bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotypic and phenotypic spectrum of maple syrup urine disease in Zhejiang of China
Authors: Yang X , Yang R , Zhang T , Tan D J , Pan R , Chen Z , Wu D , Chen C , Xu Y , Zhang L , Li X , Shu Q , Hu L
Published: June 2024

Background

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder originating from defects in the branched-chain α-ketoacid dehydrogenase (BCKDH) complex encoded by BCKDHA, BCKDHB and DBT. This condition presents a spectrum of symptoms and potentially fatal outcomes. Although numerous mutations in the BCKDH complex genes associated with MSUD have been identified, the relationship between specific genotypes remains to be fully elucidated.

Aim

Our objective was to predict the pathogenicity of these genetic mutations and establish potential links between genotypic alterations and the clinical phenotypes of MSUD.

Design

Retrospective population-based cohort.

Methods

We analyzed 20 MSUD patients from the Children’s Hospital at Zhejiang University School of Medicine (Hangzhou, China), recorded from January 2010 to December 2023. Patients’ blood samples were collected by heel-stick through neonatal screening, and amino acid profiles were measured by tandem mass spectrometry. In silico methods were employed to assess the pathogenicity, stability and biophysical properties. Various computation tools were utilized for assessment, namely PredictSNP, MAGPIE, iStable, Align GVGD, ConSurf and SNP effect.

Results

We detected 25 distinct mutations, including 12 novel mutations. The BCKDHB gene was the most commonly affected (53.3%) compared to the BCKDHA gene (20.0%) and DBT gene (26.7%). In silico webservers predicted all novel mutations were disease-causing.

Conclusions

This study highlights the genetic complexity of MSUD and underscores the importance of early detection and intervention. Integrating neonatal screening with advanced sequencing methodologies is pivotal in ensuring precise diagnosis and effective management of MSUD, thereby significantly improving the prognosis for individuals afflicted with this condition.
FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα–CPT1a pathway
Authors: Wang Rui-Xue , Wang Luo-Yi , Han Xiang-Yu , Chen Su-Fang , Sun Xiao-Jing , Li Zhi-Ying , Little Mark A , Zhao Ming-Hui , Chen Min
Published: June 2024

Objectives

Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation.

Methods

The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis).

Results

FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis.

Conclusion

FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα–CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.
IEnglish Language
Authors: Schönefeld Doris , Kostadinova Viktorija , Dreschler Gea , Rivas Tamara Bouso , Benczes Réka , Zhong Ai , Scott Maggie , Anderwald Lieselotte , Ahlers Wiebke , Vida-Mannl Manuela , Al-Thubaiti Kholoud A , Cogo Alessia , Ting Shawnea Sum Pok , Parise Ida , Da Silva Juliana Souza , Reber Elisabeth , Adam Naomi , Stradling Fransina
Published: June 2024

This chapter has fourteen sections: 1. General; 2. History of English Linguistics; 3. Phonetics and Phonology will resume next year; 4. Morphology; 5. Syntax; 6. Semantics; 7. Lexicography, Lexicology, and Lexical Semantics; 8. Onomastics; 9. Dialectology and Sociolinguistics; 10. New Englishes and Creolistics; 11. Second Language Acquisition; 12. English as a Lingua Franca; 13. Pragmatics and Discourse Analysis; 14. Stylistics. Section 1 is by Doris Schönefeld; section 2 is by Viktorija Kostadinova; sections 4 and 5 are by Gea Dreschler and Tamara Bouso Rivas; section 6 is by Réka Benczes; section 7 is by Ai Zhong; section 8 is by Maggie Scott; section 9 is by Lieselotte Anderwald; section 10 is by Manuela Vida-Mannl and Wiebke Ahlers; section 11 is by Kholoud A. Al-Thubaiti; section 12 is by Alessia Cogo, Shawnea Sum Pok Ting, Ida Parise, and Juliana Souza Da Silva; section 13 is by Elisabeth Reber; section 14 is by Naomi Adam and Fransina Stradling.
Leadership Experiences and Perceptions of Mid-Career to Senior Clinician-Scientists: A Qualitative Exploration
Authors: Greene Amanda K. , Szczygiel Lauren A. , Thomas J. Denard , Jones Rochelle D. , Cutter Christina M. , Feldman Eva L. , Kerr Eve A. , Paradis Kelly C. , Settles Isis H. , Singer Kanakadurga , Spector Nancy D. , Stewart Abigail J. , Telem Dana , Ubel Peter A. , Jagsi Reshma
Published: June 2024

Purpose

This study aimed to elucidate the experiences and perceptions of mid-career to senior clinician-scientists in academic medicine regarding pursuing, attaining, or rejecting leadership roles as well as their conceptualization of the influence of leadership in their broader career trajectories.

