bluuebunny/crossref_metadata_2025 huggingface dataset:
New Caledonian rovers and the historical biogeography of a hyper‐diverse endemic lineage of South Pacific leaf beetles
Authors: Platania Leonardo , Cardoso Anabela , Anderson Mark , Fikáček Martin , Gauthier Jérémy , Hendrich Lars , Mille Christian , Morii Yuta , Reid Chris A. M. , Seidel Matthias , Morgan‐Richards Mary , Trewick Steven A. , Toussaint Emmanuel F. A. , Gómez‐Zurita Jesús
Published: March 2024

South Pacific archipelagos are central in the biogeographic debate on the relative importance of vicariance and dispersal in shaping the distribution of species. However, each taxonomic group was subject to different processes and histories, and here, we reveal the historical biogeography of the diverse Eumolpinae leaf beetles, widely distributed in the region. Extensive taxon sampling focusing on South Pacific Eumolpinae was used to infer the first molecular phylogeny of the group using three single‐copy protein‐coding nuclear and two mitochondrial markers. Upon assessing the clade of interest for lineage‐specific variation in substitution rates, the age of the most recent common ancestors was estimated using out‐group calibration and multi‐gamma site models (MGSMs). Biogeographic analyses used standard event‐based inferences also incorporating phylogenetic uncertainty. Zealandian Eumolpinae are monophyletic and appear to have split from their global relatives in the transition from the Cretaceous to the Paleogene. Variation in the rates of molecular evolution affected the in‐group stem branch, with a significant drop in the substitution rate, and the MGSM correction recovered the crown age of Zealandian Eumolpinae during the Late Eocene–Oligocene transition. Biogeographic inference resolved the origin of the radiation in New Caledonia, favouring a null model without island age constraints, and repeated dispersal events to the other islands, including three independent but synchronous colonisations of New Zealand during the Miocene. New Caledonia, with a highly diverse Eumolpinae fauna of uncertain origin, acted as a hub and pump of biodiversity of these beetles in the entire South Pacific region, sending migrants to other islands through long‐distance dispersal with lineages establishing when land became available.
The novel HLA‐C*08:273 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual
Authors: Wu Cheng‐ye , Xie Zhi‐cong , Ma Li , Hu Xiao‐zhuang , Zhu Zun‐min
Published: March 2024

HLA‐C*08:273 differs from HLA‐C*08:01:01:01 by one nucleotide in exon 2.
Rice small secreted peptide, OsRALF26, recognized by FERONIA‐like receptor 1 induces immunity in rice and Arabidopsis
Authors: Kwon Oh‐Kyu , Moon Hyeran , Jeong A‐Ram , Yeom Gunn , Park Chang‐Jin
Published: March 2024

Rapid alkalinization factors (RALFs), belonging to a family of small secreted peptides, have been considered as important signaling molecules in diverse biological processes, including immunity. Current studies on RALF‐modulated immunity mainly focus on Arabidopsis, but little is reported in crop plants. The rice immune receptor XA21 confers immunity to the bacterial blight pathogen, Xanthomonas oryzae pv. oryzae (Xoo). Here, we pursued functional characterization of rice RALF26 (OsRALF26) up‐regulated by Xoo during XA21‐mediated immune response. When applied exogenously as a recombinant peptide, OsRALF26 induced a series of immune responses, including pathogenesis‐related genes (PRs) induction, reactive oxygen species (ROS) production, and callose deposition in rice and/or Arabidopsis. Transgenic rice and Arabidopsis overexpressing OsRALF26 exhibited significantly enhanced resistance to Xoo and Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), respectively. In yeast two‐hybrid, pull‐down assays, and co‐immunoprecipitation analyses, rice FER‐like receptor 1 (OsFLR1) was identified as a receptor of OsRALF26. Transient expression of OsFLR1 in Nicotiana benthamiana leaves displayed significantly increased ROS production and callose deposition after OsRALF26 treatment. Together, we propose that OsRALF26 induced by Xoo in an XA21‐dependent manner is perceived by OsFLR1 and may play a novel role in the enforcement of XA21‐mediated immunity.
Evaluation of economic inequality in ‘the Belt and Road’ region – The application of night‐time satellite imagery
Authors: Yang Zhen , Zhang Lu , Liu Chengkun , Chen Yu , Wu Rongwei , Zheng Yaomin
Published: March 2024

The main aim of this paper is to explore economic inequality in ‘the Belt and Road’ region where the investigation of the economic status is important but remains underdeveloped. The application of night‐time satellite imagery in 2015 can effectively make up for the shortcomings of insufficient data at various scales, especially for developing countries. We explored inequality at a multi‐scale level using the Theil decomposition method. As a result, (1) night‐time light data can present economic development and assess inequality in ‘the Belt and Road’ region. (2) The between‐sub‐region inequality contributed most to disparity, while the between‐country inequality was the least. Night‐time light data in West Asia and Central and Eastern Europe was higher than that in other sub‐regions. Countries within Central, Southeast and West Asia exhibited high inequalities, indicating an obvious sub‐regional pattern. (3) Both positive and negative impacts of economic growth on inequality are observed, indicating that ‘the Belt and Road’ countries are in different stages of economic development. Nightlight satellite imagery can effectively monitor social‐economic development and will play an important role in the implementation of ‘the Belt and Road’ initiative and achieving the sustainable development goals.
Influence of Amputation on Kinetic Chain Musculature Activity During Basic and Modified Core Exercises
Authors: Liu Kaiqi , Ji Linhong , Lu Yijia
Published: March 2024

