bluuebunny/crossref_metadata_2025 huggingface dataset:
Rotational stability and visual performance of aberration-free, hydrophobic acrylic monofocal toric intraocular lens with enhanced material
Authors: Wiley William F. , Epitropoulos Alice T. , Whitman Jeffrey , Liang Eva , Sadri Ehsan , Lau George
Published: September 2024

Purpose:

To evaluate the rotational stability and visual performance of the enVista toric intraocular lens (IOL) (MX60ET) in cataract patients with preexisting astigmatism.

Setting:

6 U.S. sites.

Design:

Prospective, multicenter.

Methods:

Cataract patients 18 years and older with preexisting astigmatism (0.77 to 4.53 diopters [D]) underwent phacoemulsification and implantation of enVista toric IOL (MX60ET). Outcome measures were the proportion of patients with absolute IOL axis rotation of ≤5 degrees, uncorrected and corrected distance visual acuities (UDVA and CDVA) at 4 m, uncorrected intermediate visual acuity (UIVA) at 66 cm, manifest refraction, and adverse events. The patients were followed up on days 1 to 2, 7 to 14, 30 to 60, and 120 to 180.

Results:

Mean astigmatism of 101 eyes (101 patients) reduced from 1.47 ± 0.64 D preoperatively to 0.38 ± 0.38 D at days 120 to 180 (P < .001), with 88.1% (N = 89/101) of eyes achieving astigmatism within 0.75 D. Mean postoperative UDVA and UIVA were 0.10 ± 0.16 and 0.25 ± 0.15 logMAR, respectively. While 79.2% (N = 80/101) of patients had postoperative UDVA of 20/32 or better, 63.9% (N = 62/97) had UIVA of 20/40 or better. The mean toric IOL rotation from the operative visit to days 30 to 60 was 1.97 ± 2.06 degrees, with 97.4% (N = 74/76) of eyes showing toric IOL rotation of 5 degrees or less.

Conclusions:

The enhanced enVista toric IOL (MX60ET) demonstrated excellent rotational stability and astigmatic outcomes indicating good efficacy of the IOL for the correction of astigmatism during cataract surgery.
Association Between Urinary Rare Earth Element Levels and Metabolic Syndrome
Authors: Xu Xuemei , Lu Peini , Luo Xingxi , Wei Gangjie , Huang Xuanqian , Lv Fangfang , Mo Caimei , Lei Lidi , Huang Dongping , Su Li , Zeng Xiaoyun , Qiu Xiaoqiang , Liu Shun
Published: September 2024

Objective

This study aimed to investigate the association between rare earth elements (REEs) and metabolic syndrome (MetS).

Methods

We used a cross-sectional design based on the baseline data of the Prospective Cohort Study of Chronic Diseases in Ethnic Minority Natural Population in Guangxi in China. Logistic regression and BKMR models were employed to evaluate the association between REEs and risk of MetS.

Results

Although REEs were not significantly associated with MetS, certain elements such as La, Pr, and Nd were negatively associated with abdominal obesity, whereas Ce, Pr, Nd, and Dy were positively associated with hypertension. BKMR models suggested a U-shaped relationship between mixed REEs and MetS, with varying effects on abdominal obesity and high blood pressure.

Conclusions

This study suggests that exposure to REEs may be associated with a reduced risk of abdominal obesity and an increased risk of high blood pressure.
Human umbilical cord mesenchymal stem cells-derived extracellular vesicles ameliorate kidney ischemia-reperfusion injury by suppression of senescent tubular epithelial cells: experimental study
Authors: Ma Ming , Zeng Jun , Zhu Mengli , Li Hui , Lin Tao , Yang Hao , Wei Xin , Song Turun
Published: September 2024

Background:

Human umbilical cord mesenchymal stem cells-derived extracellular vesicles (HUMSC-EVs) have drawn much interest in kidney transplantation, mainly because of their renoprotection by alleviating cell injury and stimulating tissue repair. Cellular senescence has been proven to play a dual regulatory role in kidney ischemia-reperfusion injury (IRI), and the regulation of HUMSC-EVs on tubular epithelial cell senescence may be a potential therapeutic target.

