bluuebunny/crossref_metadata_2025 huggingface dataset:
Interventions to de-implement unnecessary antibiotic prescribing for ear infections (DISAPEAR Trial): protocol for a cluster-randomized trial
Authors: Jenkins Timothy C. , Keith Amy , Stein Amy B. , Hersh Adam L. , Narayan Rashmi , Eggleston Alice , Rinehart Deborah J. , Patel Payal K. , Walter Eve , Hargraves Ian G. , Frost Holly M. ,   for the DISAPEAR Study Group, Andersen Leisha , Cosgrove Shaun , Gilbert Aiden , Jensen Hannah , Morin Theresa , Nelson Barbora , Seibert Allan M. , Stanfield Valoree , Willis Park
Published: January 2024

Background

Watchful waiting management for acute otitis media (AOM), where an antibiotic is used only if the child’s symptoms worsen or do not improve over the subsequent 2–3 days, is an effective approach to reduce antibiotic exposure for children with AOM. However, studies to compare the effectiveness of interventions to promote watchful waiting are lacking. The objective of this study is to compare the effectiveness and implementation outcomes of two pragmatic, patient-centered interventions designed to facilitate use of watchful waiting in clinical practice.

Methods

This will be a cluster-randomized trial utilizing a hybrid implementation-effectiveness design. Thirty-three primary care or urgent care clinics will be randomized to one of two interventions: a health systems-level intervention alone or a health systems-level intervention combined with use of a shared decision-making aid. The health systems-level intervention will include engagement of a clinician champion at each clinic, changes to electronic health record antibiotic orders to facilitate delayed antibiotic prescriptions as part of a watchful waiting strategy, quarterly feedback reports detailing clinicians’ use of watchful waiting individually and compared with peers, and virtual learning sessions for clinicians. The hybrid intervention will include the health systems-level intervention plus a shared decision-making aid designed to inform decision-making between parents and clinicians with best available evidence. The primary outcomes will be whether an antibiotic was ultimately taken by the child and parent satisfaction with their child’s care. We will explore the differences in implementation effectiveness by patient population served, clinic type, clinical setting, and organization. The fidelity, acceptability, and perceived appropriateness of the interventions among different clinician types, patient populations, and clinical settings will be compared. We will also conduct formative qualitative interviews and surveys with clinicians and administrators, focus groups and surveys of parents of patients with AOM, and engagement of two stakeholder advisory councils to further inform the interventions.

Discussion

This study will compare the effectiveness of two pragmatic interventions to promote use of watchful waiting for children with AOM to reduce antibiotic exposure and increase parent satisfaction, thus informing national antibiotic stewardship policy development.

Clinical trial registration

NCT06034080.
Acute ischemic stroke in Tsutsugamushi: understanding the underlying mechanisms and risk factors
Authors: Kim Dain , Cho Yeon Hee , Bong Jeong Bin , Kim Young Seo , Shin Byoung-Soo , Kang Hyun Goo
Published: January 2024

Background

Tsutsugamushi (scrub typhus) is an acute infectious febrile disease common in the Asia-Pacific region. Common symptoms of tsutsugamushi include lymphadenopathy, fever, and myalgia, and it rarely causes acute ischemic stroke (AIS). However, we hypothesized that tsutsugamushi infection could trigger AIS.

Method

We retrospectively examined patients diagnosed with AIS within 2 weeks of tsutsugamushi diagnosis at three hospitals over a 15-year period. We categorized patients who developed AIS while being treated for tsutsugamushi as the case group and those (of similar age and sex) who did not develop AIS as the control group. The case and control groups consisted of 22 and 66 participants, respectively. When a scattered pattern was observed or lesions were found in two or more vascular territories on diffusion-weighted imaging, the pattern was defined as embolic. Other patterns were defined as nonembolic.

Results

Among the 19 patients, excluding three with transient ischemic stroke, 15 (78.9%) showed an embolic pattern. Although fever was common in the control group, it was less common in the case group. A higher D-dimer level at the time of hospitalization was associated with the development of AIS in patients with tsutsugamushi.

Conclusions

AIS in patients with tsutsugamushi showed an embolic rather than a non-embolic pattern on brain magnetic resonance imaging. It was more likely to occur in patients with risk factors for stroke. Tsutsugamushi patients with AIS were likely to have no fever or high D-dimer levels. We hypothesized that D-dimers play an important role in the pathophysiology, where tsutsugamushi infection increases the likelihood of AIS.
Perioperative outcomes and continence following robotic-assisted radical cystectomy with mainz pouch II urinary diversion in patients with bladder cancer
Authors: Jing Suoshi , Yang Enguang , Luo Zuoxi , Zhang Yunxin , Ding Hui , Yang Li , Dong Zhilong , Shang Panfeng , Yue Zhongjin , Wu Gongjin , Bao Junsheng , Tian Junqiang , Wang Jiaji , Xiao Nan , Wang Zhiping
Published: January 2024

Purpose

To present the widely unknown perioperative outcomes and continence status of bladder cancer patients following robotic-assisted radical cystectomy (RARC) with Mainz pouch II urinary diversion (UD).

