA-UAG-U sequences, which resulted in the highest enrichment scores, we constructed highly diverse libraries of monobodies and macrocyclic peptides. The present study provides insights into how mRNA sequences affect the protein/mRNA complex formation yield and will accelerate the identification of functional peptides and proteins involved in various biological processes and having therapeutic applications.
Hop2-Mnd1 and Swi5-Sfr1 stimulate Dmc1 filament assembly using distinct mechanisms
Authors: Lee Wei , Iwasaki Hiroshi , Tsubouchi Hideo , Li Hung-Wen
Published: July 2023

In meiosis, Dmc1 recombinase and the general recombinase Rad51 are responsible for pairing homologous chromosomes and exchanging strands. Fission yeast (Schizosaccharomyces pombe) Swi5-Sfr1 and Hop2-Mnd1 stimulate Dmc1-driven recombination, but the stimulation mechanism is unclear. Using single-molecule fluorescence resonance energy transfer (smFRET) and tethered particle motion (TPM) experiments, we showed that Hop2-Mnd1 and Swi5-Sfr1 individually enhance Dmc1 filament assembly on single-stranded DNA (ssDNA) and adding both proteins together allows further stimulation. FRET analysis showed that Hop2-Mnd1 enhances the binding rate of Dmc1 while Swi5-Sfr1 specifically reduces the dissociation rate during the nucleation, about 2-fold. In the presence of Hop2-Mnd1, the nucleation time of Dmc1 filaments shortens, and doubling the ss/double-stranded DNA (ss/dsDNA) junctions of DNA substrates reduces the nucleation times in half. Order of addition experiments confirmed that Hop2-Mnd1 binds on DNA to recruit and stimulate Dmc1 nucleation at the ss/dsDNA junction. Our studies directly support the molecular basis of how Hop2-Mnd1 and Swi5-Sfr1 act on different steps during the Dmc1 filament assembly. DNA binding of these accessory proteins and nucleation preferences of recombinases thus dictate how their regulation can take place.
Electrochemical flow aziridination of unactivated alkenes
Authors: Wang Shengchun , Wang Pengjie , Li Shu-Jin , Chen Yi-Hung , Sun Zhi-Jun , Lei Aiwen
Published: July 2023

Aziridines derived from bioactive molecules may have unique pharmacological activities, making them useful in pharmacology (e.g. mitomycin C). Furthermore, the substitution of the epoxide moiety in epothilone B with aziridine, an analog of epoxides, yielded a pronounced enhancement in its anticancer efficacy. Thus, there is interest in developing novel synthetic technologies to produce aziridines from bioactive molecules. However, known methods usually require metal catalysts, stoichiometric oxidants and/or pre-functionalized amination reagents, causing difficulty in application. A practical approach without a metal catalyst and extra-oxidant for the aziridination of bioactive molecules is in demand, yet challenging. Herein, we report an electro-oxidative flow protocol that accomplishes an oxidant-free aziridination of natural products. This process is achieved by an oxidative sulfonamide/alkene cross-coupling, in which sulfonamide and alkene undergo simultaneous oxidation or alkene is oxidized preferentially. Further anticancer treatments in cell lines have demonstrated the pharmacological activities of these aziridines, supporting the potential of this method for drug discovery.
Arabidopsismetacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence
Authors: Ruiz-Solaní Nerea , Salguero-Linares Jose , Armengot Laia , Santos Jaime , Pallarès Irantzu , van Midden Katarina P , Phukkan Ujjal J , Koyuncu Seda , Borràs-Bisa Júlia , Li Liang , Popa Crina , Eisele Frederik , Eisele-Bürger Anna Maria , Hill Sandra Malgrem , Gutiérrez-Beltrán Emilio , Nyström Thomas , Valls Marc , Llamas Ernesto , Vilchez David , Klemenčič Marina , Ventura Salvador , Coll Nuria S
Published: July 2023

Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity.
عليم متخصصي شرطة المستقبل وسط كوفيد -19 من منظور الإمارات العربية المتحدة
Authors: امي الشريفين , أماندا ديفيز
Published: July 2023

الملخص:

ركز العالم في عام 2020 جهودَه على التصدي للتحديات الإنسانية التي واجهت العالم إثر تفشي جائحة كوفيد-19، حيث واجه مجتمع التعليم حول العالم تحديات مماثلة في إظهار مدى المرونة والابتكار لدعم مستوى “الحياة الطبيعية” للطلاب على جميع المستويات والمهن. يعرض البحث المقدم في هذه المقالة نظرة فاحصة عن إعداد ونشر عملية الانتقال التعليمي لطلاب الشرطة سواء التعليم وجهًا لوجه أو عن بُعد في بيئة لم تعتد في الماضي على تلقي التعلم عن بُعد. وتشير النتائج إلى أن الاهتمام الحاسم الذي يولى إلى الانتقال إلى التعليم عن بعد ليس فقط في تقديم المادة العلمية -لكلٍ من الطلاب وأعضاء هيئة التدريس- كان اهتمامًامحوريًا في تحقيق نتائج تعلم إيجابية لدى الطلاب. إن نهج الانتقال إلى بيئة التعلم عن بُعد والحصول على أكثر البيانات الشائعة التي تشير إلى الحد الأدنى من التأثير على مدى تحصيل الطلاب يُساهم في اتخاذ القرار لدى مؤسسات التعليم التي تركز على تطوير متخصصي الجاهزية مثل ضباط الشرطة.
التأثير على العلاقات بين الشرطة والمجتمع في أبو ظبي من خلال نهج القوة الناعمة أثناء جائحة كوفيد 19
Authors: الهنائي محمد , ديفيس ديفيز وأماندا
Published: July 2023