Purpose: Core strength is vital for athletic performance, and many more exercises that involve the kinetic chain have been designed for able-bodied athletes. Disabilities that impair the kinetic chain can reduce the effectiveness of strength training. However, the impact of amputation on core strength training of people with disabilities and its underlying mechanism remains unclear. This study aimed to evaluate the muscle activation patterns and levels in athletes with amputation during 4 basic and modified weight-bearing core strength-training exercises. Methods: Fifteen elite athletes with unilateral amputation (170.6 [7.3] cm; 63.9 [11.9] kg; 25.9 [5.3] y) volunteered for this study. Surface electromyography was used to measure the muscle activity mainly in the lumbopelvic–hip complex-stabilizing muscles during 4 kinetic chain trunk exercises with and without modifications. Results: The significance level was set at α = .05. The results showed a significant difference in muscle activation between different body sides (P < .05). Specifically, amputation on the support position resulted in a diagonal pattern of muscle activation, and amputation on the free distal segments resulted in a unilateral dominant pattern with higher activation in muscles on the nonamputated side (P < .05). Modifications led to significant decreases in muscle activation asymmetry index (P < .05). Conclusions: Amputation caused muscle activation asymmetry and 2 activation patterns. Modifications by enhancing proximal stability and adjusting distal loading effectively reduced the asymmetry of muscle activation. Coaches and clinicians can use these results to tailor exercises for athletes with disabilities in training and rehabilitation.
Distributed sensing along fibers for smart clothing
Authors: Hannigan Brett C. , Cuthbert Tyler J. , Ahmadizadeh Chakaveh , Menon Carlo
Published: March 2024

Textile sensors transform our everyday clothing into a means to track movement and biosignals in a completely unobtrusive way. One major hindrance to the adoption of “smart” clothing is the difficulty encountered with connections and space when scaling up the number of sensors. There is a lack of research addressing a key limitation in wearable electronics: Connections between rigid and textile elements are often unreliable, and they require interfacing sensors in a way incompatible with textile mass production methods. We introduce a prototype garment, compact readout circuit, and algorithm to measure localized strain along multiple regions of a fiber. We use a helical auxetic yarn sensor with tunable sensitivity along its length to selectively respond to strain signals. We demonstrate distributed sensing in clothing, monitoring arm joint angles from a single continuous fiber. Compared to optical motion capture, we achieve around five degrees error in reconstructing shoulder, elbow, and wrist joint angles.
Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams
Authors: Lai Shirong , Zhang Libo , Tu Xinyu , Ma Xinyue , Song Yujing , Cao Kexin , Li Miaomiao , Meng Jihong , Shi Yiqiang , Wu Qing , Yang Chen , Lan Zifan , Lau Chunyue Geoffrey , Shi Jie , Ma Weining , Li Shaoyi , Xue Yan-Xue , Huang Zhuo
Published: March 2024

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin–brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.
Ultralow-loss optical interconnect enabled by topological unidirectional guided resonance
Authors: Wang Haoran , Zuo Yi , Yin Xuefan , Chen Zihao , Zhang Zixuan , Wang Feifan , Hu Yuefeng , Zhang Xiaoyu , Peng Chao
Published: March 2024

Grating couplers that interconnect photonic chips to off-chip components are crucial for various optoelectronics applications. Despite numerous efforts in past decades, the existing grating couplers are still far from optimal in energy efficiency and thus hinder photonic integration toward a larger scale. Here, we propose a strategy to achieve ultralow-loss grating couplers by using unidirectional guided resonances (UGRs), suppressing the useless downward radiation with no mirror on the bottom. By engineering the dispersion and apodizing the geometry of grating, we experimentally realize a grating coupler with a record-low loss of −0.34 dB and 1-dB bandwidth exceeding 30 nm at the telecom wavelength of 1550 nm and further demonstrate an optic via with a loss of only −0.94 dB. Given that UGRs ubiquitously exist in a variety of grating geometries, our work sheds light on a systematic method to achieve energy-efficient optical interconnect and paves the way to large-scale photonic integration.
Restoration of virulence in the attenuated Candid#1 vaccine virus requires reversion at both positions 168 and 427 in the envelope glycoprotein GPC
Authors: Nunberg Jack H. , Westover Jonna B. , York Joanne , Jung Kie Hoon , Bailey Kevin W. , Boardman Kirsten M. , Li Minghao , Furnell Rachel S. , Wasson Samantha R. , Murray Justin S. , Kaundal Rakesh , Thomas Aaron J. , Gowen Brian B.
Published: March 2024