Materials and methods:

In vitro, the hypoxia-reoxygenation of human kidney-2 cells was used to simulate kidney IRI, and the regulation of HUMSC-EVs on human kidney-2 cells was detected. Transcriptome sequencing of human kidney-2 cells was used to explore the potential regulatory mechanism. In vivo, adult male mice were divided into five groups: control group, IRI group, HUMSC-EVs treatment group, senolytics treatment group (dasatinib + quercetin), and combined treatments group (HUMSC-EVs and senolytics). Kidney function, senescent features of tubular epithelial cells, acute kidney injury, and chronic interstitial fibrosis in mice were detected to explore the renoprotection effects of HUMSC-EVs.

Results:

Kidney IRI significantly up-regulated expressions of LaminB1, p53, p21, p16, senescence-associated beta-galactosidase, and apoptosis of tubular epithelial cells. In the mouse kidney IRI model, kidney subcapsular injection of HUMSC-EVs significantly improved kidney function, reducing the senescent features of tubular epithelial cells and alleviating acute kidney injury and chronic interstitial fibrosis. HUMSC-EVs mainly achieved renoprotection by regulating Bax/Bcl-2-dependent apoptosis during acute kidney injury and mostly reduced tubular atrophy and kidney interstitial fibrosis by regulating Ras-pERK-Ets1-p53 pathway-dependent cell senescence. Oral administration of senolytics also alleviated kidney injury induced by IRI, while the combined treatments of HUMSC-EVs and senolytics had better renoprotection effects.

Conclusions:

The combination of HUMSC-EVs and senolytics alleviated acute kidney injury and chronic interstitial fibrosis by dynamic regulation of cell senescence and apoptosis, which provides a therapeutic potential strategy for organ preservation and tissue repair in kidney transplantation.
Daytime Somnolence and Sleep Apnea Are Associated With Dizziness in the Elderly
Authors: Szeto Betsy , Kesser Bradley
Published: September 2024

Objective

Dizziness is a debilitating multifactorial disorder commonly affecting the elderly. Daytime somnolence and sleep apnea have been linked to dizziness, but previous studies were limited by small sample sizes. The purpose of this study was to examine the relationship between dizziness and daytime somnolence and sleep-disordered breathing, in a nationally representative sample of elderly adults, while adjusting for possible confounders and mediators.

Study Design

Data from the National Health and Nutrition Examination Study (NHANES; 2017–2020 prepandemic data) were analyzed in a cross-sectional manner using survey methods.

Setting

Community-based setting in the United States.

Participants

A total of 1,490 nationally representative participants aged ≥70 years.

Main Outcomes

Multivariable logistic regression was used to examine the relationship between dizziness and daytime somnolence, snoring, and apnea, while adjusting for covariates (gender, age, body mass index, and various medical conditions that may confound this relationship).

Results

Frequent daytime somnolence five or more times monthly (odds ratio, 2.13; 95% confidence interval, 1.49–3.06) and presence of apnea (odds ratio, 1.65; 95% confidence interval, 1.20–2.27) were found to be associated with greater odds of dizziness when adjusting for medical comorbidities. A significant association was not found between snoring and dizziness.

Conclusions and Relevance

In the elderly, daytime somnolence and apnea were independently associated with increased odds of dizziness, even after adjusting for medical comorbidities. Daytime somnolence and sleep apnea should be added to the differential diagnosis in this patient population. Optimizing sleep may help reduce symptoms of dizziness in this population, but prospective studies would be required to confirm these findings.

Level of evidence: 4
Temporal bone fracture related facial palsy: efficacy of decompression with and without grafting
Authors: Natour Amed , Doyle Edward , DeDio Robert , Samy Ravi N.
Published: September 2024

Purpose of review

This systematic review investigates the recent literature and aims to determine the approach, efficacy, and timing of facial nerve decompression with or without grafting in temporal bone fractures with facial palsy.