الملخص

برزت عبارة العمل الشرطي باستخدام القوة الناعمة بِعدّها شعار العمل الشرطي في عام 2021 وقد نشأت نتيجة للعديد من تحديات العلاقات بين الشرطة والمجتمع التي تكتسب تركيزًاعامًا متزايدًا على مستوى العالم. يعرض هذا المقال نهج القوة الناعمة في العمل الشرطي والذي تبنّته شرطة أبو ظبي قبل وأثناء جائحة فيروس كورونا (COVID-19) والاستراتيجيات والمبادرات الداعمة التي تم نشرها للحفاظ على ثقة المجتمع ومستويات الثقة في شرطة أبو ظبي. تروج المؤشرات العالمية لشرطة أبو ظبي كقائدة عالمية في العلاقات بين الشرطة والمجتمع، وهو إنجاز مستدام طوال أزمة فيروس كورونا العالمية COVID-19. يستكشف هذا البحث الطرق التي تتأثر بها الإنجازات من خلال نهج شرطي مستدام وشامل للجميع، يضع القوة الناعمة في مركز العلاقات بين الشرطة والمجتمع.
New finite-type multi-indexed orthogonal polynomials obtained from state-adding Darboux transformations
Authors: Odake Satoru
Published: July 2023

The Hamiltonians of finite-type discrete quantum mechanics with real shifts are real symmetric matrices of order N + 1. We discuss the Darboux transformations with higher-degree (>N) polynomial solutions as seed solutions. They are state-adding and the resulting Hamiltonians after M steps are of order N + M + 1. Based on 12 orthogonal polynomials ((q-)Racah, (dual, q-)Hahn, Krawtchouk, and five types of q-Krawtchouk), new finite-type multi-indexed orthogonal polynomials are obtained, which satisfy second-order difference equations, and all the eigenvectors of the deformed Hamiltonian are described by them. We also present explicit forms of the Krein–Adler-type multi-indexed orthogonal polynomials and their difference equations, which are obtained from the state-deleting Darboux transformations with lower-degree (≤N) polynomial solutions as seed solutions.
Self-reported reasons for having difficulty reaching orgasm in men with diverse etiologies
Authors: Rowland David L , Padilla Sarah , Kӧvi Zsuzsanna , Hevesi Krisztina
Published: July 2023

Background

Difficulty reaching orgasm/ejaculation during partnered sex, a primary characteristic of delayed or absent ejaculation, affects about 5% to 10% of men, but the reasons underlying this problem are poorly understood.

Aim

The study sought to gain insight into possible etiologies of delayed ejaculation by assessing men’s self-perceptions as to why they experience difficulty reaching orgasm.

Methods

We drew 351 men reporting moderately severe to severe difficulty reaching orgasm during partnered sex from a sample of over 3000 respondents obtained through an online survey. As part of the 55-item survey, participants responded to 2 questions asking about their self-perceived reasons for having difficulty reaching orgasm and selected from a list of 14 options derived from the research literature, a series of men’s focus groups, and expert opinion. The first question allowed respondents to select all the reasons that they felt contributed to the problem, the second to select only the most important reason. In addition, both men with and without comorbid erectile dysfunction were investigated and compared.

Outcomes

Hierarchical ordering of men’s self-pereceived reasons for having difficulty reaching orgasm, including typal reasons established through principal component analysis.

Results

The major reasons for difficulty were related to anxiety/distress and lack of adequate stimulation, with relationship and other factors endorsed with lower frequency. Further exploration using principal components analysis identified 5 typal reasons, in descending order of frequency: anxiety/distress (41%), inadequate stimulation (23%), low arousal (18%), medical issues (9%), and partner issues (8%). Few differences emerged between men with and without comorbid ED other than ones related to erectile problems, such as higher level of endorsement of medical issues. Typal reasons showed correlations, albeit mostly weak, with a number of covariates, including sexual relationship satisfaction, frequency of partnered sex, and frequency of masturbation.

Clinical Implications

Until supplemental medical treatments for delayed ejaculation are developed and approved, a number of men’s purported reasons for difficult or absent ejaculation/orgasm—anxiety/distress, inadequate stimulation, low arousal, relationship issues—fall into areas that can be addressed in couples counseling by a trained sex therapist.

Strengths and Limitations

This study is unique in scope and robust in sample size. Drawbacks include those associated with online surveys, including possible bias in sample selection, limitation to Western-based samples, and the lack of differentiation between men with lifelong and acquired difficulty.