Method

The authors conducted a qualitative analysis of in-depth, semistructured interviews conducted in 2022 with a diverse sample of clinician-scientists who received new National Institutes of Health K08 or K23 Career Development Awards between 2006 and 2009. A total of 859 of the 915 survey respondents (94%) were eligible to be recruited for the qualitative study. Qualitative analysis was informed by thematic analysis and used a social constructionist approach to understanding participants’ conceptualizations of their experiences. Interview transcripts were coded using an iterative, inductive coding process. Themes were generated by reviewing coded data and identifying common patterns in participant narratives, affording particular attention to participants’ discussion of the effect of race and/or gender on their leadership experiences.

Results

Sixty clinician-scientists participated in individual interviews. Five themes were generated surrounding participants’ conceptualizations of their leadership experiences. Themes were (1) feeling unprepared for leadership roles, (2) reluctance and lack of intention in attaining leadership positions, (3) influence of networks on leadership access and decision-making, (4) impact-related benefits and downsides of leadership, and (5) confining ideas of who leaders are.

Conclusions

The study highlighted the need for formal leadership training in academic medicine and the importance of mentorship and sponsorship in attaining and succeeding in leadership positions. Individuals from communities underrepresented in leadership positions faced additional challenges internalizing a leadership identity. Efforts to encourage current leaders to engage in intentional succession planning and development of faculty toward leadership roles, including expansion of institutional leadership development programs, are needed to promote equitable distribution of leadership opportunities.
Using Community Engagement to Move Upstream to Address Social Determinants of Health
Authors: Jones Ross , Bilello Lori , Knight Ann-Marie , Livingood William C. , Whitner Chardaé , Webb Fern
Published: June 2024

Given its role as a safety net institution, the University of Florida Health (UF Health) Jacksonville has responded to the community’s needs through partnerships with the community for decades. Such academic-community partnerships have a broad emphasis on population health and primary care that expands the model of care to include community engagement, which allows such partnerships to promote health and well-being and reduce health inequalities by addressing social determinants of health (SDOH).

This report describes the UF Health Jacksonville and University of Florida College of Medicine—Jacksonville’s creation of the Urban Health Alliance (UHA) in June 2019 due to continued poor health outcomes and inequities within the community. The mission of the UHA is to improve community health using community-focused, self-sustainable strategies and solutions to impact SDOH (i.e., more upstream interventions). Using the tenets of the collective impact model, the UHA acts as a backbone organization to achieve these objectives by empowering community partners to affect changes in policy, systems, and other structures necessary for the optimal health of the community. The UHA’s work is divided across 4 pillars: services, research, education, and policy. These pillars reflect the traditional missions of academic medical centers—clinical care, research, and education—and the need to address structural changes to improve community health—namely, policy. By addressing the issues that most impact the patients and community of UF Health Jacksonville, the UHA can serve as an example of how an academic medical center can use the traditional missions to improve the community’s health and move toward health equity.
New tools for learning airway management
Authors: Onrubia Xavier , Martínez Estefanía , Charco Pedro , Baldó Joana , Reviriego Laura , Greif Robert
Published: June 2024

INTRODUCTION

Game-based learning, also called edutainment, has been promoted as an alternative to the unidirectional, passive teaching of traditional medical education. Solving enigmas and problems through creativity and critical thinking, which is encapsulated in ‘escape rooms’, has been adapted to teach medicine as a way to enhance the mental models of proceeding.

We considered an educational escape room as an activity to promote teaching and training in airway management, integrating knowledge, technical and nontechnical skills and collaborative teamwork during crisis situations.

METHODS

No published experience on this topic was found. Therefore, we created an educational escape room focused on airway management.

We describe the steps undertaken from the design and development of the escape room process (as part of the curriculum of an international airway course) to the results of a survey completed by the participants at the end of the escape room process.

RESULTS

Satisfaction with the experience was rated at least 8 points (0 to 10 numerical rating scale) by 80% of the 147 course participants. Two thirds also rated the experience as at least 8 points (0 to 10 Likert scale) as being helpful in improving behaviour in real cases, and enhance organisational teamwork skills.

CONCLUSION

The airway escape room was feasible for training in airway management. Participants rated it as valuable to gain team competencies. The experience encourages further development and its possible use in other clinical settings.
TcPO2 changes are more pronounced than SpO2 changes during simulated altitude changes in a hypobaric oxygen chamber: a nonrandomized controlled trial
Authors: Li Yang , Chen Liang , Fu Ziyu , Wang Zhiwei , Sun Shijun , Luan Xiaorong , Ma Dedong , Hu Tianliang
Published: June 2024

Background

Hypoxia is a significant risk factor of hypertension. However, no studies have used transcutaneous tissue partial pressure of oxygen (TcPO2) and partial pressure of carbon dioxide (TcPCO2) monitors to measure the respective partial pressures in healthy individuals. Oxygen saturation (SpO2) is often used for traditional monitoring of vital signs. This study investigated the changes in TcPO2 and SpO2 values during rapid changes in altitude. The trial was registered at ClinicalTrials.gov (registration no. NCT06076057).