Recent findings

The surgical management of facial palsy is reserved for a small population of cases in which electrophysiologic tests indicate a poor likelihood of spontaneous recovery. The transmastoid (TM), middle cranial fossa (MCF), and translabyrinthine (TL) approaches to the facial nerve provide access to the entire intracranial and intratemporal segments of the facial nerve. In temporal bone (TB) related facial palsy, the peri-geniculate and labyrinthine portions of the facial nerve are most commonly affected by either direct trauma and/or subsequent edema. When hearing is still serviceable, the combined TM/MCF approach provides the best access to these regions. In the presence of severe sensorineural hearing loss (SNHL), the TL approach is the most appropriate for total facial nerve exploration (this can be done in conjunction with simultaneous cochlear implantation if the cochlear nerve has not been avulsed). Grade I to III House-Brackmann (HB) results can be anticipated in timely decompression of facial nerve injury caused by edema or intraneuronal hemorrhage. Grade III outcomes, with slight weakness and synkinesis, is the outcome to be expected from the use of interpositional grafts or primary neurorrhaphy. In addition to good eye care and the use of systemic steroids (if not contraindicated in the acute trauma setting), surgical decompression with or without grafting/neurorrhaphy may be offered to patients with appropriate electrophysiologic testing, physical examination findings, and radiologic localization of injury.

Surgery of the facial nerve remains an option for select patients. Here, we discuss the indications and results of treatment as well as the best surgical approach to facial nerve determined based on patient's hearing status and radiologic data. Controversy remains about whether timing of surgery (e.g., immediate vs. delayed intervention) impacts outcomes. However, no one with facial palsy due to a temporal bone fracture should be left with a complete facial paralysis.
Mental Health and Mental Health Care Utilization Across Political Affiliation in US Adults
Authors: Ettman Catherine K. , Hatton C. Ross , Castrucci Brian C. , Galea Sandro
Published: September 2024

In the past decade, depression has become more visible in the public conversation; depression has also become bound in national divides. We sought to assess (1) whether positive screen for depression is associated with political party affiliation and (2) whether use of mental health care varies by political affiliation. Positive screen for depression did not differ significantly for Republicans versus Democrats in Spring 2023. However, Republicans were less likely to have received treatment for their mental health in the past 12 months. Depression is a bipartisan issue, and improving access to mental health care could be a priority that unites political groups during the upcoming election season.
Risk Factor Prediction and Categorization for Glenohumeral Osteoarthritis: A Classification and Regression Tree (CART) Analysis
Authors: McNamara-Pittler Elyse N. , Prakash Ravi , Atem Folefac D , Pathak Rashmi , Liu Wenting , Khazzam Michael , Jain Nitin B.
Published: September 2024

Objective

This study aimed to apply Classification and Regression Tree (CART) analysis to determine factors associated with glenohumeral osteoarthritis (GH OA) and establish specific cut-off points for risk factors based on this methodology.

Design

The cross-sectional study included 3,383 participants with shoulder pain. Cases were selected for GH OA. Patients with other shoulder pathologies were included as controls. 33 potential risk factors were assessed. The CART analysis was used to determine the highest-ranked risk factors associated with GH OA. Multivariable logistic regression analysis was then performed using the cut-off points obtained from the CART analysis.

Results

The CART analysis showed that age and body mass index (BMI) were the two most significant risk factors for GH OA. Multivariable logistic regression revealed that age categories ≥31- < 58 years (OR = 8.92), ≥58- < 64 years (OR = 20.20), and ≥ 64 years (OR = 42.20), and BMI categories ≥25-30 kg/ m2 (OR = 1.47) and ≥ 30 kg/ m2 (OR = 1.71) had higher odds of developing GH OA compared to age < 31 years and BMI <25 kg/m2.

Conclusion

This was the first study to use CART analysis to evaluate significant risk factors for GH OA and establish cut-off points for increased risk. The findings present age categories that are distinct from the arbitrary age groups used in previous studies.
The Effect on Constipation of Abdominal Massage Applied to the Elderly in the Nursing Home
Authors: Çetinkaya Onur , Ovayolu Özlem
Published: September 2024