Conclusion

Men who have difficulty reaching ejaculation/orgasm identify putative reasons for their problem, ranging from anxiety/stress, inadequate stimulation, and low arousal to partner issues and medical reasons.
Non-melanoma skin cancer event rates in a formalized clinical trial setting: considerations for clinical trial design
Authors: Lozar Taja , Kim Kyungmann , Havighurst Thomas C. , Wood Gary S. , Kolesar Jill M. , Bailey Howard H.
Published: July 2023

Background

Here we report clinical risk factors and event rates for the development of new non-melanoma skin cancer (NMSC) in a randomized, double-blind, placebo-controlled trial of the irreversible ornithine decarboxylase (ODC) inhibitor, difluromethylornithine (DFMO), over a 3–5-year follow-up.

Methods

147 placebo patients (white; mean age 60.2 years; 60% male) were evaluated for event rates and association of initial skin biomarkers and baseline patient characteristics with the development of squamous cell (SCC) and basal cell (BCC) carcinomas.

Results

Post-study evaluation (median follow-up 4.4 years) indicates the measures of prior NMSCs (P ≤ 0.001), prior BCCs (P ≤ 0.001), prior SCCs (P = 0.011), prior tumor rate (P = 0.002), hemoglobin (P = 0.022), and gender (P = 0.045) as significant predictors for new NMSC development. Similarly, all measures of prior BCCs and NMSCs (P < 0.001), prior tumor rate (P = 0.014), and SCCs in the prior 2 years (P = 0.047) were statistically significant predictors for new BCC development. Total prior NMSCs and those in the prior 5 years (P < 0.001), total prior SCCs and those in the prior 5 years (P < 0.001), total prior BCCs and those in the prior 5 years (P ≤ 0.001), prior tumor rate (P = 0.011) as well as age (P = 0.008), hemoglobin (P = 0.002), and gender (P = 0.003) were statistically significant predictors of new SCC development. TPA-induced ODC activity at baseline showed no statistically significant association with the development of new NMSC (P = 0.35), new BCCs (P = 0.62), or new SCCs (P = 0.25).

Conclusion

In the studied population, the history of and rate at which prior NMSCs occur are predictive and should be controlled for in future NMSC prevention trials.
Estimating survival in patients with melanoma brain metastases: prognostic value of lactate dehydrogenase
Authors: Pelizzari Giacomo , Bertoli Elisa , Buriolla Silvia , Vitale Maria Grazia , Basile Debora , Palmero Lorenza , Zara Diego , Iacono Donatella , Andrea Freschi , Pascoletti Gaetano , Bolzonello Silvia , Garutti Mattia , Fasola Gianpiero , Puglisi Fabio , Minisini Alessandro Marco
Published: July 2023

Patients with melanoma brain metastases (MBM) have poor prognosis, albeit advances in locoregional and systemic treatments. The melanoma-specific Graded Prognostic Assessment (GPA) effectively stratifies survival for patients with MBM. Nevertheless, lactate dehydrogenase (LDH), a well known prognostic factor for patients with melanoma, is not represented in the GPA scores and might add prognostic information for patients with MBM. In this study, 150 consecutive patients with MBM were retrospectively analyzed with the aim of evaluating independent prognostic factors for MBM patients, including LDH. Furthermore, we implemented a disease-specific prognostic score and estimated survival according to treatment modalities. On the basis of multivariable Cox regression analyses, six prognostic factors (age, BRAF status, number of MBM, number of extracranial metastatic sites, performance status, and LDH level) resulted statistically significant in terms of survival and were combined in a prognostic score to stratify patients in distinct prognostic groups (P < 0.0001). Among treatment modalities, a multimodal approach with stereotactic radiosurgery or neurosurgery associated with systemic therapy showed the best outcome (median overall survival: 12.32 months, 95% confidence interval, 7.92–25.30). This is the first study to demonstrate that LDH has independent prognostic value for patients with MBM and might be used to improve prognostic stratification, albeit external validation is mandatory. Survival of patients with MBM is affected by both disease-specific risk factors and treatment modalities, with locoregional treatments associated with better outcomes.
Effect of l-Dopa in acute temozolomide-induced cognitive impairment in male mice: a possible antineuroinflammatory role
Authors: Salarinejad Alireza , Esmaeilpour Khadije , Shabani Mohammad , Jafarinejad-Farsangi Saeideh , Pardakhty Abbas , Asadi-Shekaari Majid , Ahmadi-Zeidabadi Meysam
Published: July 2023

Temozolomide is used commonly in the treatment of some types of cancers, but it may also result in cognitive impairments such as memory deficits. l-Dopa, a well known medicine for the central nervous system, has been shown to have positive effects on some cognitive disorders. Here we sought to investigate the effect of l-Dopa on temozolomide-induced cognitive impairments. BALB/c mice were subjected to 3-days temozolomide and 6-days concomitant l-Dopa/benserazide administration in six groups (control, l-Dopa 25 mg/kg, l-Dopa 75 mg/kg, temozolomide, temozolomide + l-Dopa 25 mg/kg, and temozolomide + l-Dopa 75 mg/kg). Open field test, object location recognition, novel object recognition test, and shuttle-box test were carried out to determine the locomotor, anxiety-like behavior, and memory function of subjects. TNF-α and brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus was measured by real-time PCR. Mice treated with temozolomide showed recognition memory impairment, along with hippocampal TNF-α and BDNF mRNA expression level raise, and detection of histological insults in hematoxylin and eosin hippocampal slides. Mice that received temozolomide + l-Dopa showed normal behavioral function and lower TNF-α and BDNF hippocampal mRNA expression levels, and histologically normal hippocampal CA1 region in comparison with mice in the temozolomide group. Our results provide evidence that l-Dopa prevents temozolomide-induced recognition memory deficit in mice at the acute phase probably via l-Dopa antineuroinflammatory effects.
Head-Tilt Perfluorocarbon-Air Exchange Technique with Heads-Up Surgery for Giant Retinal Tear-Associated Retinal Detachments to Prevent Retinal Slippage without Using Silicone Oil
Authors: Ishida Yuichiro , Saito Seiya , Tsuboi Kotaro , Atsuya Miki , Kamei Motohiro , Wakabayashi Taku
Published: July 2023