Methods

Healthy adult volunteers were instructed to sit vertically in a hypobaric oxygen chamber, which ascended from 0 m to 2500 m at a uniform speed within 10 min. The Danish Radiometer TCM4 was used to measure TcPO2 and TcPCO2 with the ventral side of the upper arm as the measurement site. The Shenzhen Kerokan P0D-1 W pulse oximeter was used to measure heart rate and SpO2, with values recorded once every 500 m.

Results

Altogether, 49 healthy volunteers were recruited between March 2023 and August 2023. With increasing altitude, TcPO2 and SpO2 decreased significantly (P < 0.01). During the ascent from 0 m, TcPO2 began to change statistically at 500 m (P < 0.05), whereas SpO2 began to change statistically at 1000 m (P < 0.05). At the same altitude, the difference in TcPO2 was greater than the difference in SpO2. At 1000 m, there were statistically significant changes in TcPO2 and SpO2 (P < 0.001). At altitudes >500 m, statistical significance was identified between TcPO2 in both sexes (P < 0.05). Statistical significance in TcPCO2 and heart rate was observed at the different elevations (P < 0.05).

Conclusion

In acutely changing low-pressure hypoxic environments, TcPO2 changed more dramatically than SpO2.
Metformin-Induced Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition Further Decreases Low-Density Lipoprotein Cholesterol Following Statin Treatment in Patients With Coronary Artery Disease and Without Diabetes
Authors: Hu Die , Qin Donglu , Kuang Jie , Yang Yang , Weng Shuwei , Chen Jin , Wu Sha , Wang Shuai , Mao Ling , Peng Daoquang , Yu Bilian
Published: June 2024

In vitro investigations have established metformin's capacity to downregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (cholesterol-lowering agents alone: atorvastatin ± ezetimibe, n = 38) and Met + CLA groups (metformin plus CLA, n = 33) in a 1:1 ratio. The primary end point was the therapeutic impact of 1-month metformin combination treatment on low-density lipoprotein cholesterol (LDL-C) and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL−1 and 80.54 ng·mL−1, respectively. After 1 month, metformin significantly reduced LDL-C (−20.81%, P < 0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (−15.03%, P < 0.001) were observed. Moreover, Met + CLA markedly reduced LDL particle number more than CLA alone (−10.65% vs. 1.45%, P = 0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a 1-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression.

Trial registration:

Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (26/10/2019).
The Expanded Forehead Flap for Resurfacing of Multi-unit Congenital Nevi of the Face
Authors: Wu Meagan , Pontell Matthew E. , Massenburg Benjamin B. , Ng Jinggang J. , Romeo Dominic J. , Swanson Jordan W. , Taylor Jesse A. , Bartlett Scott P.
Published: June 2024

The forehead flap is a timeless and robust reconstructive option for complex facial defects. In accordance with aesthetic subunit principles, it has traditionally been used to resurface defects affecting a single cervicofacial region, most commonly the nose or periorbital unit. In this article, we present three cases of congenital nevi treated with expanded forehead flap reconstruction of the nasal, periorbital, and cheek units in early childhood. This series demonstrates an approach that, while violating facial units, limits total scar burden and optimizes aesthetic and functional results. With precise staging and execution, this reconstructive technique allows for a single flap to resurface multi-unit defects in the pediatric population with excellent long-term results.
An Alternative Technique For Intraocular Lens Removal: Bimanual Cleavage In The Vitreous Chamber
Authors: Carlà Matteo Mario , Mateo Carlos
Published: June 2024

Purpose:

To present a new technique for lens explantation, involving intraocular lens (IOL) cleavage in the vitreous chamber using two forceps and successive removal from the anterior chamber.

Methods:

Retrospective monocentric analysis of 10 eyes affected by IOL subluxation/luxation who underwent IOL explantation and 23-G vitrectomy. After separating the capsular bag rests from the IOL using the vitrectomy probe, serrated forceps were used to grab the IOL, while microscissors performed an “initiation” cut at the midpoint of the lens plate. A second pair of serrated forceps grabbed the IOL plate on the other side. Then, the two forceps were slowly pulled one apart from the other, exerting a separative force perpendicular to the initiation cut and causing the IOL to cleave in two pieces. In case of asymmetric cleavage, a second cleavage was performed. The pieces of the IOL were then moved to the anterior chamber and removed through a clear corneal incision.

Results:

Intraoperative mean IOL removal time was 14.1 ± 6.5 minutes. The IOLs (seven 1-piece and three three-pieces IOLs) were successfully explanted with this technique in all patients. Overall, four cases underwent exclusive IOL explantation, and the eyes were left aphakic. Postoperatively, best corrected visual acuity improved in all patients at 1-week follow-up, and no intraoperative or postoperative adverse events were reported. Cornea was completely clear in every case since postoperative Day 1.