The aim of this study was to evaluate how abdominal massage affects the constipation of the elderly in the nursing home. This randomized controlled experimental study was conducted with an intervention group (n = 30) and a control group (n = 31) in the nursing home of a government institution. A 15-minute abdominal massage was applied to the intervention group once a day, 5 days a week for 1 month. The control group received only routine treatment. The data were collected with a questionnaire, the Constipation Severity Instrument, the Visual Analogue Scale, the Bristol Stool Scale, and the defecation diary. It was determined that the Constipation Severity Instrument mean score, which was 40.6 ± 10.0 before the massage in the intervention group, decreased to 16.0 ± 11.6 after the application. The Visual Analogue Scale total score of the intervention and control groups, which was 40.2 ± 8.4 and 33.2 ± 5.9 before the massage, decreased to 18.7 ± 9.3 and 29.1 ± 6.58, respectively, at the end of the fourth week; the decrease was higher in the intervention group, and this difference between the groups was significant (p < .05). It was determined that abdominal massage applied to elderly individuals residing in a nursing home reduced constipation. In this sense, it is recommended for nurses to implement abdominal massage in the management of constipation for elderly individuals.
Assessment of Antibiotics Resistance from Isolates Responsible for UTI in Four Regional Referral Hospitals in Tanzania.
Authors: Mtenga Adelard Bartholomew , Fimbo Adam Mitangu , Shewiyo Danstan Hipolite , Makonope Revocatus , Mwambene Saxon , Hebron Yonah , Mwamitwa Kissa , Sangeda Raphael Zozimus
Published: September 2024

Introduction

The global impact of antimicrobial resistance (AMR) includes increased morbidity and mortality rates and healthcare costs, particularly in low- and middle-income countries (LMICs), and it has dire economic and security implications.

Methodology

This study assessed the resistance of clinical isolates responsible for urinary tract infections (UTI) to antibacterial agents for treating UTIs in selected healthcare facilities in Tanzania.

Results

A total of 151 clinical isolates of E. coli and S. aureus isolated from urine samples in selected health facilities were analyzed for antimicrobial susceptibility to establish the presence of individual and multi-drug resistance (MDR). The results revealed that E. Coli displayed a significant difference in resistance (χ2 =12.808, p =0.002) across the selected antibiotics, in which E. coli showed the highest resistance to amoxicillin (AML) and the least resistance to meropenem (p <0.005). In contrast, S. aureus isolates showed a significant difference.
(χ2=53.627, p-value<0.001) in resistance across the selected antibiotics, in which S. aureus showed the highest resistance to AML, peaking at more than 91%, and least resistant (4%) to nitrofurantoin (NIT) (4%). When p-value<0.005, both E. coli and S. aureus demonstrated MDR against selected antibiotics in all health facilities under study, in which Morogoro Regional Referral Hospital showed the highest (65.4%) for E. coli and Benjamin Mkapa Hospital showed the highest (83.3%) for S. aureus. Similarly, Maweni Regional Referral Hospital demonstrated the lowest MDR for E. coli (23%) and S. aureus (13%).

Conclusion

Our finding suggest that some antibiotic are still in used in clinical practice despite of the evidence of emerging resistance against them hence it call for effective regular AMR surveillance and antimicrobial stewardship implementation to optimize antibiotics use in clinical practice and exclude less efficacious ones.
Quantification of Pseudomonas aeruginosa biofilms using electrochemical methods
Authors: Riordan Lily , Lassere Perrine , Corrigan Damion , Duncan Katherine R
Published: September 2024

Currently 2.29% of deaths worldwide are caused by antimicrobial resistance (AMR), compared to 1.16% from malaria, and 1.55% from human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDs). Furthermore, deaths resulting from AMR are projected to increase to more than 10 million per annum by 2050. Biofilms are common in hospital settings, such as medical implants and pose a particular problem as they have shown resistance to antibiotics up to 1000-fold higher than planktonic cells because of dormant states and reduced growth rates. This is compounded by the fact that many antibiotics target mechanisms of active metabolism and are therefore less effective. The work presented here aimed to develop a method for biofilm quantification which could be translated into the clinical setting, as well as used in the screening of antibiofilm agents. This was carried out alongside crystal violet staining, as a published point of reference. Using electrochemical impedance spectroscopy and square wave voltammetry, P. aeruginosa biofilm formation was detected within an hour after seeding P. aeruginosa on the sensor. A 40% decrease in impedance modulus was shown when P. aeruginosa biofilm had formed, compared to the media only control. As such, this work offers a starting point for the development of real-time biofilm sensing technologies, which can be translated into implantable materials.
Pancreatic Tuberculosis Revealed by a Mass with Neoplastic Appearance: A Case Report
Authors: Hachimi Idrissi Mariam , Benass Jihane , Zegmout Adil , Tazi Imane , Ben Lahlou Yassine , Benaissa Elmostafa , Seddik Hassan , Chadli Mariama
Published: September 2024