Live-attenuated virus vaccines provide long-lived protection against viral disease but carry inherent risks of residual pathogenicity and genetic reversion. The live-attenuated Candid#1 vaccine was developed to protect Argentines against lethal infection by the Argentine hemorrhagic fever arenavirus, Junín virus. Despite its safety and efficacy in Phase III clinical study, the vaccine is not licensed in the US, in part due to concerns regarding the genetic stability of attenuation. Previous studies had identified a single F427I mutation in the transmembrane domain of the Candid#1 envelope glycoprotein GPC as the key determinant of attenuation, as well as the propensity of this mutation to revert upon passage in cell culture and neonatal mice. To ascertain the consequences of this reversion event, we introduced the I427F mutation into recombinant Candid#1 (I427F rCan) and investigated the effects in two validated small-animal models: in mice expressing the essential virus receptor (human transferrin receptor 1; huTfR1) and in the conventional guinea pig model. We report that I427F rCan displays only modest virulence in huTfR1 mice and appears attenuated in guinea pigs. Reversion at another attenuating locus in Candid#1 GPC (T168A) was also examined, and a similar pattern was observed. By contrast, virus bearing both revertant mutations (A168T+I427F rCan) approached the lethal virulence of the pathogenic Romero strain in huTfR1 mice. Virulence was less extreme in guinea pigs. Our findings suggest that genetic stabilization at both positions is required to minimize the likelihood of reversion to virulence in a second-generation Candid#1 vaccine.

IMPORTANCE

Live-attenuated virus vaccines, such as measles/mumps/rubella and oral poliovirus, provide robust protection against disease but carry with them the risk of genetic reversion to the virulent form. Here, we analyze the genetics of reversion in the live-attenuated Candid#1 vaccine that is used to protect against Argentine hemorrhagic fever, an often-lethal disease caused by the Junín arenavirus. In two validated small-animal models, we find that restoration of virulence in recombinant Candid#1 viruses requires back-mutation at two positions specific to the Candid#1 envelope glycoprotein GPC, at positions 168 and 427. Viruses bearing only a single change showed only modest virulence. We discuss strategies to genetically harden Candid#1 GPC against these two reversion events in order to develop a safer second-generation Candid#1 vaccine virus.
Congenital midline upper lip sinus in an infant
Authors: Sahu Avilash , Mahalik Santosh Kumar , Tripathy Tara Prasad
Published: March 2024

Congenital lip sinus is a rare entity with upper lip sinus being rarer than the lower lip sinus. It can be an isolated entity or associated with cleft lip, palate or Van der Woude syndrome. Syndromic association requires proper evaluation and aggressive surgical treatment. Preoperative delineation of the sinus tract with ultrasound sonography or MRI is mandatory. Simple excision is sufficient in cases of isolated sinuses. In this article, we report an infant with upper lip sinus managed successfully with simple excision and reviewed the literature.
Temporal trends of ambulance time intervals for suspected stroke/transient ischaemic attack (TIA) before and during the COVID-19 pandemic in Ireland: a quasi-experimental study
Authors: Burton Edel , Quinn Rory , Crosbie-Staunton Kieran , Deasy Conor , Masterson Siobhan , O'Donnell Cathal , Merwick Áine , Willis David , Kearney Patricia M. , Mc Carthy Vera J.C. , Buckley Claire M.
Published: March 2024

Objectives

Time is a fundamental component of acute stroke and transient ischaemic attack (TIA) care, thus minimising prehospital delays is a crucial part of the stroke chain of survival. COVID-19 restrictions were introduced in Ireland in response to the pandemic, which resulted in major societal changes. However, current research on the effects of the COVID-19 pandemic on prehospital care for stroke/TIA is limited to early COVID-19 waves. Thus, we aimed to investigate the effect of the COVID-19 pandemic on ambulance time intervals and suspected stroke/TIA call volume for adults with suspected stroke and TIA in Ireland, from 2018 to 2021.

Design

We conducted a secondary data analysis with a quasi-experimental design.

Setting

We used data from the National Ambulance Service in Ireland. We defined the COVID-19 period as ‘1 March 2020–31 December 2021’ and the pre-COVID-19 period ‘1 January 2018–29 February 2020’.

Primary and secondary outcome measures

We compared five ambulance time intervals: ‘allocation performance’, ‘mobilisation performance’, ‘response time’, ‘on scene time’ and ‘conveyance time’ between the two periods using descriptive and regression analyses. We also compared call volume for suspected stroke/TIA between the pre-COVID-19 and COVID-19 periods using interrupted time series analysis.

Participants

We included all suspected stroke/TIA cases ≥18 years who called the National Ambulance Service from 2018 to 2021.

Results

40 004 cases were included: 19 826 in the pre-COVID-19 period and 20 178 in the COVID-19 period. All ambulance time intervals increased during the pandemic period compared with pre-COVID-19 (p<0.001). Call volume increased during the COVID-19-period compared with the pre-COVID-19 period (p<0.001).