Materials and methods

From November 2020 to December 2023, 37 bladder cancer patients who underwent RARC with Mainz pouch II UD were retrospectively assessed (ChiCTR2300070279). The results, which included patient demographics, perioperative data, continence, and complications (early ≤ 30 days and late ≤ 30 days) were reported using the RC-pentafecta criteria. RC-pentafecta criteria included ≥ 16 lymph nodes removed, negative soft tissue surgical margins, absence of major (Grade III–IV) complication at 90 days, absence of clinical recurrence at ≤ 12 months, and absence of long-term UD-related sequelae. A numeric rating scale assessed patient satisfaction with urinary continence 30 days after surgery. The validated Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire was used to evaluate bowel function. The Kaplan-Meier curve was used to evaluate overall survival (OS).

Results

Of the 37 patients evaluated over a median (range) follow-up period of 23.0 (12.0-36.5) months. The median (range) age was 65 (40–81) years. The median (range) time to urinary continence after surgery was 2.3 (1.5-6) months. Of the 37 patients, 31 (83.8%) were continent both during the day and at night, 34 (91.9%) were continent during the day, 32 (86.5%) were continent at night, 35 (94.6%) were satisfied with their urinary continence status, and 21 (56.8%) were very satisfied. The mean (range) voiding frequency was 6 (4–10) during the day and 3 (2-5.5) at night. The mean (range) PAC-SYM total score was 9.50 (4.00–15.00). In 12 (32.4%) of the patients, RC-pentafecta was achieved, and achieving RC-pentafecta was linked to better satisfaction scores (7.3 vs. 5.5, p = 0.034). There was no significant difference between RC-pentafecta and No RC-pentafecta groups in terms of OS (25.6 vs. 21.5 months, p = 0.16). 7 (19.4%) patients experienced late complications.

Conclusions

Mainz pouch II UD following RARC in bladder cancer patients results in a satisfactory continence rate. Achieving RC-pentafecta was correlated with better satisfaction scores. The intracorporeal approach to Mainz pouch II UD is beneficial for female patients due to its reduced invasiveness.

Trial registration

ChiCTR2300070279; Registration: 07/04/2023, Last updated version: 01/06/2023. Retrospectively registered.
TIM-3/Galectin-9 interaction and glutamine metabolism in AML cell lines, HL-60 and THP-1
Authors: Shapourian Hooriyeh , Ghanadian Mustafa , Eskandari Nahid , Shokouhi Abolfazl , Demirel Gülderen Yanikkaya , Bazhin Alexandr V. , Ganjalikhani-Hakemi Mazdak
Published: January 2024

Background

T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a cell surface molecule that was first discovered on T cells. However, recent studies revealed that it is also highly expressed in acute myeloid leukemia (AML) cells and it is related to AML progression. As, Glutamine appears to play a prominent role in malignant tumor progression, especially in their myeloid group, therefore, in this study we aimed to evaluate the relation between TIM-3/Galectin-9 axis and glutamine metabolism in two types of AML cell lines, HL-60 and THP-1.

Methods

Cell lines were cultured in RPMI 1640 which supplemented with 10% FBS and 1% antibiotics. 24, 48, and 72 h after addition of recombinant Galectin-9 (Gal-9), RT-qPCR analysis, RP-HPLC and gas chromatography techniques were performed to evaluate the expression of glutaminase (GLS), glutamate dehydrogenase (GDH) enzymes, concentration of metabolites; Glutamate (Glu) and alpha-ketoglutarate (α-KG) in glutaminolysis pathway, respectively. Western blotting and MTT assay were used to detect expression of mammalian target of rapamycin complex (mTORC) as signaling factor, GLS protein and cell proliferation rate, respectively.

Results

The most mRNA expression of GLS and GDH in HL-60 cells was seen at 72 h after Gal-9 treatment (p = 0.001, p = 0.0001) and in THP-1 cell line was observed at 24 h after Gal-9 addition (p = 0.001, p = 0.0001). The most mTORC and GLS protein expression in HL-60 and THP-1 cells was observed at 72 and 24 h after Gal-9 treatment (p = 0.0001), respectively. MTT assay revealed that Gal-9 could promote cell proliferation rate in both cell lines (p = 0.001). Glu concentration in HL-60 and α-KG concentration in both HL-60 (p = 0.03) and THP-1 (p = 0.0001) cell lines had a decreasing trend. But, Glu concentration had an increasing trend in THP-1 cell line (p = 0.0001).

Conclusion

Taken together, this study suggests TIM-3/Gal-9 interaction could promote glutamine metabolism in HL-60 and THP-1 cells and resulting in AML development.
Development and psychometric evaluation of nurse’s intention to care for patients with infectious disease scale: an exploratory sequential mixed method study
Authors: Hoseinzadeh Esmaeil , Sharif-Nia Hamid , Ashktorab Tahereh , Ebadi Abbas
Published: January 2024

Aims

Nurses who care for patients with infectious disease may experince significant stress and negative psychological reactions. The intention of nurses to care is a complex and multifaceted concept that is influenced by a range of factors. Therefore, this study was conducted to explain the concept of nurses’ intention to care for patients with infectious disease and then develop a reliable and valid scale to measure this concept accurately in Iranian nurses.

Design

This study is a cross-sectional study with a sequential-exploratory mixed-method approach from May 2022 to July 2023. The concept of nurses’ intent to care for patients with infectious disease was explain using deductive content analysis, and item pools were generated. In the sconed step the samples were 455 nurses. Data was collected by an online form questionnaire using a convenience sampling technique. In this step to determine the psychometric properties of nurse’s intention to care for patients with infectious disease scale (NICPS), face and content validity performed. Then construct validity was determined and confirmed using exploratory and confirmatory factor analysis followed by convergent and divergent validity respectively. Finally, scale reliability including stability and internal consistency were evaluated.