Introduction : Pancreatic tuberculosis is an extremely rare form of extrapulmonary tuberculosis. This condition can be challenging to diagnose due to its rarity, nonspecific symptoms, and radiological features that may mimic a neoplastic origin.
Case report: A 46-year-old immunocompetent patient with no past history of tuberculosis exposure, presented with spontaneously resolving jaundice over the past month, accompanied by non specific fever episodes and general fatigue with no other associated digestive symptoms. Abdominal CT and MRI scans revealed a poorly defined, partially necrotic mass in the pancreatic head with heterogeneous hypodensity and enhancement after contrast injection. Additionally, there were nodal and hilar macro-nodal lesions with necrotic appearances, as well as peripancreatic lymphadenopathy. The patient was scheduled for an Endoscopic ultrasound (EUS) examination which revealed the presence of a heterogeneous lesion with areas of necrosis  in the posterosuperior aspect of the head and isthmus of the pancreas, accompanied by perilesional and celiac lymphadenopathies with necrotic centers. EUS-guided tissue sampling allowed the diagnosis of pancreatic tuberculosis, with both histological examination and GeneXpert MTB/RIF testing rapidly positive for Mycobacterium tuberculosis, followed by culture on solid Loewenstein-Jensen medium. The patient responded well to antitubercular chemotherapy .
Conclusion: Pancreatic tuberculosis, though rare, should be considered in cases of pancreatic masses, especially in endemic regions. Tissue samples with necrosis should be tested for Mycobacterium tuberculosis using GeneXpert and Loewenstein-Jensen culture. This work highlights the GeneXpert MTB/RIF test as highly sensitive, specific, and fast, making it ideal for diagnosing extra-pulmonary tuberculosis, particularly when smear results are negative.
PIEZO1variants that reduce open channel probability are associated with familial osteoarthritis
Authors: Jurynec Michael J. , Nosyreva Elena , Thompson David , Munoz Crystal , Novak Kendra A. , Matheson Derek J. , Kazmers Nikolas H. , Syeda Ruhma
Published: September 2024

The synovial joints senses and responds to a multitude of physical forces to maintain joint homeostasis. Disruption of joint homeostasis results in development of osteoarthritis (OA), a disease characterized by loss of joint space, degeneration of articular cartilage, remodeling of bone and other joint tissues, low-grade inflammation, and pain. How changes in mechanosensing in the joint contribute to OA susceptibility remains elusive. PIEZO1 is a major mechanosensitive cation channel in the joint directly regulated by mechanical stimulus. To test whether altered PIEZO1 channel activity causes increased OA susceptibility, we determined whether variants affectingPIEZO1are associated with dominant inheritance of age-associated familial OA. We identified four rare coding variants affectingPIEZO1that are associated with familial hand OA. Single channel analyses demonstrated that all four PIEZO1 mutant channels act in a dominant-negative manner to reduce the open probability of the channel in response to pressure. Furthermore, we show that a GWAS mutation inPIEZO1associated with reduced joint replacement results in increased channel activity when compared with WT and the mutants. Our data support the hypothesis that reduced PIEZO1 activity confers susceptibility to age-associated OA whereas increased PIEZO1 activity may be associated with reduced OA susceptibility.
Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients with hereditary gastric cancer linked to a family history of hereditary breast and ovarian cancer (HBOC)
Authors: Hayashi Takuma , Sano Kenji , Okada Mako , Muto Manabu , Konishi Ikuo
Published: September 2024