Purpose:

To report the efficacy of the perfluorocarbon liquid (PFCL)-air exchange with a head tilt toward the area of the giant retinal tear (GRT) using the heads-up surgery (HUS) system to prevent retinal slippage during vitrectomy for GRT-associated retinal detachments.

Methods:

Eyes with GRT-associated retinal detachments underwent vitrectomy using the HUS system and PFCL-air exchange with a head tilt 45 degrees toward the GRT to put the area of the tear in the most dependent position to drain fluid. We evaluated this technique to prevent the retinal slippage.

Results:

We evaluated 5 consecutive cases. The mean GRT size was 174 degrees (range, 90 to 240 degrees) and the GRT was located temporally in 2 eyes, nasally in 2 eyes, and superiorly in 1 eye. The tamponade types were air (1 eye), sulfur hexafluoride (3 eyes), and perfluoropropane (1 eye). Our technique was feasible and the slippage did not occur in any eyes. Although the microscope needed to be tilted for optimal fundus visualization, HUS allowed surgeons to maintain ergonomic postures. Retinal reattachment was achieved with a single surgery in all eyes.

Conclusion:

The head-tilt PFCL-air exchange with HUS is useful in preventing retinal slippage in eyes with GRT.
Machine Learning Approach for Screening Cochlear Implant Candidates: Comparing With the 60/60 Guideline
Authors: Patro Ankita , Perkins Elizabeth L. , Ortega Carlos A. , Lindquist Nathan R. , Dawant Benoit M. , Gifford René , Haynes David S. , Chowdhury Naweed
Published: July 2023

Objective

To develop a machine learning–based referral guideline for patients undergoing cochlear implant candidacy evaluation (CICE) and to compare with the widely used 60/60 guideline.

Study Design

Retrospective cohort.

Setting

Tertiary referral center.

Patients

772 adults undergoing CICE from 2015 to 2020.

Interventions

Variables included demographics, unaided thresholds, and word recognition score. A random forest classification model was trained on patients undergoing CICE, and bootstrap cross-validation was used to assess the modeling approach's performance.

Main Outcome Measures

The machine learning–based referral tool was evaluated against the 60/60 guideline based on ability to identify CI candidates under traditional and expanded criteria.

Results

Of 587 patients with complete data, 563 (96%) met candidacy at our center, and the 60/60 guideline identified 512 (87%) patients. In the random forest model, word recognition score; thresholds at 3000, 2000, and 125; and age at CICE had the largest impact on candidacy (mean decrease in Gini coefficient, 2.83, 1.60, 1.20, 1.17, and 1.16, respectively). The 60/60 guideline had a sensitivity of 0.91, a specificity of 0.42, and an accuracy of 0.89 (95% confidence interval, 0.86–0.91). The random forest model obtained higher sensitivity (0.96), specificity (1.00), and accuracy (0.96; 95% confidence interval, 0.95–0.98). Across 1,000 bootstrapped iterations, the model yielded a median sensitivity of 0.92 (interquartile range [IQR], 0.85–0.98), specificity of 1.00 (IQR, 0.88–1.00), accuracy of 0.93 (IQR, 0.85–0.97), and area under the curve of 0.96 (IQR, 0.93–0.98).

Conclusions

A novel machine learning–based screening model is highly sensitive, specific, and accurate in predicting CI candidacy. Bootstrapping confirmed that this approach is potentially generalizable with consistent results.
Isolation of Bioactive Compounds from Low-cost Agricultural Resources and its Utilization in Daily Life.
Authors: Debnath Anirban , Das Arpita
Published: July 2023

The ethanolic, methanolic and aqueous decoction of whole plant of Oxalis corniculate Linn was evaluated for its anti‐microbial and antioxidant properties by in vitro methods.  Methanolic and ethanolic decoctions showed significant antibacterial property against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi bacterial strains. In comparison to Chloramphenicol (C30) against bacteria, ethanolic decoctions showed significant effect, among the decoctions. Nowadays though the standard soap is in a huge demand but it’s also facing major backlashes due to the presence of synthetic compounds in it, which over long use may cause harmful effects on the skin health. Therefore, the organic soaps which are made up of natural ingredients, herbs or any sort ayurvedic compound have less side effects on the human skin and are much safer than standard daily soap. The formulated therapeutic soap exhibits significant amount of reducing potential (high FRAP and TAC values) and antioxidant activity (DPPH, ABTS assay).The ethanolic, methanolic and aqueous decoction of whole plant of Oxalis corniculate Linn was evaluated for its anti‐microbial and antioxidant properties by in vitro methods.  Methanolic and ethanolic decoctions showed significant antibacterial property against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi bacterial strains. In comparison to Chloramphenicol (C30) against bacteria, ethanolic decoctions showed significant effect, among the decoctions. Nowadays though the standard soap is in a huge demand but it’s also facing major backlashes due to the presence of synthetic compounds in it, which over long use may cause harmful effects on the skin health. Therefore, the organic soaps which are made up of natural ingredients, herbs or any sort ayurvedic compound have less side effects on the human skin and are much safer than standard daily soap. The formulated therapeutic soap exhibits significant amount of reducing potential (high FRAP and TAC values) and antioxidant activity (DPPH, ABTS assay).
Microbial Primer: The logic of bacterial plasmids
Authors: Lloyd Georgina S. , Thomas Christopher M.
Published: July 2023