Results

The finding showed that NICPS with seventeen items were classified into three factors namely “Social support” with seven items, “Spiritual motivation” with six items and “Job satisfaction” with four items. These three factors explained 56.14% of the total variance. The fit indices showed that the model has a fit and acceptable (TLI, CFI, IFI > 0.9; PNFI, PCFI > 0.5, REMSEA > 0.049, CMIN/DF = 2.477). Reliability revealed acceptable internal consistency and stability (> 0.7).

Conclusion

The finding showed that NICPS has three factors in Iranian nurses. Nursing managers can use these results to provide training and support intervention for nurses in order to increase their intention to care for this patient. Also, the NICPS is a reliable and valid for evaluating this concept in future studies.
Comparison of two single-pill dual combination antihypertensive therapies in Chinese patients: a randomized, controlled trial
Authors: Huang Qi-Fang , Zhang Di , Luo Yihong , Hu Kun , Wu Qiong , Qiu Hailong , Xu Fei , Wang Mei-Ling , Chen Xin , Li Yan , Wang Ji-Guang ,   on behalf of the ACEI/CCB Versus ACEI/DIU Combination Antihypertensive Therapy in Chinese Hypertensive Patients (ACvAD) investigators
Published: January 2024

Background

Current hypertension guidelines recommend combination of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker with a calcium-channel blocker or thiazide diuretic as initial antihypertensive therapy in patients with monotherapy uncontrolled hypertension. However, to what extent these two different combinations are comparable in blood pressure (BP)-lowering efficacy and safety remains under investigation, especially in the Chinese population. We investigated the BP-lowering efficacy and safety of the amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies in Chinese patients.

Methods

In a multi-center, randomized, actively controlled, parallel-group trial, we enrolled patients with stage 1 or 2 hypertension from July 2018 to June 2021 in 20 hospitals and community health centers across China. Of the 894 screened patients, 560 eligible patients were randomly assigned to amlodipine/benazepril 5/10 mg (n = 282) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 278), with 213 and 212 patients, respectively, who completed the study and had a valid repeat ambulatory BP recording during follow-up and were included in the efficacy analysis. The primary outcome was the change from baseline to 24 weeks of treatment in 24-h ambulatory systolic BP. Adverse events including symptoms and clinically significant changes in physical examinations and laboratory findings were recorded for safety analysis.

Results

In the efficacy analysis (n = 425), the primary outcome, 24-h ambulatory systolic BP reduction, was − 13.8 ± 1.2 mmHg in the amlodipine/benazepril group and − 12.3 ± 1.2 mmHg in the benazepril/hydrochlorothiazide group, with a between-group difference of − 1.51 (p = 0.36) mmHg. The between-group differences for major secondary outcomes were − 1.47 (p = 0.18) in 24-h diastolic BP, − 2.86 (p = 0.13) and − 2.74 (p = 0.03) in daytime systolic and diastolic BP, and − 0.45 (p = 0.82) and − 0.93 (p = 0.44) in nighttime systolic and diastolic BP. In the safety analysis (n = 560), the incidence rate of dry cough was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (5.3% vs 10.1%, p = 0.04).

Conclusions

The amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies were comparable in ambulatory systolic BP lowering. The former combination, compared with the latter, had a greater BP-lowering effect in the daytime and a lower incidence rate of dry cough.

Trial registration

ClinicalTrials.gov, NCT03682692. Registered on 18 September 2018.
Intestinal mucosal microbiota mediate amino acid metabolism involved in the gastrointestinal adaptability to cold and humid environmental stress in mice
Authors: Zhang Chen-Yang , Peng Xin-Xin , Wu Yi , Peng Mai-Jiao , Liu Tiao-Hao , Tan Zhou-Jin
Published: January 2024

Growing evidence has demonstrated that cold and humid environmental stress triggers gastrointestinal (GI) disorders. In this study, we explored the effects of intestinal microbiota homeostasis on the intestinal mucus barrier and GI disorders by cold and humid environmental stress. Moreover, the inner link between the intestinal mucosal microbiota and metabolites in mice with cold and humid environmental stress was interpreted by integrative analysis of PacBio HiFi sequencing microbial genomics and targeted metabolomics. In the current study, we found (1) after the cold and wet cold and humid environmental stress intervened in the intestinal microbiota disorder and homeostasis mice respectively, the bacterial culturing and fluorescein diacetate (FDA) microbial activity detection of intestinal microbiota including feces, intestinal contents, and intestinal mucosa suggested that the cold and humid environmental stress decreased the colony of culturable bacteria and microbial activity, in which intestinal microbiota disorder aggravated the injury of the intestinal mucus barrier and the GI symptoms related to cold and humid environmental stress; (2) the serum amino acid transferases such as glutamate pyruvic transa (GPT), and glutamic oxaloacetic transaminase (GOT) in cold and humid environmental stressed mice increased significantly, indicating that the intestinal microbiota adapted to cold and humid environmental stress by regulating the host's amino acid metabolism; (3) the integrative analysis of multi-omics illustrated a prediction model based on the microbiota Lactobacillus reuteri abundance and host amino acid level that can predict intestinal mucoprotein Muc2 with an adjusted R2 of 75.0%. In conclusion, the cold and humid environmental stress regulates the neurotransmitter amino acids metabolic function both in intestinal mucosal microbiota and host serum by adjusting the composition of the dominant bacterial population Lactobacillus reuteri, which contributes to the intestinal mucus barrier injury and GI disorders caused by cold and humid environmental stress.
LINC01852 inhibits the tumorigenesis and chemoresistance in colorectal cancer by suppressing SRSF5-mediated alternative splicing of PKM
Authors: Bian Zehua , Yang Fan , Xu Peiwen , Gao Ge , Yang Chunyu , Cao Yulin , Yao Surui , Wang Xue , Yin Yuan , Fei Bojian , Huang Zhaohui
Published: January 2024