Conclusions

A ’shock' like a pandemic has a negative impact on the prehospital phase of care for time-sensitive conditions like stroke/TIA. System evaluation and public awareness campaigns are required to ensure maintenance of prehospital stroke pathways amidst future healthcare crises. Thus, this research is relevant to routine and extraordinary prehospital service planning.
Self-help friendliness and cooperation with self-help groups among rehabilitation clinics in Germany (KoReS): a mixed-methods study protocol
Authors: Ziegler Elâ , Bartzsch Thea , Trojan Alf , Usko Nicole , Krahn Ines , Bütow Sabine , Kofahl Christopher
Published: March 2024

Introduction

Self-help is an important complement to medical rehabilitation for people with chronic diseases and disabilities. It contributes to stabilising rehabilitation success and further coping with disease and disability. Rehabilitation facilities are central in informing and referring patients to self-help groups. However, sustainable cooperation between rehabilitation and self-help, as can be achieved using the concept of self-help friendliness in healthcare, is rare, as is data on the cooperation situation.

Methods and analysis

The KoReS study will examine self-help friendliness and cooperation between rehabilitation clinics and self-help associations in Germany, applying a sequential exploratory mixed-methods design. In the first qualitative phase, problem-centred interviews and focus groups are conducted with representatives of self-help-friendly rehabilitation clinics, members of their cooperating self-help groups and staff of self-help clearinghouses involved based on a purposeful sampling. Qualitative data collected will be analysed through content analysis using MAXQDA. The findings will serve to develop a questionnaire for a quantitative second phase. Cross-sectional online studies will survey staff responsible for self-help in rehabilitation clinics nationwide, representatives of self-help groups and staff of self-help clearinghouses. Quantitative data analysis with SPSS will include descriptive statistics, correlation, subgroup and multiple regression analyses. Additionally, a content analysis of rehabilitation clinics’ websites will evaluate the visibility of self-help in their public relations.

Ethics and dissemination

The University Medical Center Hamburg-Eppendorf Local Psychological Ethics Committee at the Center for Psychosocial Medicine granted ethical approval (reference number LPEK-0648; 10.07.2023). Informed consent will be obtained from all participants. Results dissemination will comprise various formats such as workshops, presentations, homepages and publications for the international scientific community, rehabilitation centres, self-help organisations and the general public in Germany. For relevant stakeholders, practical guides and recommendations to implement self-help friendliness will derive from the results to strengthen patient orientation and cooperation between rehabilitation and self-help to promote the sustainability of rehabilitation processes.
Call for sustainable food systems including (medical) nutrition for hospitalised children and their families
Authors: Verbruggen Sascha C A T , Cochius den Otter Suzan , Bakker Johanna , Briassoulis George , Ilia Stavroula , Latten Lynne , Joosten Koen , Rooze Shancy , van Zanten Eva , Beattie R Mark , Marino Luise V
Published: March 2024

The climate emergency presents a profound threat to global health, adversely affecting the health and well-being of children who are projected to bear a substantial disease burden, as well as impacting children’s right to food, water, healthcare and education. The healthcare sector strives to prioritise preventative healthcare policies improving the health of individuals across the life course. However, current healthcare practices significantly contribute to greenhouse gas (GHG) emissions and waste generation, in which (medical) nutrition plays an important role.

Plant-based proteins offer sustainability benefits, and potential health advantages, and have a lower climate footprint, although there may also be unintended consequences of land-use change and deforestation for certain crops. However, to develop suitable plant-based alternatives to medical nutrition, it will be necessary to address regulatory obstacles as well as ensure nutritional profiles are suitable, particularly protein (amino acid) and micronutrient composition. Additionally, the development of heat-tolerant and water-efficient plant genotypes could bolster adaptation to changing climatic conditions.

Effective waste management, including wasted food and medical nutrition, emerges as a key strategy in mitigating the climate impact of medical nutrition. While research on food waste in healthcare settings is limited, minimising waste spillage in medical nutrition is a crucial area to explore. Healthcare professionals must acknowledge their roles in curbing the climate footprint of medical nutrition as well as recommendations for food-based approaches. This review aims to investigate the sustainability of medical nutrition for paediatric care, focusing on factors contributing to GHG emissions, plant-based alternatives, waste management and plastic packaging. Such an exploration is vital for healthcare professionals to fulfil their responsibilities in addressing the climate crisis while advocating for change.
First evidence of a biomarker-based dose-response relationship in chronic pain using physiological closed-loop spinal cord stimulation
Authors: Muller Leah , Pope Jason , Verrills Paul , Petersen Erika , Kallewaard Jan Willem , Gould Ian , Karantonis Dean M
Published: March 2024

Background and objectives

In spinal cord stimulation (SCS) therapy, electricity is the medication delivered to the spinal cord for pain relief. In contrast to conventional medication where dose is determined by desired therapeutic plasma concentration, there is lack of equivalent means of determining dose delivery in SCS. In open-loop (OL) SCS, due to the dynamic nature of the epidural space, the activating electric field delivered is inconsistent at the level of the dorsal columns. Recent Food and Drug Administration guidance suggests accurate and consistent therapy delivered using physiologic closed-loop control (PCLC) devices can minimize underdosage or overdosage and enhance medical care. PCLC-based evoked compound action potential (ECAP)-controlled technology provides the ability to prescribe a precise stimulation dose unique to each patient, continuously measure neural activation, and objectively inform SCS therapy optimization.