Helicobacter pylori (H. pylori), a type of nematode, is a common cause of chronic stomach infection around the world. In 2014, the World Health Organization (WHO) reported that H. pylori infection is a leading cause of gastric cancer (80%) worldwide and has specific carcinogenic factors. H. pylori infection is presumed to be the cause of gastric cancer in more than 98% of gastric cancer patients in East Asia, including Japan. However, only some types of gastric cancers are associated with H. pylori infection. Previous clinical studies have revealed that the bacterium secretes the cytotoxin-associated gene A (CagA) antigen, which inhibits the nuclear translocation of breast cancer susceptibility gene 1 (BRCA1) or BRCA2, a factor that repairs damaged DNA. Accordingly, an association has been pointed out between hereditary breast and ovarian cancers (HBOC) and the development of gastric cancer; however, there is a lack of clarity about the detailed mechanisms underlying the development of gastric cancer by H. pylori infection. Using the information base on hereditary cancers built up through cancer genomic medicine, our group highlighted the higher incidence of gastric cancer in HBOC families, with a preponderance for gastric cancer in male patients from HBOC families. We also verified the safety and efficacy of using poly ADP-ribose polymerase (PARP) inhibitors in patients with hereditary gastric cancer. The present study offers substantial evidence for guiding the establishment of early treatment for patients with advanced/metastatic gastric cancer in whom BRCA1/2 mutations have been detected.
Spike frequency adaptation in primate lateral prefrontal cortex neurons results from interplay between intrinsic properties and circuit dynamics
Authors: Koch Nils A. , Corrigan Benjamin W. , Feyerabend Michael , Gulli Roberto A. , Jimenez-Sosa Michelle S. , Abbass Mohamad , Sunstrum Julia K. , Matovic Sara , Roussy Megan , Luna Rogelio , Mestern Samuel A. , Mahmoudian Borna , Vijayraghavan Susheel , Igarashi Hiroyuki , Pradeepan Kartik S. , Assis William J. , Pruszynski J. Andrew , Tripathy Shreejoy , Staiger Jochen F. , Gonzalez-Burgos Guillermo , Neef Andreas , Treue Stefan , Everling Stefan , Inoue Wataru , Khadra Anmar , Martinez-Trujillo Julio C.
Published: September 2024

Recordings of cortical neurons isolated from brain slices and dissociated from their networks, display intrinsic spike frequency adaptation (I-SFA) to a constant current input. Interestingly, extracellular recordings in behaving subjects also show extrinsic-SFA (E-SFA) in response to sustained visual stimulation. Because neurons are isolated from brain networks in slice recordings, it is challenging to infer how I-SFA contributes to E-SFA in interconnected brains during behavior. To investigate this, we recorded responses of macaque lateral prefrontal cortex neuronsin vivoduring a visually guided saccade task and in acute brain slicesin vitro. Broad spiking (BS) putative pyramidal cells and narrow spiking (NS) putative inhibitory interneurons exhibited E-SFAin vivo. In acute brain slices, both cell types displayed I-SFA though their magnitudes differed. To investigate howin vitroI-SFA contributes toin vivoE-SFA, we developed a data-driven hybrid circuit model in which local NS neurons are driven by BS input. We observed that model NS cell responses show longer SFA than observedin vivo. Introducing inhibition of NS cells to the model circuit removed this discrepancy. Our results indicate that both I-SFA and inhibitory circuit dynamics contribute to E-SFA in LPFC neurons. They highlight the contribution of single neuron and network dependent computations to neural activity underlying behavior.
Tensions on the actin cytoskeleton and apical cell junctions in theC. elegansspermatheca are influenced by spermathecal anatomy, ovulation state and activation of myosin
Authors: Sadeghian Fereshteh , Grooms Noa W.F. , Chung Samuel H. , Cram Erin J.
Published: September 2024

Cells generate mechanical forces mainly through myosin motor activity on the actin cytoskeleton. InC. elegans, actomyosin stress fibers drive contractility of the smooth muscle-like cells of the spermatheca, a distensible, tube-shaped tissue in the hermaphrodite reproductive system and the site of oocyte fertilization. Stretching of the spermathecal cells by oocyte entry triggers activation of the small GTPase Rho. In this study, we asked how forces are distributed in vivo using the spermatheca, and explored how this tissue responds to alterations in myosin activity. Using laser ablation, we show that the basal actomyosin fibers are under tension in the occupied spermatheca. Reducing actomyosin contractility by depletion of the phospholipase C-ε/PLC-1 or non-muscle myosin II/NMY-1, leads to distended spermathecae occupied by one or more embryos, but does not alter tension on the basal actomyosin fibers. This suggests that much of the tension on the basal actin fibers in the occupied spermatheca is due to the presence of the embryo. However, activating myosin through depletion of the Rho GAP SPV-1 increases tension on the actomyosin fibers, consistent with earlier studies showing Rho drives spermathecal contractility. On the inner surface of the spermathecal tube, tension on the apical junctions is decreased by depletion of PLC-1 and NMY-1. Surprisingly, when basal contractility is increased through SPV-1 depletion, the tension on apical junctions also decreases, with the most significant effect on the junctions aligned in perpendicular to the axis of the spermatheca. This suggests tension on the outer basal surface may compress the apical side, and suggests the three-dimensional shape of the spermatheca plays a role in force distribution and contractility during ovulation.
Gigaxonin, mutated in Giant Axonal Neuropathy, interacts with TDP-43 and other RNA binding proteins
Authors: Phillips Cassandra L. , Faridounnia Maryam , Battaglia Rachel A. , Evangelista Baggio A. , Cohen Todd J. , Opal Puneet , Bouldin Thomas W. , Armao Diane , Snider Natasha T.
Published: September 2024