Background

Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide, and chemoresistance is a major obstacle in its treatment. Despite advances in therapy, the molecular mechanism underlying chemoresistance in CRC is not fully understood. Recent studies have implicated the key roles of long noncoding RNAs (lncRNAs) in the regulation of CRC chemoresistance.

Methods

In this study, we investigated the role of the lncRNA LINC01852 in CRC chemoresistance. LINC01852 expression was evaluated in multiple CRC cohorts using quantitative reverse transcription PCR. We conducted in vitro and in vivo functional experiments using cell culture and mouse models. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of LINC01852 in CRC.

Results

Our findings revealed that a lncRNA with tumor-inhibiting properties, LINC01852, was downregulated in CRC and inhibited cell proliferation and chemoresistance both in vitro and in vivo. Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis.

Conclusions

Our results demonstrate that LINC01852 plays an important role in repressing CRC malignancy and chemoresistance by regulating SRSF5-mediated alternative splicing of PKM, and that targeting the LINC01852/TRIM72/SRSF5/PKM2 signaling axis may represent a potential therapeutic strategy for CRC.
Porcine epidemic diarrhea virus strain CH/HLJ/18 isolated in China: characterization and phylogenetic analysis
Authors: Guo Yuyao , Sui Ling , Kong Deming , Liu Dan , Gao Yueyi , Jiang Yanping , Cui Wen , Li Jiaxuan , Li Yijing , Wang Li
Published: January 2024

Background

Porcine epidemic diarrhea (PED) is an infectious disease of the digestive tract caused by the porcine epidemic diarrhea virus (PEDV), characterized by vomiting, severe diarrhea, and high mortality rates in piglets. In recent years, the distribution of this disease in China has remarkably increased, and its pathogenicity has also increased. PEDV has been identified as the main cause of viral diarrhea in piglets. This study aimed to understand the genetic evolution and diversity of PEDV to provide a theoretical basis for the development of new vaccines and the prevention and treatment of PED.

Methods

A PEDV strain was isolated from the small intestine of a diarrheal piglet using Vero cells. The virus was identified using reverse transcription-polymerase chain reaction (RT-PCR), indirect immunofluorescence assay (IFA), and transmission electron microscopy. The whole genome sequence was sequenced, phylogenetic analysis was conducted using MEGA (version 7.0), and recombination analysis was performed using RDP4 and SimPlot. The S protein amino acid sequence was aligned using Cluster X (version 2.0), and the S protein was modeled using SWISS-MODEL to compare differences in structure and antigenicity. Finally, the piglets were inoculated with PEDV to evaluate its pathogenicity in newborn piglets.

Result

PEDV strain CH/HLJ/18 was isolated. CH/HLJ/18 shared 89.4–99.2% homology with 52 reference strains of PEDV belonging to the GII-a subgroup. It was a recombinant strain of PEDV BJ-2011-1 and PEDV CH_hubei_2016 with a breakpoint located in ORF1b. Unique amino acid deletions and mutations were observed in the CH/HLJ/18 S protein. The piglets then developed severe watery diarrhea and died within 7 d of inoculation with CH/HLJ/18, suggesting that CH/HLJ/18 was highly pathogenic to newborn piglets.

Conclusion

A highly pathogenic recombinant PEDV GII-a strain, CH/HLJ/18, was identified in China, with unique deletion and mutation of amino acids in the S protein that may lead to changes in protein structure and antigenicity. These results will be crucial for understanding the prevalence and variation of PEDV and for preventing and controlling PED.
Are we ready for "green surgery" to promote environmental sustainability in the operating room? Results from the WSES STAR investigation
Authors: Dal Mas Francesca , Cobianchi Lorenzo , Piccolo Daniele , Balch Jeremy , Biancuzzi Helena , Biffl Walter L. , Campostrini Stefano , Cicuttin Enrico , Coccolini Federico , Damaskos Dimitris , Filiberto Amanda C. , Filisetti Claudia , Fraga Gustavo , Frassini Simone , Fugazzola Paola , Hardcastle Timothy , Kaafarani Haytham M. , Kluger Yoran , Massaro Maurizio , Martellucci Jacopo , Moore Ernest , Ruta Federico , Sartelli Massimo , Stahel Philip F. , Velmahos George , Weber Dieter G. , Catena Fausto , Loftus Tyler J. , Ansaloni Luca ,   the STAR Study Group
Published: January 2024

Background

The importance of environmental sustainability is acknowledged in all sectors, including healthcare. To meet the United Nations Sustainable Development Goals 2030 Agenda, healthcare will need a paradigm shift toward more environmentally sustainable practices that will also impact clinical decision-making. The study investigates trauma and emergency surgeons’ perception, acceptance, and employment of environmentally friendly habits.