Methods

Neurophysiological indicator metrics of therapy dose, usage above neural activation threshold, and accuracy of SCS therapy were assessed for relationship with pain reduction in over 600 SCS patients.

Results

Significant relationships between objective metrics and pain relief across the patient population are shown, including first evidence for a dose-response relationship in SCS.

Conclusions

Higher dose, more time over ECAP threshold, and higher accuracy are associated with better outcomes across patients. There is potential to optimize individual patient outcomes based on unique objective measurable electrophysiological inputs.
Some Topological Approaches of Rough Sets through Minimal Neighborhoods and Decision Making
Authors: Shbair Ismail T. , Salama Amgad S. , Embaby Osama A. , El-Atik Abdelfattah A.
Published: March 2024

Rough set has an important role to deal with uncertainty objects. The aim of this article is to introduce some kinds of generalization for rough sets through minimal neighborhoods using special kinds of binary relations. Moreover, four different types of dual approximation operators will be constructed in terms of minimal neighborhoods. The comparison between these types of approximation operators is discussed. Some new kinds of topological structures induced by minimal neighborhoods are established and some of their properties are studied. Finally, we give a comparison between these topologies that help for determining the major components of COVID-19 infections. In this application, the components of infections help the expert in decision making in medicine.
Clinical Outcomes of Ileostomy Closure during versus after Adjuvant Chemotherapy in Patients with Rectal Cancer
Authors: He Fan , Yang Fuyu , Tang Chenglin , Chen Defei , Zhao Dongqin , Xiong Junjie , Zou Yu , Huang Guoquan , Qian Kun
Published: March 2024

Background. Protective ileostomy can effectively prevent severe anastomotic leakage after rectal cancer surgery; however, the optimal timing for ileostomy closure during adjuvant chemotherapy remains unclear. This study aimed to explore the safety and long-term outcomes of early ileostomy closure during adjuvant chemotherapy. Method. Patients who underwent laparoscopic rectal cancer surgery combined with protective ileostomy and adjuvant chemotherapy between April 2017 and April 2021 were retrospectively evaluated. Patients were divided into an early closure group during chemotherapy (group A) and a late closure group after chemotherapy (group B). Results. A total of 215 patients were included in this study, with 115 in group A and 100 in group B. There were no significant differences in demographic and clinical characteristics between the two groups. In group A, durations of stoma status (p<0.001) and low anterior resection syndrome (LARS) (p<0.001) were shorter, and rectal stenosis (p=0.036) and stoma-related complications (p=0.007), especially stoma stenosis (p=0.041), were less common. However, compliance with chemotherapy was worse (p=0.009). There were no significant differences in operative time, postoperative hospital stay, postoperative complications, incidence and severity of LARS, disease-free survival, or overall survival between groups. Conclusion. Early ileostomy closure can effectively reduce the duration of stoma status, duration of LARS, rectal stenosis, and stoma-related complications while not affecting surgical complications and oncological outcomes. Ileostomy closure should not be delayed because of adjuvant chemotherapy. However, follow-up should be strengthened to increase compliance and integrity with chemotherapy.
Exploring the Interplay between Mitochondrial DNA and Lifestyle Factors in the Pathogenesis of Psychiatric Disorders
Authors: Wei Wenming , Cheng Bolun , Zhao Yijing , He Dan , Chu Xiaoge , Qin Xiaoyue , Zhang Na , Shi Sirong , Cai Qingqing , Hui Jingni , Wen Yan , Liu Huan , Jia Yumeng , Zhang Feng
Published: March 2024

The objectives of this study were to investigate the interaction of mitochondrial DNA (mtDNA) and lifestyle factors in the development of psychiatric disorders and to gain greater insight into their pathogenesis and comorbidity. We analyzed data from approximately 150,000 individuals from the UK Biobank. Mitochondrial gene-by-environment interaction studies (mtGEIS) were performed to assess the relationships between mtDNA and psychiatric disorders, such as anxiety, depression, and self-harm. These disorders were defined using diagnostic and severity indicators derived from the General Anxiety Disorder (GAD-7) and Patient Health Questionnaire (PHQ-9). Smoking and drinking behaviors were characterized based on UK Biobank criteria. For the mtGEIS, logistic and linear regression models from PLINK 2.0 were employed, accounting for covariates like age, sex, PC1-10, Townsend Deprivation Index (TDI), and educational attainment. We also conducted sex-stratified analyses to detect any gender-specific effects. Our findings highlighted significant associations between mtDNA and three psychiatric disorders. Moreover, the interplay between mtDNA and lifestyle factors showed significant associations with psychiatric disorders (all P values < 0.05). Specifically, two mutant loci, T5004C (BAnx_self=−0.0026, BDep_self=−0.0024, BSelf−harm=−0.0018) and G9123A (BAnx_self=−0.0030, BDep_self=−0.0024, BSelf−harm=−0.0017), were found to reduce the risk of three disorders after interacting with alcohol. Sex-specific differences were also observed. In summary, the expression of mitochondrial genes could be modulated by lifestyle factors like smoking and drinking, potentially affecting psychiatric disorders. These habits might influence mitochondrial respiratory chain activity and the replication and transcriptional regulation of mitochondrial genes, culminating in changes in mitochondrial functionality and subsequently psychiatric disorders.
Beninese Plant Extracts with Antiplasmodial Activity Select New Allele Variants Msp1 and Msp2 in Plasmodium falciparum
Authors: Lagnika Hamirath O. , Medjigbodo Adandé A. , Djihinto Oswald Y. , Saïzonou Helga M. , Mousse Wassiyath A. , Akoton Romaric , Djossou Laurette , Vodounkpe Doris N. , Lagnika Latifou , Djogbénou Luc S.
Published: March 2024