Conclusion:

Bimanual cleavage technique for IOL removal ensured safer IOL handling in the larger vitreous chamber and minimized the procedures to be performed in the anterior chamber.
PREVALENCE OF DIDANOSINE-RELATED RETINAL TOXICITY AT AN URBAN ACADEMIC CENTER AS DIAGNOSED WITH ULTRA-WIDEFIELD IMAGING
Authors: Kim Joshua Seokju , Shah Jaffer , Papakostas Thanos , Mahrous M. Abdallah , D'Amico Donald J. , Kiss Szilard , Kovacs Kyle D.
Published: June 2024

Purpose:

Antiretroviral therapy has revolutionized HIV treatment with didanosine (DDI) as a pioneering drug. However, DDI has been associated with retinal toxicity, characterized by peripheral chorioretinal degeneration with macular sparing. Despite its clinical recognition, the prevalence and risk factors for didanosine-induced retinopathy are not well described.

Methods:

This retrospective case series analyzed 127 DDI-treated patients at Weill Cornell Medicine Department of Ophthalmology. Inclusion criteria included at least 6 months of DDI use and available ultra-widefield imaging. Patients were categorized as affected or unaffected based on retinal imaging assessed by two reviewers. The affected group was further divided into “probable” or “possible” retinopathy. Patient demographics, DDI usage characteristics, and imaging findings were analyzed with statistical comparisons drawn between affected and unaffected cohorts.

Results:

Of the 127 patients, 9 (7%) showed signs of didanosine-induced retinal toxicity. On average, the affected group was older compared with the unaffected group (65.1 vs. 56.5 years, P = 0.025), with lower BMI (23.2 vs. 27.4, P = 0.04), and older at the start of the treatment (51.6 vs. 40.8 years, P = 0.026). Mild phenotypes with peripheral pigmentary changes were also identified using ultra-widefield imaging.

Conclusion:

This pioneering academic study highlighted a notable prevalence of DDI-induced retinal toxicity. Statistical analysis demonstrated age, BMI, and age at treatment initiation as potential risk factors. Ultra-widefield autofluorescence emerged as a valuable tool in detecting and delineating findings. Follow-up studies are needed to determine the necessity of regular screening for individuals on or with a history of didanosine use.
Short-term plasticity as ‘energetic memory’ of ion channel components of action potential
Authors: Ben Abu Yuval , Wolfson Ira
Published: June 2024

Information transfer in the nervous system is traditionally understood by the transmission of action potentials along neuronal dendrites, with ion channels in the membrane as the basic unit operator for their creation and propagation. We present here a new model for the multiphysics behaviour of ion channels and the action potential dynamics in nervous and other signal-transmitting systems. This model is based on the long-term suppression of an action potential as a response to mechanical input. While other models focus on electrical aspects of the action potential, an increasing body of experiments highlights its electro-mechanical nature and points in particular towards an alteration of the action potential when subjected to a mechanical input. Here, we propose a new phenomenological framework able to capture the mechanical aspect of ion channel dynamics and the resulting effect on the overall electrophysiology of the membrane. The model is introduced here through a set of coupled differential equations that describe the system while agreeing with the general findings of the experiments that support an electro-mechanical model. It also confirms that transient quasi-static mechanical loads reversibly affect the amplitude and rate of change of neuronal action potentials, which are smaller and slower under indentation loading conditions. Changes after the loading release are also reversible, albeit on a different time scale.
Efficient base- and ligand-free palladium catalysed
O
-arylation of phenols in choline chloride:triethanolamine as a reusable deep eutectic solvent
Authors: Abbasi Fatemeh , Sardarian Ali Reza
Published: June 2024

In this paper, we present a novel and sustainable approach using choline chloride:triethanolamine as a green, efficient and reusable deep eutectic solvent (DES) for Pd-catalysed
O
-arylation reactions with Pd/BaSO
4
(10%). By using the unique properties of DESs, we successfully achieved C–O bond formation without the need for additional solvents, bases and ligands. This solvent/catalyst system ([ChCl][TEA]
2
) functioned as a dual catalyst and solvent system, enabling fast and environmentally friendly C–O bond formation from phenol derivatives and electron-deficient aryl halides, leading to remarkable yields under mild reaction conditions. To identify and characterize this DES, we employed differential scanning calorimetry, thermogravimetric analysis, Fourier-transform infrared spectroscopy, refractive index, viscosity, the potential of hydrogen (pH) and conductivity measurements. One of the remarkable advantages of this DES system is its exceptional stability. This solvent/catalyst system exhibited high stability throughout the reaction cycles, showing no significant loss of activity. As a result, this DES and catalyst (Pd/BaSO
4
(10%)) can be easily recycled and re-used for up to three consecutive cycles, making it an economically and environmentally attractive option for organic reactions. Our approach offers several key benefits, including simple catalyst preparation, quick reaction times and excellent production efficiency.
Enhanced antifouling and antibacterial performances of novel UV-curable polysiloxane/microcapsules/Ag composite coatings for marine applications
Authors: Liu Ze , Zheng Nan , Liu Jie , Jia Bo , Wang Xiaojun , Yao Pan , Zhang Yayu , Xia Fu , Guo Xinyu
Published: June 2024