Methods

An online survey based on the most recent literature regarding environmental sustainability in healthcare and surgery was created by a multidisciplinary committee and endorsed by the World Society of Emergency Surgery (WSES). The survey was advertised to the 917 WSES members through the society’s website and Twitter/X profile.

Results

450 surgeons from 55 countries participated in the survey. Results underline both a generally positive attitude toward environmental sustainability but also a lack of knowledge about several concepts and practices, especially concerning the potential contribution to patient care.

Discussion

The topic of environmental sustainability in healthcare and surgery is still in its infancy. There is a clear lack of salient guidance and knowledge, and there is a critical need for governments, institutions, health agencies, and scientific societies to promote, disseminate, and report environmentally friendly initiatives and their potential impacts while employing an interdisciplinary approach.
Mechanism exploration of Osteoking in the treatment of lumbar disc herniation based on network pharmacology and molecular docking
Authors: Luo Xinlei , Liu Jingjing , Wang Xiaoxi , Chen Qiaojun , Lei Yanfa , He Zewei , Wang Xiaowei , Ye Yan , Na Qiang , Lao Changtao , Yang Zhengchang , Jiang Jun
Published: January 2024

Objective

Lumbar disc herniation (LDH) is a common spinal surgical disease. Low back and leg pain caused by LDH is the main factor leading to functional disability, which has caused a serious burden to patients and society. Osteoking can delay the progression of osteoporosis and osteoarthritis, and even has a significant effect on the prevention of deep vein thrombosis after fracture surgery. In recent years, it has been gradually used in the treatment of LDH and has received significant results. However, the underlying mechanism remains unclear. The aim of this study was to predict the mechanism of Osteoking in the treatment of LDH through network pharmacology and verify it by molecular docking method.

Methods

The TCMSP database was used to collect the relevant active components and targets of Osteoking, while the GeneCards, OMIM and DisGeNET databases were utilized to collect the relevant disease targets of LDH. The Venny 2.1.0 software was employed to obtain the intersecting gene targets of Osteoking and LDH. PPI network construction and core target selection were performed using Cytoscape 3.9.0 software. The Metascape database was used for GO and KEGG enrichment analysis of the relevant targets. Finally, molecular docking was conducted using AutoDock software.

Results

The study identified 116 potential targets and 26 core targets for the treatment of LDH with Osteoking. Pathways in cancer, Alzheimer's disease, microRNAs in cancer and the IL-17 signalling pathway were among the main involved signalling pathways. Molecular docking results demonstrated that the key targets AKT1, IL-6, ALB, TNF and IL-1β exhibited relatively stable binding activities with the main active components of Osteoking.

Conclusions

Osteoking can alleviate the symptoms of lumbar disc herniation through the modulation of multiple targets and signalling pathways.
Fluid biomarkers for amyotrophic lateral sclerosis: a review
Authors: Irwin Katherine E. , Sheth Udit , Wong Philip C. , Gendron Tania F.
Published: January 2024

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.
The unusual gene architecture of polyubiquitin is created by dual-specific splice sites
Authors: Duan Chaorui , Mooney Truman , Buerer Luke , Bowers Cory , Rong Stephen , Kim Seong Won , Fredericks Alger M. , Monaghan Sean F. , Fairbrother William G.
Published: January 2024

Background

The removal of introns occurs through the splicing of a 5′ splice site (5′ss) with a 3′ splice site (3′ss). These two elements are recognized by distinct components of the spliceosome. However, introns in higher eukaryotes contain many matches to the 5′ and 3′ splice-site motifs that are presumed not to be used.

Results

Here, we find that many of these sites can be used. We also find occurrences of the AGGT motif that can function as either a 5′ss or a 3′ss—previously referred to as dual-specific splice sites (DSSs)—within introns. Analysis of the Sequence Read Archive reveals a 3.1-fold enrichment of DSSs relative to expectation, implying synergy between the ability to function as a 5′ss and 3′ss. Despite this suggested mechanistic advantage, DSSs are 2.7- and 4.7-fold underrepresented in annotated 5′ and 3′ splice sites. A curious exception is the polyubiquitin geneUBC, which contains a tandem array of DSSs that precisely delimit the boundary of each ubiquitin monomer. The resulting isoforms splice stochastically to include a variable number of ubiquitin monomers. We found no evidence of tissue-specific or feedback regulation but note the 8.4-fold enrichment of DSS-spliced introns in tandem repeat genes suggests a driving role in the evolution of genes likeUBC.

Conclusions

We find an excess of unannotated splice sites and the utilization of DSSs in tandem repeats supports the role of splicing in gene evolution. These findings enhance our understanding of the diverse and complex nature of the splicing process.
MiR-31-5p regulates the neuroinflammatory response via TRAF6 in neuropathic pain
Authors: Liu Yuqi , Wang Lijuan , Zhou Chengcheng , Yuan Yuan , Fang Bin , Lu Kaimei , Xu Fangxia , Chen Lianhua , Huang Lina
Published: January 2024

Background

Neuropathic pain is chronic pain and has few effective control strategies. Studies have demonstrated that microRNAs have functions in neuropathic pain. However, no study has been conducted to demonstrate the role and mechanism of microRNA (miR)-31-5p in neuropathic pain. Accordingly, this study sought to determine the pathological role of miR-31-5p in chronic constriction injury (CCI) -induced neuropathic pain mouse models.