This short primer is intended to give an overview of bacterial plasmids for those not yet familiar with these fascinating genetic elements. It covers their basic properties but does not attempt to cover the diversity of phenotypic properties that can be encoded by plasmids, and includes suggestions for further reading.
Cross-sectional study on Intention to be vaccinated against COVID-19 in Benin and Senegal : a structural equation modelling (SEM)
Authors: Gaye Ibrahima , Ridde Valery , Avahoundjea Elías , Ba Mouhamadou F. , Dossoua Jean-Paul , Diallo Amadou I. , Faye Adama
Published: July 2023

Introduction

Vaccination is considered one of the solutions to the COVID-19 pandemic. However, a small proportion of the population was fully vaccinated in Benin (20.9%) and Senegal (7.6%) by December 2022. This study explores the determinants of intent to vaccinate.

Methods

This was a cross-sectional, descriptive, and analytical study of 865 Beninese and 607 Senegalese aged 18 years and older. Marginal quota sampling by age, gender and region was adopted. Data collection, using a survey instrument based on the Random Digit Dialing (RDD) method, was conducted from December 24, 2020, to January 16, 2021, in Senegal and from March 29 to May 14, 2021, in Benin. The questionnaire used the Theory of Planned Behavior (TPB) and the Health Belief Model (HBM). The influence of factors was tested using a structural equation model. All analyses were conducted in R.

Results

Results show that a good perception of the benefits of vaccination (βsen=0.33***; βBen=0.12***), a positive attitude (βsen=0.22***; βBen=0.20***), and sensitivity to subjective norms (βsen=0.19***; βBen=0.32***) positively influence the intention to vaccinate. Low trust in health care providers (βsen=-0.40***; βBen=-0.36***) amplifies the perceived risk of vaccination (βsen=-0.14***; βBen=-0.25***), which negatively impacts intention to vaccinate. Perceived vaccine efficacy was affected by perceived risk (βsen=-0.12***; βBen=-0.05***) of the disease and improved by good apprehension of the benefits of vaccination (βsen=0.60***; βBen=0.13***). Aspects related to behavioral control, vaccine information seeking, efficacy, or fairness did not appear as correlates of vaccine intention (P>0.05).

Conclusion

Beninese and Senegalese public health authorities could develop additional intervention strategies to improve immunization coverage by considering these influencing factors, the basis of which could be better understood through subsequent qualitative studies.
Population-based estimates of the prevalence of children with congenital heart disease and associated comorbidities
Authors: Parker Devin M. , Stabler Meagan E. , MacKenzie Todd A , Zimmerman Meghan S. , Shi Xun , Everett Allen D. , Bucholz Emily M. , Brown Jeremiah R.
Published: July 2023

Background

Congenital heart defects (CHD) are the most common birth defects and are estimated to affect almost 1% of births annually in the US. CHDs are the leading cause of infant mortality associated with birth defects and can result in chronic disability, morbidity and increased healthcare costs. Most CHD prevalence estimates rely on data from population-based birth defects surveillance systems and these estimates are inconsistent due to varied definitions. It is therefore important to derive high-quality, population-based estimates of the prevalence of CHD to help care for this vulnerable population.

Methods

We performed a descriptive, retrospective 8-year analysis using all payer claims data (APCD) from Colorado (CO) from 2012 - 2019. Children with CHD were identified by applying ICD-9 and ICD-10 diagnoses codes from the American Heart Association-American College of Cardiology (AHA-ACC) harmonized cardiac codes. We included children with CHD <18 years of age who resided in CO, had a documented zip code, and had at least one healthcare claim. CHD type was categorized as simple, moderately complex and complex disease. Association with comorbid conditions and genetic diagnoses were analyzed using chi-square test. We used direct standardization to calculate adjusted prevalence rates, controlling for age, sex, primary insurance provider and urban-rural residence.

Results

We identified 1,566,328 children receiving care in CO from 2012 – 2019. Of those, 30,512 children had at least one CHD diagnosis, comprising 1.9% (95% CI: 1.93 – 1.97) of the pediatric population. Over half of the children with CHD also had at least one complex chronic condition and 11% had a genetic diagnosis.