Background. Natural medicinal products are commonly used as a remedy against malaria infections in African populations and have become a major source of information for the screening of new and more effective antiplasmodial molecules. Therefore, in vitro studies are needed to validate the efficacy of these medicinal products and to explore the potential effects of such drugs on the genetic diversity of Plasmodium falciparum. The current study has investigated the impact of some Beninese plant extracts with antiplasmodial activity on the genetic diversity of P. falciparum. Method. Five (5) ethanolic plant extracts (Dissotis rotundifolia, Ehretia cymosa Thonn, Hibiscus surattensis L., Cola millenii K. Shum, and Costus afer Ker Gawl) and a compound extracted from Ehretia cymosa Thonn (encoded CpE2) were tested against asexual stage parasites of a culture-adapted strain of P. falciparum. Subsequently, the P. falciparum Msp1 and Msp2 markers were genotyped, and the number of allelic variants and the multiplicity of infection (MOI) were compared between drug-exposed and unexposed parasites. Results. All plant extracts have shown inhibitory activity against asexual P. falciparum and selected new allelic variants of the Msp1 and Msp2 genes compared to unexposed parasites. The newly selected allelic variants were K1_100bp and RO33_300bp of the Msp1 gene and FC27_150bp, FC27_300bp, FC27_400bp, and FC27_600bp of the Msp2 gene. However, there was no significant difference in MOI between drug-exposed and unexposed parasites. Conclusion. Our study highlights a source for the selection of new Msp1 and Msp2 alleles after exposure to antimalarial drugs. These findings pave the way for further studies investigating the true roles of these newly selected alleles in P. falciparum.
A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer
Authors: Uo Takuma , Ojo Kayode K. , Sprenger Cynthia C.T. , Epilepsia Kathryn S. , Perera B. Gayani K. , Damodarasamy Mamatha , Sun Shihua , Kim Soojin , Hogan Hannah H. , Hulverson Matthew A. , Choi Ryan , Whitman Grant R. , Barrett Lynn K. , Michaels Samantha A. , Xu Linda H. , Sun Vicky L. , Arnold Samuel L.M. , Pang Haley J. , Nguyen Matthew M. , Vigil Anna-Lena B.G. , Kamat Varun , Sullivan Lucas B. , Sweet Ian R. , Vidadala Ram , Maly Dustin J. , Van Voorhis Wesley C. , Plymate Stephen R.
Published: March 2024

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.
Supplementary Figure 8 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Fig. S8 and its legend
Supplementary Figure 3 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Fig. S3 and its legend
Supplementary Figure 2 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Fig. S2 and its legend
Supplementary Figure 12 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Fig. S12 and its legend
Supplementary Figure 11 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Fig. S11 and its legend
FIGURE 5 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Combined treatment with ATRA and MRT retards the progression of AML in vivo. A, Schematic representation of the experimental procedure of combined treatment with ATRA and MRT in mice bearing AML. As a control, mice were treated with a corresponding vehicle. B, Survival rates of mice bearing AML (8 mice per group). Total WBC count (C) and percentages (D) of GFP+ AML cells in the PB of mice at the indicated timepoints. Each symbol represents an individual mouse (n = 8). E, Schematic representation of drug treatment for the analysis of leukemia cell differentiation in the SP and BM. The number of GFP+ AML cells and percentages of c-kit+ blast cells in the SP (F and G) and BM (H and I). Each symbol represents the value in an individual mouse (n = 4). **, P < 0.01; *, P < 0.05; N.S., no significant difference using Tukey-Kramer test or log-rank test.
FIGURE 2 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