Marine biological fouling is a widespread phenomenon encountered by various oceanic ships and naval vessels, resulting in enormous economic losses. Herein, novel 4,5-dichloro-2-octyl-isothiazolone@sodium alginate/chitosan microcapsules (DCOIT@ALG/CS) were prepared through composite gel method using DCOIT as core materials, ALG and CS as shells, and CaCl
2
as the cross-linking agent. The formed microcapsules (MCs) with Ag nanoparticles (AgNPs) were then filled in UV-curable polysiloxane (UV-PDMS), followed by UV irradiation to yield UV-PDMS/microcapsules/AgNPs (UV-PDMS/MCs/Ag) composite coatings. The constructed micro–nano dual-scale surface using the MCs and AgNPs improved the antifouling and antibacterial properties of UV-PDMS/MCs/Ag coatings. The as-obtained UV-PDMS/MCs/Ag coatings exhibited a static contact angle of about 160°, shear strength of 2.24 MPa, tensile strength of 3.32 MPa and elongation at break of 212%. The synergistic bacteriostatic effects of DCOIT and AgNPs in UV-PDMS/MCs/Ag coatings resulted in a bactericidal rate of 200 μg ml
−1
towards
Escherichia coli
and
Staphylococcus aureus
with saturation at 100% within 10 min. In sum, the proposed composite coatings look promising for future marine transportation, pipeline networks and undersea facilities.
Social experiences shape song preference learning independently of developmental exposure to song
Authors: Wall Erin M. , Woolley Sarah C.
Published: June 2024

Communication governs the formation and maintenance of social relationships. The interpretation of communication signals depends not only on the signal’s content but also on a receiver’s individual experience. Experiences throughout life may interact to affect behavioural plasticity, such that a lack of developmental sensory exposure could constrain adult learning, while salient adult social experiences could remedy developmental deficits. We investigated how experiences impact the formation and direction of female auditory preferences in the zebra finch. Zebra finches form long-lasting pair bonds and females learn preferences for their mate’s vocalizations. We found that after 2 weeks of cohabitation with a male, females formed pair bonds and learned to prefer their partner’s song regardless of whether they were reared with (‘normally reared’) or without (‘song-naive’) developmental exposure to song. In contrast, females that heard but did not physically interact with a male did not prefer his song. In addition, previous work has found that song-naive females do not show species-typical preferences for courtship song. We found that cohabitation with a male ameliorated this difference in preference. Thus, courtship and pair bonding, but not acoustic-only interactions, strongly influence preference learning regardless of rearing experience, and may dynamically drive auditory plasticity for recognition and preference.
Is ZIKA Virus re-emerging as a distinct genetic lineage in India?
Authors: Narendran Pradeep Kumar , Lal Ajith , Saini Prasanta , S AISWARYA R , Suresh Abidha , Samuel Philip , R Balasubramaniam , Mathew Jessu , Thankachy Sonia , K P Amju , K H K Raju , A Veerapathiran , A Selvam , T Balaji , Kumar Ashwani
Published: June 2024

An outbreak of Zika fever occurred in Thiruvananthapuram City, Kerala, India during 2021. On the request of Kerala state health administration, we investigated the same, towards proposing requisite containment strategies of the disease outbreak. Epidemiological investigations indicated a clustering pattern of Zika cases with the presumed index case from a multi-speciality hospital in the city. Preliminary reports on the same had been already reported elsewhere during 2021. Further, entomological surveys carried out evinced the predominant mosquito species in the City viz., Aedes albopictus (65.55%), Aedes aegypti (22.0%) and Aedes vittatus (12.0%) were naturally infected with Zika Virus (ZIKV), the Minimum Infection Rates (MIR) being 17.9, 7.8 and 3.6 respectively. Also, the trans-ovarian transmission was recorded in Ae. albopictus. Analysis of phylogenetically informative genes of ZIKV genome indicated the emergence of a distinct lineage of the Asian strain of the virus with four unique non-synonymous mutations viz., “I22T” & “I160M” (pre-Membrane) and “D348N” & “V473L” (Envelope) was involved in the outbreak. The altered gene expression pattern and evolutionary implications of these unique mutations remain to be investigated. Genetic analysis of the virus isolates from this and other investigations carried out on sporadic outbreaks of ZIKV in the country subsequently, indicated ZIKV is reemerging as a distinct genetic lineage in India. These findings warrant the urgent need for a systematic country-wide surveillance strategy, towards the prevention/ preparedness/ containment of a massive outbreak of this emerging neurovirulent arboviral disease.
Whole-genome analysis of human group A rotaviruses in 1980s Japan and evolutionary assessment of global Wa-like strains across half a century
Authors: Fukuda Yuya , Kondo Kenji , Nakata Shuji , Morita Yasuyuki , Adachi Noriaki , Kogawa Keiko , Ukae Susumu , Kudou Yoshimasa , Adachi Shuhei , Yamamoto Masaki , Fukumura Shinobu , Tsugawa Takeshi
Published: June 2024