Giant Axonal Neuropathy (GAN) is a neurodegenerative disease caused by loss-of-function mutations in theKLHL16gene, encoding the cytoskeleton regulator gigaxonin. In the absence of functional gigaxonin, intermediate filament (IF) proteins accumulate in neurons and other cell types due to impaired turnover and transport. GAN neurons exhibit distended, swollen axons and distal axonal degeneration, but the mechanisms behind this selective neuronal vulnerability are unknown. Our objective was to identify novel gigaxonin interactors pertinent to GAN neurons. Unbiased proteomics revealed a statistically significant predominance of RNA-binding proteins (RBPs) within the soluble gigaxonin interactome and among differentially-expressed proteins in iPSC-neuron progenitors from a patient with classic GAN. Among the identified RBPs was TAR DNA-binding protein 43 (TDP-43), which associated with the gigaxonin protein and its mRNA transcript. TDP-43 co-localized within large axonal neurofilament IFs aggregates in iPSC-motor neurons derived from a GAN patient with the ‘axonal CMT-plus’ disease phenotype. Our results implicate RBP dysfunction as a potential underappreciated contributor to GAN-related neurodegeneration.

This work reveals that the neurodegeneration-associated protein and cytoskeleton regulator gigaxonin and its mRNA associate with numerous RNA binding proteins. These findings shift understanding of normal gigaxonin function and provide insights into how disease-causing mutations in the gigaxonin-encoding gene (KLHL16) may ignite a pathogenic cascade in neurons.
Oxytocin salvages context-specific hyperaltruistic preference through moral framing
Authors: Zhang Hong , Ni Yinmei , Li Jian
Published: September 2024

An intriguing advancement in recent moral decision-making research suggests that people are more willing to sacrifice monetary gains to spare others from suffering than to spare themselves, yielding a hyperaltruistic tendency. Other studies, however, indicate an opposite egoistic bias in that subjects are less willing to harm themselves for the benefits of others than for their own benefits. These results highlight the delicate inner workings of moral decision and call for a mechanistic account of hyperaltruistic preference. We investigated the boundary conditions of hyperaltruism by presenting subjects with trade-off choices combing monetary gains and painful electric shocks, or, choices combing monetary losses and shocks. We first showed in study 1 that switching the decision context from gains to losses effectively eliminated the hyperaltruistic preference and the decision context effect was associated with the altered relationship between subjects' instrumental harm (IH) trait attitudes and their relative pain sensitivities. In the pre-registered study 2, we tested whether oxytocin, a neuropeptide linked to parochial altruism, might salvage the context-dependent hyperaltruistic preference. We found that oxytocin increased subjects' reported levels of framing the task as harming (vs. helping) others, which mediated the correlation between IH and relative pain sensitivities. Thus, the loss decision context and oxytocin nullified and restored the mediation effect of subjective harm framing, respectively. Our results help to elucidate the psychological processes underpinning the contextual specificity of hyperaltruism and carry implications in promoting prosocial interactions in our society.
Pannexin 1 crosstalk with the Hippo pathway in malignant melanoma
Authors: Sayedyahossein Samar , Huang Kenneth , Zhang Christopher , Karimi Mehdi , Bahmani Mehrnoosh , O’Donnell Brooke L. , Wakefield Brent , Li Zhigang , Johnston Danielle , Leighton Stephanie E. , Huver Matthew S. , Dagnino Lina , Sacks David B. , Penuela Silvia
Published: September 2024