The AIM2 inflammasome is responsible for the accumulation of the p21 protein and regulation of cell cycle progression. A, GO functional analysis of differentially expressed genes between HL-60 cells treated with 1 µmol/L ATRA and 1 µmol/L MRT and cells treated with ATRA alone for 48 hours. The result from a single experiment is shown. B, Here, we show that the representative gene sets, which were identified with GSEA using hallmark gene sets among differentially regulated gene sets, were related to cell cycle and leukocyte activation. FDR and normalized enrichment score (NES) values were calculated from a single-sample experiment. C, Relative mRNA expression of p21 in shControl- and shAIM2-transduced HL-60 cells 24 hours after ATRA+MRT or ATRA treatment. Data represent the mean ± SD from three independent experiments. D, Expression of p21 protein 24 and 48 hours after ATRA+MRT or ATRA treatment. Non-treated cells were used as a control. Representative results from three independent experiments are shown here. E, Expression of the p21 protein in shControl- and shAIM2-transduced HL-60 cells 24 hours after ATRA+MRT treatment. Data represent the mean ± SD from four independent experiments. F, Change of cell cycle status 24 hours after ATRA+MRT treatment. The left panel demonstrates representative data of cell cycle status in shControl-transduced HL-60 cells either untreated or treated with ATRA+MRT. shControl- and shAIM2-transduced HL-60 cells were either untreated or treated with ATRA+MRT. Fold increases in G1-phase were calculated on shControl- or shAIM2-transduced HL-60 cells by dividing the percentage of cells in G1-phase of ATRA+MRT-treated cells with that of untreated cells, and are shown in the right. Data represent the mean ± SD from three independent experiments. **, P < 0.01; N.S., no significant difference using two-sided Student t test. GO, Gene Ontology.
FIGURE 1 from Autophagy Inhibition–induced Cytosolic DNA Sensing Combined with Differentiation Therapy Induces Irreversible Myeloid Differentiation in Leukemia Cells
Authors: Baba Tomohisa , Tomaru Utano , Hirao Atsushi , Mukaida Naofumi , Johmura Yoshikazu
Published: March 2024

Combined treatment with MRT and ATRA induces the irreversible differentiation of human leukemia cells by activating the AIM2 inflammasome. A, HL-60 cells were treated with the indicated concentrations of MRT in the presence or absence of 1 µmol/L ATRA for 48 hours. Fold change in cell number was calculated by dividing the values of the treated samples by the mean value of the untreated control. Data represent the mean ± SD from four independent experiments. B, Giemsa staining of HL-60 cells 48 hours after combined or single treatment with 1 µmol/L ATRA and 1 µmol/L MRT. Representative results from three independent experiments are shown here. C, Expression of CD38 and CD11b on untreated (black dots) and treated [with ATRA, MRT, or ATRA+MRT for 24 hours (blue dots) or 48 hours (red dots)] HL-60 cells. Percentage of each quadrant is shown (24 hours, blue; 48 hours, red). Representative results from three independent experiments are shown here. D, Cell growth in drug-free medium after prior incubation with ATRA, MRT, or ATRA+MRT for 24 and 48 hours (n = 4). Fold change in cell number was calculated by dividing the values at each timepoint with the values at 0d. E, Alteration of CD38 and CD11b expression in HL-60 cells. Surface phenotypes were determined at the indicated timepoints after replating in drug-free medium following incubation with ATRA or ATRA+MRT for 24 hours. Representative results from three independent experiments are shown here. F, Cytoplasmic dsDNA in HL-60 cells 18 hours after combined or single treatment with 1 µmol/L ATRA and 1 µmol/L MRT. Data represent the mean ± SD from three independent experiments. Single data of non-treated cells are shown as a basement level of cytoplasmic dsDNA. G, Cell proliferation of shControl-, shSTING-, and shAIM2-transduced HL-60 cells in drug-free medium after 24 hours pre-exposure to ATRA+MRT (n = 4). Fold change in cell number was calculated by dividing the values at each timepoint with the values at 0d. H, Expression of CD11b on shControl- and shAIM2-transduced HL-60 cells after ATRA+MRT treatment for 24 hours. Representative results and mean ± SD of mean fluorescent intensities (MFI) from three independent experiments are shown here. I, Expression of CD11b on HL-60 cells after ATRA+MRT treatment in the presence of 100 µmol/L Z-WEHD-FMK (BioVision) or DMSO (control) for 24 hours. Representative results and mean ± SD of MFI from three independent experiments are shown here. **, P < 0.01; *, P < 0.05 using two-sided Student t test. d, day.
AKAP12 Upregulation Associates With PDE8A to Accelerate Cardiac Dysfunction
Authors: Qasim Hanan , Rajaei Mehrdad , Xu Ying , Reyes-Alcaraz Arfaxad , Abdelnasser Hala Y. , Stewart M. David , Lahiri Satadru K. , Wehrens Xander H.T. , McConnell Bradley K.
Published: March 2024

BACKGROUND:

In heart failure, signaling downstream the β2-adrenergic receptor is critical. Sympathetic stimulation of β2-adrenergic receptor alters cAMP (cyclic adenosine 3′,5′-monophosphate) and triggers PKA (protein kinase A)-dependent phosphorylation of proteins that regulate cardiac function. cAMP levels are regulated in part by PDEs (phosphodiesterases). Several AKAPs (A kinase anchoring proteins) regulate cardiac function and are proposed as targets for precise pharmacology. AKAP12 is expressed in the heart and has been reported to directly bind β2-adrenergic receptor, PKA, and PDE4D. However, its roles in cardiac function are unclear.