Methods

We used CCI surgery to establish mouse neuropathic pain model. Behavioral tests were performed to evaluate pain sensitivity of mice. Expressions of miR-31-5p and inflammatory cytokines in dorsal root ganglion (DRG) were examined by polymerase chain reaction. Animals or cells were received with/without miR-31-5p mimic or inhibitor to investigate its role in neuropathic pain. The mechanism of miR-31-5p was assayed using western blotting, immunofluorescence staining and dual-luciferase reporter assay.

Results

We found that CCI led to a significant decrease in miR-31-5p levels. Knockout of miR-31-5p and administration of miPEP31 exacerbated pain in C57BL/6 mice. Meanwhile, miR-31-5p overexpression increased the paw withdrawal threshold and latency. TRAF6 is one of the target gene of miR-31-5p, which can trigger a complex inflammatory response. TRAF6 was associated with pain and that reducing the DRG expression of TRAF6 could alleviate pain. In addition, miR-31-5p overexpression inhibited the TRAF6 expression and reduced the neuroinflammatory response.

Conclusions

All the results reveal that miR-31-5p could potentially alleviate pain in CCI mouse models by inhibiting the TRAF6 mediated neuroinflammatory response. MiR-31-5p upregulation is highlighted here as new target for CCI treatment.
Cyclic-di-AMP confers an invasive phenotype on Escherichia coli through elongation of flagellin filaments
Authors: Tanaka Rika , Imai Jin , Sugiyama Eiji , Tsubaki Shogo , Hozumi Katsuto , Tsugawa Hitoshi
Published: January 2024

Background

Adherent-invasive Escherichia coli (AIEC) is isolated from patients with Crohn’s disease (CD). AIEC can invade the intestinal epithelium, suggesting that it is involved in the development and pathogenesis of CD. However, the mechanism by which AIEC acquired the invasive phenotype remains unknown.

Results

This study was designed to examine the mechanisms of AIEC invasiveness. We found that the flagellin (fliC) expression in AIEC was two-fold higher than that in non-AIEC strains, and this overexpression induced the formation of long-filament flagellin. Deletion of fliC in the AIEC LF82 strain resulted in the disappearance of flagellar filaments and attenuated the motility and invasive ability of the bacterium, suggesting that the formation of long filament flagellin induced by increased fliC expression is required by AIEC to invade the intestinal epithelium. In AIEC and non-AIEC K12 strains cultured in the presence of cyclic-di-AMP (c-di-AMP), the expression of fliC was enhanced, and flagellar filaments were elongated. Stimulation with c-di-AMP enhanced the bacterial motility and ability to invade epithelial cells, even in the non-AIEC K12 strain.

Conclusions

Our findings show that c-di-AMP confers an AIEC-like phenotype on non-AIEC strains by enhancing the expression of fliC. The results should be useful for understanding the pathogenesis of CD.
METTL3 promotes osteoblast ribosome biogenesis and alleviates periodontitis
Authors: Zhang Yiwen , Kong Yiping , Zhang Wenjie , He Jinlin , Zhang Zhanqi , Cai Yongjie , Zhao Yiqing , Xu Qiong
Published: January 2024

Background

Periodontitis is a highly prevalent oral disease characterized by bacterium-induced periodontal inflammation and alveolar bone destruction. Osteoblast function is impaired in periodontitis with a global proteome change. METTL3 is the pivotal methyltransferase of N6-methyladenosine (m6A) that is recently proved to exert a crucial role in osteoblast differentiation. This study aims to investigate the role of METTL3 in osteoblast ribosome biogenesis in periodontitis progression.

Results

METTL3 was knocked down in osteoblasts, and the downregulated genes were enriched in ribosome and translation. METTL3 knockdown inhibited ribosome biogenesis and oxidative phosphorylation in LPS-stimulated osteoblasts, whereas METTL3 overexpression facilitated ribosomal and mitochondrial function. Mechanistically, METTL3 mediated osteoblast biological behaviors by activating Wnt/β-catenin/c-Myc signaling. METTL3 depletion enhanced the mRNA expression and stability of Dkk3 and Sostdc1 via YTHDF2. In periodontitis mice, METTL3 inhibitor SAH promoted alveolar bone loss and local inflammatory status, which were partially rescued by Wnt/β-catenin pathway activator CHIR-99021 HCl.

Conclusions

METTL3 promoted ribosome biogenesis and oxidative phosphorylation by activating Wnt/β-catenin/c-Myc signaling in LPS-treated osteoblasts and alleviated the inflammatory alveolar bone destruction in periodontitis mice.
Chronicles of an uncommon term abdominal pregnancy with successful outcome: a case report
Authors: Magezi Joad , Wacha Joshua , Pebalo Pebolo Francis
Published: January 2024

Background

Intra-abdominal pregnancies, while rare, present with unique diagnostic and management challenges. We present a case of a 25-year-old para 2 + 1, black African woman, who was referred from a peripheral Health Centre level IV in the Northern part of Uganda to a Regional Referral Hospital due to an abnormal presentation with easily palpable fetal parts. This case emphasizes the significance of prompt diagnosis, interdisciplinary collaboration, surgical planning, and managing the placenta in advanced intra-abdominal pregnancies.