Historically, the Wa-like strains of human group A rotavirus (RVA) have been major causes of gastroenteritis. However, since the 2010s, the circulation of non-Wa-like strains has been increasingly reported, indicating a shift in the molecular epidemiology of RVA. Although understanding RVA evolution requires the analysis of both current and historical strains, comprehensive pre-1980’s sequencing data are scarce globally. We determined the whole-genome sequences of representative strains from six RVA gastroenteritis outbreaks observed at an infant home in Sapporo, Japan, between 1981 and 1989. These outbreaks were mainly caused by G1 or G3 Wa-like strains, resembling strains from the United States in the 1970s–1980s and from Malawi in the 1990s. Phylogenetic analysis of these infant home strains, together with Wa-like strains collected worldwide from the 1970s to 2020, revealed a notable trend: pre-2010 strains diverged into multiple lineages in many genomic segments, whereas post-2010 strains tended to converge into a single lineage. However, Bayesian skyline plot indicated near-constant effective population sizes from the 1970s to 2020, and selection pressure analysis identified positive selection only at amino acid 75 of NSP2. These results suggest that evidence supporting the influence of rotavirus vaccines, introduced globally since 2006, on Wa-like RVA molecular evolution is lacking at present, and phylogenetic analysis may simply reflect natural fluctuations in RVA molecular evolution. Evaluating the long-term impact of RV vaccines on the molecular evolution of RVA requires sustained surveillance.
Trends in analgesia prescribing in primary care in Ireland and England between 2014 and 2022 - a repeated cross-sectional study
Authors: Mattsson Molly , Flood Michelle , MacKenna Brian , Wallace Emma , Boland Fiona , Kirke Ciara , Walsh Mary E , Fahey Tom , Moriarty Frank
Published: June 2024

Background

Pain is a major public health issue, and a common reason people seek medical care. Pharmacological treatments depend on the type of pain and carry different risks and benefits. The aim of this study was to examine trends in analgesic prescribing in Ireland and England between 2014 and 2022.

Methods

Monthly data on medicines prescribed and dispensed in primary care were used. For Ireland, data on the means-tested General Medical Services (GMS) scheme were used, covering approximately 32% of the population. For England, data from the NHS Digital platform for all general practices were used. Outcomes were the volume of prescribed analgesic use, including rates of dispensings, costs, and standard doses (including oral morphine equivalents (OMEs) for opioids) per 1,000 population, summarised per year for each drug class/drug.

Results

In Ireland, the rate of analgesia dispensings increased between 2014 and 2022 for most drugs. Opioid dispensings increased from 979 to 1,220 per 1,000 population, while paracetamol increased from 1,295 to 1,824. Systemic NSAIDs decreased from 781 to 734. In England, most analgesia dispensing rates decreased, with opioids decreasing from 721 to 585 per 1,000 population, paracetamol from 734 to 484, and systemic NSAIDs from 259 to 167.

Discussion

Substantially different dispensing patterns were found in Ireland and England, with higher increasing overall rates in Ireland and lower decreasing rates in England, potentially driven by the older age and lower socioeconomic status of GMS patients in Ireland. Further research to understand drivers for this higher volume of use is required.
Beyond Exploratory Data: Using Cluster Detection Tests to Pinpoint Malaria Hotspots in Nigeria
Authors: Oyamakin S. O. , Mayowa Owolabi
Published: June 2024

Malaria is not communicable, but it can deteriorate and even kill a person within a day if treatment is not taken. Plasmodium falciparum is the malaria parasite that is most prevalent and deadly in Africa. This study attempts to identify malaria hotspots and potentially high-risk areas in Oyo state, Nigeria. Data on malaria cases from 2013 to 2016 were provided by the Department of Research, Planning, and Statistics (DPRS) of the Oyo State Ministry of Health. Spatial autocorrelation testing, spatiotemporal analysis, and descriptive statistics were performed using SatScan V9.11 and ArcGIS V10.8. The four-year malaria incidence study was conducted in Oyo West LGA and is geographically focused. Four clusters were found using spatial analysis, with the majority of the clusters located in the Oyo South region. Spatial-temporal research revealed three noteworthy groups. The cluster that happened between January 2013 and December 2014 is located in the Oyo South and Oyo Central region. High-high malaria clusters were identified by spatial autocorrelation analysis, particularly in Oyo Central; the yearly clustered pattern of malaria incidence was not coincidental. In order to better achieve effective disease surveillance, this study suggests employing more cluster detection tests (or CDTs) rather than just exploratory data analysis prior to the implementation of health treatments and regulations.
Determinants of de novo mutations in extended pedigrees of 43 dog breeds
Authors: Zhang Shao-Jie , Ma Jilong , Riera Meritxell , Besenbacher Søren , Niskanen Julia , Salokorpi Noora , Hundi Sruthi , Hytönen Marjo K , Zhou Tong , Li Gui-Mei , Ostrander Elaine A. , Schierup Mikkel Heide , Lohi Hannes , Wang Guo-Dong
Published: June 2024