Conclusion

The current study is the first population-level analysis of pediatric CHD in the US. Our study found a higher CHD prevalence than in previously reported studies and a high comorbidity burden. These findings can inform initiatives to improve screening, treatment and planning of care for this complex population.
Wnt signaling couples G2 phase control with differentiation during hematopoiesis
Authors: Goins Lauren M. , Girard Juliet R. , Mondal Bama Charan , Buran Sausan , Su Chloe C. , Tang Ruby , Biswas Titash , Banerjee Utpal
Published: July 2023

During homeostasis, a critical balance is maintained between myeloid-like progenitors and their differentiated progeny, which function to mitigate stress and innate immune challenges. The molecular mechanisms that help achieve this balance are not fully understood. Using genetic dissection inDrosophila, we show that a Wnt6/EGFR-signaling network simultaneously controls progenitor growth, proliferation, and differentiation. Unlike G1-quiescence of stem cells, hematopoietic progenitors are blocked in the G2 phase by a β-catenin-independent Wnt6 pathway that restricts Cdc25 nuclear entry and promotes cell growth. Canonical β-catenin-dependent Wnt6 signaling is spatially confined to mature progenitors through localized activation of the tyrosine-kinases EGFR and Abl, which promote nuclear entry of β-catenin and facilitate exit from G2. This strategy combines transcription-dependent and - independent forms of both Wnt6 and EGFR pathways to create a direct link between cell-cycle control and differentiation. This unique combinatorial strategy employing conserved components may underlie homeostatic balance and stress response in mammalian hematopoiesis.
Fetal daily rhythms develop during pregnancy and entrain to the maternal circadian system
Authors: Bates Keenan , Sapiro Elizabeth , Amme Jacob L. , McCarthy Ronald , Nikhil K.L. , Speck Sarah , Vasireddy Varun , Roberts Ethan , Martin-Fairey Carmel , Domínguez-Romero Miguel-E. , Garcia Cardenas Sandra Paola , England Sarah K. , Herzog Erik D.
Published: July 2023

Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types. This study aimed to determine when daily rhythms begin in the fetus and synchronize to the mother. We developed methods to monitor the expression of fetal PERIOD2 (PER2), a core circadian clock protein, in mice longitudinally from embryonic day (E)8.5 to E17.5 throughin uterobioluminescence imaging. We found that embryonic PER2 expression increased rapidly throughout pregnancy and exhibited day-night rhythms from the start of our recordings at E8.5. The daily peak time of PER2 varied between pregnancies until it reliably peaked at night and synchronized to the mother starting around E15.5. Loss of fetal circadian rhythms associated with pregnancies that ultimately failed. Because maternal glucocorticoids have been implicated in fetal development and synchronizing circadian tissues, we tested their sufficiency to shift fetal daily rhythms in utero. Daily glucocorticoids injections over five days of late pregnancy advanced fetal PER2 rhythmsin uteroand blocking glucocorticoid signalingin vitroreduced PER2 synchrony between the maternal and fetal placenta by ∼40%. We conclude that fetal daily rhythms arise early in pregnancy and then synchronize with the maternal rhythm prior to birth depending, in part, on glucocorticoid signaling.
Optimal enzyme profiles in unbranched metabolic pathways
Authors: Noor Elad , Liebermeister Wolfram
Published: July 2023

How to optimize the allocation of enzymes in metabolic pathways has been a topic of study for many decades. Although the general problem is complex and non-linear, we have previously shown that it can be solved by convex optimization. In this paper, we focus on unbranched metabolic pathways with simplified enzymatic rate laws and derive analytic solutions to the optimization problem. We revisit existing solutions based on the limit of mass-action rate laws and present new solutions for other rate laws. Furthermore, we revisit a known relationship between flux control coefficients and enzyme abundances in optimal metabolic states. We generalize this relationship to models with density constrains on enzymes and metabolites, and present a new local relationship between optimal reaction elasticities and enzyme amounts. Finally, we apply our theory to derive simple kinetics-based formulae for protein allocation during bacterial growth.
Local Orchestration of Global Functional Patterns Supporting Loss and Restoration of Consciousness in the Primate Brain
Authors: Luppi Andrea I. , Uhrig Lynn , Tasserie Jordy , Signorelli Camilo M. , Stamatakis Emmanuel , Destexhe Alain , Jarraya Bechir , Cofre Rodrigo
Published: July 2023

Abstract

A central challenge of neuroscience is to elucidate how the orchestration of brain function is modulated by different states of consciousness. Here, we investigate the link between distributed structural and functional brain organisation in functional MRI signals of non-human primates, through bi-directional causal manipulations of consciousness. During varying levels of propofol, sevoflurane, or ketamine anaesthesia, and subsequent restoration of responsiveness by deep brain stimulation of the central thalamus, we investigate how loss of consciousness impacts distributed patterns of structure-function organisation across scales. Combining the specificity of electrical stimulation with global fMRI coverage of the entire cortex, we report that distributed brain activity under anaesthesia is increasingly constrained by brain structure across scales, coinciding with anaesthetic-induced collapse of multiple dimensions of hierarchical cortical organisation. Crucially, we show that these distributed signatures of anaesthetic-induced loss of consciousness are observed across different anaesthetics, and they are reversed by electrical stimulation of the central thalamus, coinciding with recovery of behavioural markers of consciousness during propofol anaesthesia. No such effects were observed upon stimulation of a control anatomical site, ventral lateral thalamus, demonstrating specificity. Through causal manipulations of consciousness that integrate pharmacology and electrical intracranial stimulation of the thalamus, our results identify global signatures of consciousness that are under local causal control by specific nuclei of the thalamus. Overall, the present work broadens our understanding of the link between brain network organisation and distributed function in supporting consciousness, and the interplay between local and global functional architecture.
Incidence, risk factors, and clinical outcomes of mannitol-induced acute kidney injury among acute stroke patients admitted to East Avenue Medical Center
Authors: Ramos Ralph Jefferson T. , Cabigas Karen S. , Rabara Elyzel C. , Lim Marissa Elizabeth
Published: July 2023