METHODS:

cAMP accumulation in real time downstream of the β2-adrenergic receptor was detected for 60 minutes in live cells using the luciferase-based biosensor (GloSensor) in AC16 human-derived cardiomyocyte cell lines overexpressing AKAP12 versus controls. Cardiomyocyte intracellular calcium and contractility were studied in adult primary cardiomyocytes from male and female mice overexpressing cardiac AKAP12 (AKAP12
OX
) and wild-type littermates post acute treatment with 100-nM isoproterenol (ISO). Systolic cardiac function was assessed in mice after 14 days of subcutaneous ISO administration (60 mg/kg per day). AKAP12 gene and protein expression levels were evaluated in left ventricular samples from patients with end-stage heart failure.

RESULTS:

AKAP12 upregulation significantly reduced total intracellular cAMP levels in AC16 cells through PDE8. Adult primary cardiomyocytes from AKAP12
OX
mice had significantly reduced contractility and impaired calcium handling in response to ISO, which was reversed in the presence of the selective PDE8 inhibitor (PF-04957325). AKAP12
OX
mice had deteriorated systolic cardiac function and enlarged left ventricles. Patients with end-stage heart failure had upregulated gene and protein levels of AKAP12.

CONCLUSIONS:

AKAP12 upregulation in cardiac tissue is associated with accelerated cardiac dysfunction through the AKAP12-PDE8 axis.
Long-Term Blood Pressure Reductions Following Catheter-Based Renal Denervation: A Systematic Review and Meta-Analysis
Authors: Sesa-Ashton Gianni , Nolde Janis M. , Muente Ida , Carnagarin Revathy , Macefield Vaughan G. , Dawood Tye , Lambert Elisabeth A. , Lambert Gavin W. , Walton Antony , Esler Murray D. , Schlaich Markus P.
Published: March 2024

BACKGROUND:

Renal denervation is a recognized adjunct therapy for hypertension with clinically significant blood pressure (BP)-lowering effects. Long-term follow-up data are critical to ascertain durability of the effect and safety. Aside from the 36-month follow-up data available from randomized control trials, recent cohort analyses extended follow-up out to 10 years. We sought to analyze study-level data and quantify the ambulatory BP reduction of renal denervation across contemporary randomized sham-controlled trials and available long-term follow-up data up to 10 years from observational studies.

METHODS:

A systematic review was performed with data from 4 observational studies with follow-up out to 10 years and 2 randomized controlled trials meeting search and inclusion criteria with follow-up data out to 36 months. Study-level data were extracted and compared statistically.

RESULTS:

In 2 contemporary randomized controlled trials with 36-month follow-up, an average sham-adjusted ambulatory systolic BP reduction of −12.7±4.5 mm Hg from baseline was observed (
P
=0.05). Likewise, a −14.8±3.4 mm Hg ambulatory systolic BP reduction was found across observational studies with a mean long-term follow-up of 7.7±2.8 years (range, 3.5–9.4 years;
P
=0.0051). The observed reduction in estimated glomerular filtration rate across the long-term follow-up was in line with the predicted age-related decline. Antihypertensive drug burden was similar at baseline and follow-up.

CONCLUSIONS:

Renal denervation is associated with a significant and clinically meaningful reduction in ambulatory systolic BP in both contemporary randomized sham-controlled trials up to 36 months and observational cohort studies up to 10 years without adverse consequences on renal function.
The Right to Practice Your Religion: European Legislation and the Origin of Religious Beliefs
Authors: Ringmar Erik
Published: March 2024

European human rights legislation makes a distinction between “beliefs” and “manifestations” of beliefs. Beliefs are regarded as inviolable whereas manifestations, such as various religious practices, can be restricted by law. This article criticizes this distinction and argues that practices are necessary for religious beliefs. We participate in a religious practice, not since we believe, but we believe since we participate in a religious practice. European human rights legislation must be rewritten with this consideration in mind.
A new Begonia species (sect. Baryandra, Begoniaceae) from Batangas Province, Luzon Island, Philippines
Authors: BUCAY MARK ANGELO C. , TANDANG DANILO N. , RUBITE ROSARIO R. , JALLORES JR. EDISON , CHUNG KUO-FANG
Published: March 2024

Begonia tanauanensis is a newly described endemic species in B. sect. Baryandra from Tanauan City, Batangas, southern Luzon, Philippines. Morphological data shows this species resembles B. chingipengii, a species from eastern Luzon as both species have light pink flowers, fleshy green lamina, and boat-shaped bracts. However, B. tanauanensis does not have the prominent white midrib and veins in the adaxial leaf surface, ciliate hairs on leaf margin, strongly keeled stipules and tomentose hairs on the abaxial leaf surface and petioles of B. chingipengii. The plants were observed to have a restricted and severely fragmented distribution. Unfortunately, these observed populations are also affected by human activities and threat of volcanic activity of the nearby Taal Volcano. Because of these threats, we provisionally assess the species as “Critically Endangered” (CR) following the IUCN Red List Categories and Criteria.