Case presentation

A 25 year African black female, para 2 + 1 upon arrival at Regional Referral Hospital, a University Teaching Hospital during a weekend, an ultrasound was sourced from a nearby private clinic revealing an extra-uterine intra-abdominal pregnancy at 38 weeks of gestation and she was promptly sent back to the University Teaching Hospital. Following this diagnosis, the patient, who hailed from a remote village over 30 km away, returned to her family for discussions. After three days, she was readmitted. Emergency laparotomy unveiled an omental gestation sac with extensive placental attachment. A live female infant was delivered successfully, placenta was left in situ. The postoperative course was uneventful, with initial concerns about inadequate breast milk flow which resolved after placental removal during the second exploratory laparotomy.

Conclusion

This case highlights the uncommon occurrence of an advanced intra-abdominal pregnancies and emphasizes the importance of multi-disciplinary teamwork and placental management. The favorable outcome in the management was based on thorough assessment of the placental location, attachments and blood supply during surgery. It demonstrates the possibility of reduced risk of massive bleeding if there is a delayed removal of placenta with favorable attachment. This is particularly important for milk letdown as well as reducing the needs of blood transfusion in resource limited settings.
Towards intelligent user clustering techniques for non-orthogonal multiple access: a survey
Authors: Hamedoon Syed M. , Chattha Jawwad Nasar , Bilal Muhammad
Published: January 2024

With the increasing user density of wireless networks, various user partitioning techniques or algorithms segregate users into smaller, more manageable clusters. The benefit of user clustering techniques in non-orthogonal multiple access (NOMA) is to optimize resource allocation and improve network performance, spectral efficiency, and user fairness in next-generation wireless networks, particularly in scenarios with a high density of users and diverse channel conditions. With increasing users, the network creates clusters before implementing non-orthogonal multiple access within these clusters. In this paper, we have organized and classified various user clustering techniques deployed from the perspective of NOMA-based communication in the current era. Furthermore, researchers have highlighted some works deploying joint resource allocation and clustering optimization based on various criteria to enhance the overall sum rate of the network. We also identify low-complexity user clustering techniques for multiple applications, e.g. the Internet of Things, unmanned aerial vehicles, and reconfigurable intelligent surfaces in the 5G and beyond communication networks.
A nonuniform local limit theorem for Poisson binomial random variables via Stein’s method
Authors: Auld Graeme , Neammanee Kritsana
Published: January 2024

We prove a nonuniform local limit theorem concerning approximation of the point probabilities $P(S=k)$
P
(
S
=
k
)
, where $S=\sum_{i=1}^{n}X_{i}$
S
=

∑

i
=
1

n

X
i

, and $X_{1},\ldots ,X_{n}$

X
1

,
…
,

X
n

are independent Bernoulli random variables with possibly different success probabilities. Our proof uses Stein’s method, in particular, the zero bias transformation and concentration inequality approaches.
Hotspots and trends of microglia in Alzheimer's disease: a bibliometric analysis during 2000–2022
Authors: Zhang Lijie , Yao Qiuru , Hu Jinjing , Qiu Baizhi , Xiao Yupeng , Zhang Qi , Zeng Yuting , Zheng Shuqi , Zhang Youao , Wan Yantong , Zheng Xiaoyan , Zeng Qing
Published: January 2024

Background

Alzheimer's disease is one common type of dementia. Numerous studies have suggested a correlation between Alzheimer's disease and inflammation. Microglia mainly participate in the inflammatory response in the brain. Currently, ample evidence has shown that microglia are closely related to the occurrence and development of Alzheimer's disease.

Objective

We opted for bibliometric analysis to comprehensively summarize the advancements in the study of microglia in Alzheimer's disease, aiming to provide researchers with current trends and future research directions.

Methods

All articles and reviews pertaining to microglia in Alzheimer's disease from 2000 to 2022 were downloaded through Web of Science Core Collection. The results were subjected to bibliometric analysis using VOSviewer 1.6.18 and CiteSpace 6.1 R2.

Results

Overall, 7449 publications were included. The number of publications was increasing yearly. The United States has published the most publications. Harvard Medical School has published the most papers of all institutions. Journal of Alzheimer’s Disease and Journal of Neuroscience were the journals with the most studies and the most commonly cited, respectively. Mt Heneka is the author with the highest productivity and co-citation. After analysis, the most common keywords are neuroinflammation, amyloid-beta, inflammation, neurodegeneration. Gut microbiota, extracellular vesicle, dysfunction and meta-analysis are the hotspots of research at the present stage and are likely to continue.

Conclusion

NLRP3 inflammasome, TREM2, gut microbiota, mitochondrial dysfunction, exosomes are research hotspots. The relationship between microglia-mediated neuroinflammation and Alzheimer's disease have been the focus of current research and the development trend of future research.
Localization of light in three dimensions: A mobility edge in the imaginary axis in non-Hermitian Hamiltonians
Authors: Celardo Luca Giuseppe , Angeli Mattia , Mattiotti Francesco , Kaiser Robin
Published: January 2024