Background

In the Philippines, stroke is the second most common cause of mortality and is among the five leading causes of disability. Mannitol, a hyperosmolar agent, is a mainstay for the treatment of brain edema caused by elevated intracranial pressure in acute stroke patients. It is a potent diuretic that may trigger intravascular volume depletion, electrolyte imbalance, and renal tubular damage, which may lead to acute kidney injury in acute stroke.

Objective

This study aims to describe the incidence, identify the risk factors, and determine the clinical outcomes of mannitol-induced acute kidney injury among acute stroke patients admitted to East Avenue Medical Center from January 1, 2019, to December 31, 2021.

Methods

This is a retrospective study conducted at the East Avenue Medical Center, a tertiary training hospital in Quezon City, Philippines. A three-year chart review of acute stroke patients who developed mannitol-induced acute kidney injury (MI-AKI) was conducted.

Result

A total of 348 eligible acute stroke patients were included in the study. Of these, 60 patients (17%) developed MI-AKI during confinement. There was a higher predominance among males than females with more than half of patients (65%) belonging to the 40 to 59 years age group. The risk factors identified were high National Institutes of Health Stroke Scale (NIHSS) score, chronic kidney disease, possibly cardiovascular disease, such as heart failure, intraparenchymal type hemorrhagic stroke, and high mannitol infusion dose >0.40g/kg in more than 48 hours. A high mortality rate was observed among MI-AKI patients in the study as compared with those without AKI (61.67% vs 27.43%, P<0.001) whereas spontaneous resolution of AKI was seen in 25 patients (41.67%, P<0.001). Only 4 patients (6.67%, P=0.001) who had renal replacement therapy had worsening renal function compared to the 27 patients (45%, P<0.001) who did not receive renal replacement therapy.

Conclusion

Risk factors for MI-AKI include moderate to severe NIHSS score, chronic kidney disease 3 and above, cardiovascular disease, and high-dose mannitol infusion. Early nephrology referral among patients with mannitol infusion for stroke is a must among patients who have co-morbidities including chronic kidney disease stage 3 and above, and cardiovascular disease such as heart failure. Serial monitoring of renal function should be performed especially for those patients with moderate to severe NIHSS scores and high-dose mannitol infusion for appropriate dosing to prevent MI-AKI.
Trends in cognitive function before and after diabetes onset in China
Authors: Zhu Sijia , Chen Qingmei , Shang Jing , Hua Jianian
Published: July 2023

Background

Individuals with prevalent diabetes were reported to have higher risk of dementia and lower cognitive function. However, the trends of cognitive function before diabetes and in the years following diabetes onset remain unclear.

Methods and Findings

This study included 12422 participants aged >45 years without baseline diabetes from the China Health and Retirement Longitudinal Study (CHARLS). Cognitive function was assessed at baseline (Wave 1, 2011), and at least one time from Wave 2 (2013) to Wave 4 (2018). During the 7-year follow-up, 1207 (9.7%, 59.1 ± 8.6 years, 39.9% males) participants developed new-onset diabetes. The cognitive function of both the without-diabetes group and the diabetes group declined annually during the follow-up. The annual decline rate of the diabetes group before diabetes onset was similar to that of the without-diabetes group during the follow-up. After diabetes onset, participants experienced accelerated rates of cognitive decline in global cognition (β, −0.023 SD/year; 95% CI, −0.043 to −0.004) and visuospatial abilities (−0.036 SD/year; −0.061 to −0.011), but not in orientation abilities (0.001 SD/year; −0.018 to 0.020). We also observed a tendency that episodic memory (−0.018 SD/year; −0.041 to 0.004) and attention and calculation abilities (−0.017 SD/year; −0.037 to 0.003) declined faster after new-onset diabetes, although the results did not meet our threshold of significance. In subgroup analysis, compared with those who developed diabetes between 45–54 years old, those developing diabetes older showed similar increments in cognitive decline rate after diabetes.