Intensive breeding of dogs has had dramatic effects on genetic variants underlying phenotypes. To investigate whether this also affected mutation rates, we deep-sequenced pedigrees from 43 different dog breeds representing 404 trios. We find that the mutation rate is remarkably stable across breeds and is predominantly influenced by variation in parental ages. The effect of paternal age per year on mutation rates is approximately 1.5 times greater in dogs than humans, suggesting that the elevated yearly mutation rate in dogs is only partially attributed to earlier reproduction. While there is no significant effect of breeds on the overall mutation rate, larger breeds accumulate proportionally more mutations earlier in development than small breeds. Interestingly, we find a 2.6 times greater mutation rate in CG Islands (CGIs) compared to the remaining genome in dogs, unlike humans, where there is no difference. Our estimated rate of mutation by recombination in dogs is more than 10 times larger than estimates in humans. We ascribe these to the fact that canids have lost PRDM9-directed recombination and draw away recombination from CGIs. In conclusion, our study sheds light on stability of mutation processes and disparities in mutation accumulation rates reflecting the influence of differences in growth patterns among breeds, and the impact of PRDM9 gene loss on the de novo mutations of canids.
Peptidergic neurons with extensive branching orchestrate the internal states and energy balance of maleDrosophila melanogaster
Authors: Song Yutong , Zhang Tianmu , Zhang Xiaoli , Ryu Tae Hoon , Wong Kyle , Wu Zekun , Wei Yanan , Schweizer Justine , Nguyen Khoi-Nguyen Ha , Kwan Alex , Yu Kweon , Kim Woo Jae
Published: June 2024

Neuropeptide SIFamide (SIFa) neurons inDrosophila melanogasterhave been characterized by their exceptionally elaborate arborization patterns, which extend from the brain into the ventral nerve cord (VNC). SIFa neurons are equipped to receive signals that integrate both internal physiological cues and external environmental stimuli. These signals enable the neurons to regulate energy balance, sleep patterns, metabolic status, and circadian timing. These peptidergic neurons are instrumental in orchestrating the animal’s internal states and refining its behavioral responses, yet the precise molecular underpinnings of this process remain elusive. Here we demonstrate that SIFa neurons coordinate a range of behavioral responses by selectively integrating inputs and outputs in a context-dependent manner. These neurons engage in a feedback loop with sNPF neurons in the ventral nerve cord, modifying behaviors such as long mating duration (LMD) and shorter mating duration (SMD). Furthermore, SIFa neurons receive essential inputs from neuropeptides Dsk, sNPF, and dilp2, which regulate interval timing behaviors. Activating SIFa neurons leads to reduced mating duration and increased food intake, while deactivating them reduces food intake. Overall, these findings demonstrate the importance of SIFa neurons in absorbing inputs and turning them into behavioral outputs, shedding light on animal’s intricate behavioral orchestration.
Phylogenetic divergence of GABABreceptor signalling in neocortical networks over adult life
Authors: Wilson Max A. , Taylor Lewis W. , Meftah Soraya , McGeachan Robert I. , Modebadze Tamara , Jayasekera B. Ashan P. , Cowie Christopher J. A. , LeBeau Fiona E. N. , Liaquat Imran , Durrant Claire S. , Brennan Paul M. , Booker Sam A.
Published: June 2024

Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. Much is known about fast GABA currents, GABABreceptor (GABABR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. However, little is known about how GABABRs contribute to circuit-level inhibition over the lifespan of rodents and humans. In this study, we quantitatively determine the functional contribution of GABABR signalling to pre- and postsynaptic domains in rat and human cortical principal cells (PC). We find that postsynaptic GABABR differentially control pyramidal cell activity within the cortical column as a function of age and species, and that these receptors contribute to co-ordination of local information processing in a layer- and species-dependent manner. These data directly increase our knowledge of translationally relevant local circuit dynamics, with direct impact on understanding the role of GABABRs in the treatment of seizure disorders.

Highlights

GABABreceptor signalling displays age and species differences in cortex

GABABreceptor presynaptic inhibition is stronger in humans than rodents

In vitrooscillations in human cortex are strongly regulated by GABABRs

Levetiracetam enhances endogenous GABABR signalling in human cortex
Altered dynamics of ATP synthase cause functional irregularities in senescent hiPS-cardiomyocytes
Authors: Morris Silke , Molina-Riquelme Isidora , Barrientos Gonzalo , Schmelter Frank , Peischard Stefan , Seebohm Guiscard , Eisner Verónica , Busch Karin B.
Published: June 2024

Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. Aging-related heart failure is often driven by energy depletion in cardiomyocytes (CM), which rely on their abundant, cristae-dense mitochondria for ATP production. ATP synthase, localized along the cristae rims, plays a critical role in energy conversion, but the connection between its organization and function remains unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent CM at the level of individual complexes. Using single-molecule localization and tracking microscopy, we observed reduced enzyme mobility within the cristae, coinciding with decreased ATP synthase activity, despite a stable resting mitochondrial membrane potential. This reduction in activity was independent of changes in ATP synthase expression or dimerization. Electron tomography revealed an increased prevalence of curved inner membranes and fenestrated cristae in senescent CM, explaining the reduced enzyme mobility. Senescent CM displayed irregular autonomous and paced beating patterns. These abnormalities suggest that impaired cardiac function is directly driven by disrupted energy metabolism, rooted in the suboptimal organization and function of ATP synthase in altered cristae.
Microscopy analysis of delayed co-transcriptional splicing in highly expressed thyroglobulin gene
Authors: Ullrich Simon , Nadelson Iliya , Krebs Stefan , Blum Helmut , Leonhardt Heinrich , Solovei Irina
Published: June 2024

Transcription of the majority of eukaryotic genes is accompanied by splicing, a process that depends on the assembly of the spliceosome on introns. The timing of spliceosome assembly varies significantly between introns, transcripts, genes and species. While quick co-transcriptional intron removal has been demonstrated for many mammalian genes, most splicing events do not occur immediately after intron synthesis. In this study, we utilized the highly expressedTggene, which forms exceptionally long transcription loops (Leidescher et al., 2022), providing a convenient model for studying splicing dynamics using advanced light microscopy. Our single-cell oligopainting-based analysis revealed a delay in splicing several tens of kilobases downstream of a transcribed intron, a finding further supported by standard cell population analyses. We speculate that this phenomenon is due to the abnormally high transcription rate of theTggene, which may lead to a localized deficiency in splicing factors and, consequently, delayed spliceosome assembly on thousands of nascent transcripts decorating the gene. Additionally, we found that, in contrast to short introns (<10 kb), longTgintron (>50 kb) is spliced promptly, providing further support for the idea that intron length may modulate splicing speed.
Horn size is linked to Sertoli cell efficiency and sperm size homogeneity during sexual development in common eland (Taurotragus oryx)
Authors: Pintus Eliana , Kotrba Radim , Ros-Santaella José Luis
Published: June 2024

Background

In polygynous species, the development of secondary sexual characters is usually decisive for male reproductive success. However, our understanding about the links between the growth of these traits and reproductive efficiency is still elusive. Most research efforts in this topic have been also focused on adult males, although the development of some secondary sexual characters, like bovid horns, typically starts after birth, continues during the puberty and in some species, such as the common eland, slows or even stops during adulthood. In this study, we investigated the relationships between horn size and testicular function during sexual development in common elands using a comprehensive approach that considers both spermatogenic and sperm parameters.

Methods

Twenty-two non-sexually mature common elands were analyzed for the present study. Horn size was estimated by performing a principal component analysis of horn length, spiral length, and basal circumference. In addition, body mass, testes mass, and gonadosomatic index were assessed. Spermatogenic activity was assessed by cytological and histological analyses. Sperm concentration, morphology, morphometry, and intramale variation in sperm size were evaluated on epididymal sperm samples.

Results

We found that bigger horns are associated with increased Sertoli cell efficiency and reduced intramale variation in sperm size. Both parameters were not related to one another while they have shown to be associated with enhanced sperm quality in ungulates. Moreover, horn size was positively linked to the testis mass, sperm concentration, and testicular investment in the seminiferous epithelium. Surprisingly, horn size did not correlate to the percentage of the spermatozoa over the germ cell population nor the percentage of those with normal morphology, which typically increase throughout the male sexual development. It is also remarkable to note that the spiral length and basal circumference were the horn traits most strongly correlated with spermatogenic and sperm parameters as well as those responsible for the sexual dimorphism in this species.

Conclusions

Taken together, our results indicate that horn size can be regarded as a good index of male reproductive potential during sexual development and provide insights into the role of secondary sexual characters in sexual selection dynamics.
Borg3 controls septin recruitment for primary cilia formation
Authors: Schampera Janik N. , Lehmann Friederike , Meléndez Ana Valeria , Schwan Carsten
Published: June 2024

Septin GTPases form linear hexa- or octameric rods that polymerize into higher order structures. They are incorporated into the cytoskeleton and involved in vital cellular functions. Among these, they play a role in the formation of primary cilia. Primary cilia are evolutionary conserved cellular signaling hubs. While it is accepted that septins localize to primary cilia and are involved in their formation and function, the regulation of septin assembly in the confined ciliary compartment remains elusive. Here we show, that Borg3, also known as Cdc42 effector protein 5 (Cdc42EP5), is an essential component of primary cilia. Specific Borg3 localization is facilitated by switching the Rho-GTPase Cdc42 between an inactive- and active state at the base of the primary cilium. The active form of Cdc42 has a defined localization restricted to the base of the primary cilium. Knockout of Borg3 as well as dysregulation of Cdc42 reduces septin dynamics at cilia and consequently, the formation of cilia.

The study demonstrates that Borg3 is a novel and essential regulator of ciliogenesis through the spatiotemporal control of septin dynamics downstream of Cdc42.