Searching for Anderson localization of light in three dimensions has challenged experimental and theoretical research for the last decades. Here the problem is analyzed through large-scale numerical simulations, using a radiative Hamiltonian, i.e., a non-Hermitian long-range hopping Hamiltonian, well suited to model light-matter interaction in cold atomic clouds. Light interaction in atomic clouds is considered in the presence of positional and diagonal disorder. Due to the interplay of disorder and cooperative effects (sub- and super-radiance) a novel type of localization transition is shown to emerge, differing in several aspects from standard localization transitions which occur along the real energy axis. The localization transition discussed here is characterized by a mobility edge along the imaginary energy axis of the eigenvalues which is mostly independent of the real energy value of the eigenmodes. Differently from usual mobility edges it separates extended states from hybrid localized states and it manifests itself in the large moments of the participation ratio of the eigenstates. Our prediction of a mobility edge in the imaginary axis, i.e., depending on the eigenmode lifetime, paves the way to achieve control both in the time and space domains of open quantum systems.
Iodineminho Study: Iodine Supplementation and Prevalence of Iodine Deficiency In Pregnant Women
Authors: Lopes-Pereira Maria , Roque Susana , Machado Sarai Isabel , Korevaar Tim I M , Quialheiro Anna , Machado Ana , Vilarinho Laura , Correia-Neves Margarida , Galanti Maria Rosaria , Bordalo Adriano A , Costa Patrício , Palha Joana Almeida
Published: January 2024

Context

Iodine is necessary for proper brain development. The prevalence of iodine deficiency in Portuguese pregnant women led the health authorities, in 2013, to recommend iodine supplementation for women in preconception, throughout pregnancy, and during lactation.

Objective

This work aimed to assess the effect of iodine supplementation initiated in the preconception or the first trimester of pregnancy on the prevalence of iodine deficiency and maternal thyroid status.

Methods

An observational prospective cohort study was conducted that followed the thyroid function and iodine status of women recruited during preconception or in the first trimester of pregnancy.

Results

Median urinary iodine concentration (UIC) was significantly higher among women taking iodine supplements (no-supplement group UIC = 63 µg/L; supplement group UIC = 100 µg/L; P = .002) but still below the levels recommended by the World Health Organization. Only 15% of pregnant women had adequate iodine status and 17% showed a UIC of less than 50 µg/L. There was no influence whether iodine supplementation was started during preconception or during the first trimester of gestation (UIC preconception group: 112 µg/L vs UIC pregnancy group: 91 µg/L; P = .569). In the first trimester of pregnancy, total thyroxine levels were lower and free triiodothyronine levels were higher in nonsupplemented women. Thyroglobulin levels were lower in women who started iodine supplementation during preconception compared to nonsupplemented women and women who started iodine supplementation during gestation.

Conclusion

In the Minho region of Portugal, fertile women have insufficient iodine intake. Additional public health measures are needed since the current recommendations for iodine supplementation for pregnancy are unsatisfactory to achieve adequate iodine status.
PALS1 is a key regulator of the lateral distribution of tight junction proteins in renal epithelial cells
Authors: Groh Ann-Christin , Möller-Kerutt Annika , Gilhaus Kevin , Höffken Verena , Nedvetsky Pavel , Kleimann Simon , Behrens Malina , Ghosh Sujasha , Hansen Uwe , Krahn Michael P. , Ebnet Klaus , Pavenstädt Hermann , Ludwig Alexander , Weide Thomas
Published: January 2024

The evolutionarily conserved apical Crumbs (CRB) complex, consisting of the core components CRB3a (an isoform of CRB3), PALS1 and PATJ, plays a key role in epithelial cell–cell contact formation and cell polarization. Recently, we observed that deletion of one Pals1 allele in mice results in functional haploinsufficiency characterized by renal cysts. Here, to address the role of PALS1 at the cellular level, we generated CRISPR/Cas9-mediated PALS1-knockout MDCKII cell lines. The loss of PALS1 resulted in increased paracellular permeability, indicating an epithelial barrier defect. This defect was associated with a redistribution of several tight junction-associated proteins from bicellular to tricellular contacts. PALS1-dependent localization of tight junction proteins at bicellular junctions required its interaction with PATJ. Importantly, reestablishment of the tight junction belt upon transient F-actin depolymerization or upon Ca2+ removal was strongly delayed in PALS1-deficient cells. Additionally, the cytoskeleton regulator RhoA was redistributed from junctions into the cytosol under PALS1 knockout. Together, our data uncover a critical role of PALS1 in the coupling of tight junction proteins to the F-actin cytoskeleton, which ensures their correct distribution along bicellular junctions and the formation of tight epithelial barrier.
Turn-on RNA Mango Beacons fortrans-acting fluorogenic nucleic acid detection
Authors: Abdolahzadeh Amir , Ang Quiana R. , Caine Jana R. , Panchapakesan Shanker Shyam S. , Thio Shinta , Cojocaru Razvan , Unrau Peter J.
Published: January 2024

The Mango I and II RNA aptamers have been widely used in vivo and in vitro as genetically encodable fluorogenic markers that undergo large increases in fluorescence upon binding to their ligand, TO1-Biotin. However, while studying nucleic acid sequences, it is often desirable to havetrans-acting probes that induce fluorescence upon binding to a target sequence. Here, we rationally design three types of light-up RNA Mango Beacons based on a minimized Mango core that induces fluorescence upon binding to a target RNA strand. Our first design is bimolecular in nature and uses a DNA inhibition strand to prevent folding of the Mango aptamer core until binding to a target RNA. Our second design is unimolecular in nature, and features hybridization arms flanking the core that inhibit G-quadruplex folding until refolding is triggered by binding to a target RNA strand. Our third design builds upon this structure, and incorporates a self-inhibiting domain into one of the flanking arms that deliberately binds to, and precludes folding of, the aptamer core until a target is bound. This design separates G-quadruplex folding inhibition and RNA target hybridization into separate modules, enabling a more universal unimolecular beacon design. All three Mango Beacons feature high contrasts and low costs when compared to conventional molecular beacons, with excellent potential for in vitro and in vivo applications.