Conclusions

Individuals experienced faster rate of cognitive decline after diabetes onset, but not during the pre-diabetes period. Age did not modify the effect of diabetes on future cognitive decline. Future studies are needed to learn the mechanisms of cognitive decline in a few years after new-onset diabetes.
Pan-genome and Haplotype Map of Cultivars and Their Wild Ancestors Provides Insights into Selective Evolution of Cassava (Manihot esculentaCrantz)
Authors: Xia Zhiqiang , Du Zhenglin , Zhou Xincheng , Jiang Sirong , Zhu Tingting , Wang Le , Chen Fei , Carvalho Luiz , Zou Meiling , Becerra López-Lavalle Luis Augusto , Zhang Xiaofei , Xu Liangye , Wang Zhenyu , Chen Meili , Feng Binxiao , Wang Shujuan , Li Mengtao , Li Yuanchao , Wang Haiyan , Liu Shisheng , Bao Yuting , Zhao Long , Zhang Chenji , Xiao Jianjia , Guo Fenguang , Shen Xu , Lu Cheng , Qiao Fei , Ceballos Henan , Yan Huabin , Zhang Huaifang , He Shuang , Zhao Wenmin , Wan Yinglang , Chen Yinhua , Huang Dongye , Li Kaimian , Liu Bin , Peng Ming , Zhang Weixiong , Muller Birger , Chen Xin , Luo Ming Cheng , Xiao Jingfa , Wang Wenquan
Published: July 2023

Cassava is the most important starch sources, a tropical model crop. We constructed nearly T2T genomes of cultivar AM560, wild ancestors FLA4047 and W14, pan-genome of 24 representatives and a clarified evolutionary tree with 486 accessions. Comparison of SVs and SNVs between the ancestors and cultivated cassavas revealed predominant expansion, contraction of genes and gene families. Significantly selective sweeping occurred in the cassava genomes in 122 footprints with 1,519 candidate domestication genes. We identified selective mutations inMeCSKandMeFNR3promoting photoreaction associated withMeNADP-MEof C4assimilation in modern cassava. Co-evolved retardation of floral primordia and initiation of storage roots arose fromMeCOL5mutants with altered bindings toMeFT1, MeFT2andMeTFL2. MebHLHsevolved to regulate the biosynthesis, transport and endogenous remobilization of cyanogenic glucosides, with new functionalities ofMeMATE1, MeGTRin selected sweet cassava. These findings enhanced comprehensive knowledge and database on the evolution and breeding of cassava.

HIGHLIGHTS

Three nearly T2T cassava genomes of cultivar AM560 and its wild ancestors FLA4047 and W14.

A species-level cassava panSV haplotype map across 346,322 structural variations over 31,362 gene families and 96,032,008 SNPs and InDels variations globally and a clarified evolutionary tree with 486 accessions.

Selective mutations inMeCSKandMeFNR3promoted photoreaction associated withMeNADP-MEof C4assimilation shaped the C3-C4intermediate photosynthesis of modern cassava.

Coevolution of floral primordia contrary to initiated storage root is pivotal for the domestication of cassava, and arose fromMeCOL5mutants altered the binding withMeFT1, MeFT2(SP6A), andMeTFL2.
Natural Circulation of Tick-borne Severe Fever with Thrombocytopenia Syndrome Virus in the City Ecosystem, China
Authors: Zhang Xing , Zhao Chaoyue , Si Xiaoxi , Hu Qiang , Zheng Aihua
Published: July 2023

Severe fever with thrombocytopenia syndrome virus (SFTSV) is rapidly expanding its range in China, because of the accelerated spread of the parthenogeneticHaemaphysalis longicornis, Asian long-horned tick (ALT). In this letter, we report the urban circulation of SFTSV between ALTs and hedgehogs in Beijing, China.

Highlights

Hedgehogs and ALTs can maintain the natural circulation of SFTSV in the city ecosystem.

Hedgehogs and ALTs are becoming common in Beijing.

Parthenogenetic ALTs are discovered in Beijing.
Alternative cell entry mechanisms for SARS-CoV-2 and multiple animal viruses
Authors: Ojha Ravi , Jiang Anmin , Mäntylä Elina , Modhira Naphak , Witte Robert , Gaudin Arnaud , De Zanetti Lisa , Gormal Rachel , Vihinen-Ranta Maija , Mercer Jason , Suomalainen Maarit , Greber Urs F. , Yamauchi Yohei , Yves-Lozach Pierre , Helenius Ari , Vapalahti Olli , Young Paul , Watterson Daniel , Meunier Frédéric A. , Joensuu Merja , Balistreri Giuseppe
Published: July 2023

The cell entry mechanism of SARS-CoV-2, the causative agent of the COVID-19 pandemic, is not fully understood. Most animal viruses hijack cellular endocytic pathways as an entry route into the cell. Here, we show that in cells that do not express serine proteases such as TMPRSS2, genetic depletion of all dynamin isoforms blocked the uptake and strongly reduced infection with SARS-CoV-2 and its variant Delta. However, increasing the viral loads partially and dose-dependently restored infection via a thus far uncharacterized entry mechanism. Ultrastructural analysis by electron microscopy showed that this dynamin-independent endocytic processes appeared as 150-200 nm non-coated invaginations and was efficiently used by numerous mammalian viruses, including alphaviruses, influenza, vesicular stomatitis, bunya, adeno, vaccinia, and rhinovirus. Both the dynamin-dependent and dynamin-independent infection of SARS-CoV-2 required a functional actin cytoskeleton. In contrast, the alphavirus Semliki Forest virus, which is smaller in diameter, required actin only for the dynamin-independent entry. The presence of TMPRSS2 protease rescued SARS-CoV-2 infection in the absence of dynamins. Collectively, these results indicate that some viruses such as canine parvovirus and SARS-CoV-2 mainly rely on dynamin for endocytosis-dependent infection, while other viruses can efficiently bypass this requirement harnessing an alternative infection entry route dependent on actin.