In this study, we explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes-associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, YAP, TAZ, and Hippo scaffold, IQGAP1, in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Notably, our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its co-transcriptional activity in both melanoma and breast carcinoma cells. Importantly, our study showcases the potential therapeutic relevance of targeting PANX1, as pharmacological inhibition of PANX1 using selective FDA-approved inhibitors or PANX1 knockdown reduced YAP abundance in melanoma cells. Furthermore, our Clariom™ S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), β-galactoside binding protein, galectin-3 (LGALS3), that are affected in PANX1- deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment.
Diel expression dynamics in filamentous cyanobacteria
Authors: Kennedy Sarah J. , Risser Douglas D. , Paul Blair G.
Published: September 2024

Filamentous cyanobacteria of theNostocaceaefamily are able to differentiate into multicellular forms to adapt to environmental stresses, and members can establish symbiosis with various embryophytes. Representative laboratory strains are typically grown under continuous light to maintain stable metabolic conditions, however, this departure from a natural diel cycle can result in extended stress. Early genomic examination ofNostoc punctiformesuggests the genetic potential for a circadian clock, but we lack insight into global cellular dynamics through the natural diel cycle for this model organism. Here, we comprehensively assess changes in expression of core cellular processes and the mobilome of accessory genetic elements during diel growth ofN. punctiformePCC 73102. The primary transcriptome confirmed that multicellular cyanobacteria precisely coordinate photosynthesis and carbon assimilation for cell division during the day, while control of DNA recombination and repair appeared to be sequestered to darkness. Moreover, we expanded the known repertoire of light sensing proteins to uncover a putative regulator of circadian rhythm that itself exhibits striking oscillation between day-night expression. This was in sharp contrast to the arrhythmic pattern observed for a homolog of the canonical circadian regulator in unicellular cyanobacteria. Looking beyond cellular coordination of diel growth, we uncovered dynamic mobile elements, and notably, targeted hypermutation by retroelements that are likely maintained for conflict mitigation, which is crucial to a multicellular lifestyle.
Porphyromonas gingivalisouter membrane vesicles alter neuronal architecture and Tau phosphorylation in the embryonic mouse brain
Authors: Bradley Adrienne , Mashburn-Warren Lauren , Blalock Lexie C. , Scarpetti Francesca , Lauber Christian L.
Published: September 2024

Porphyromonas gingivalis(Pg) is an oral bacterial pathogen that has been associated with systemic inflammation and adverse pregnancy outcomes such as low birth weight and preterm birth. Pg drives these sequelae through virulence factors decorating the outer membrane that are present on non-replicative outer membrane vesicles (OMV) that are suspected to be transmitted systemically. Given that Pg abundance can increase during pregnancy, it is not well known whether Pg-OMV can have deleterious effects on the brain of the developing fetus. We tested this possibility by treating pregnant C57/Bl6 mice with PBS (control) and OMV from ATCC 33277 by tail vein injection every other day from gestational age 3 to 17. At gestational age 18.5, we measured dam and pup weights and collected pup brains to quantify changes in inflammation, cortical neuron density, and Tau phosphorylated at Thr231. Dam and pup weights were not altered by Pg-OMV exposure, but pup brain weight was significantly decreased in the Pg-OMV treatment group. We found a significant increase of Iba-1, indicative of microglia activation, although the overall levels of IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ mRNA transcripts were not different between the treatment groups. Differences in IL-1β, IL-6, and TNFα concentrations by ELISA showed IL-6 was significantly lower in Pg-OMV brains. Cortical neuron density was modified by treatment with Pg-OMV as immunofluorescence showed significant decreases in Cux1 and SatB2. Overall Thr231 was increased in pups exposed to Pg-OMV with the appearance of a secondary band of 60 kD. Together these results demonstrate that Pg-OMV can significantly modify the embryonic brain and suggests that Pg may impact offspring development via multiple mechanisms.
Polygenic barriers to sex chromosome turnover
Authors: Muralidhar Pavitra
Published: September 2024

In organisms with distinct sexes, sex is commonly determined by segregation of a pair of chromosomes in paternal meiosis (male heterogamety) or maternal meiosis (female heterogamety). Evolutionary transitions between sex-chromosome systems— which change the chromosome pair that determines sex, the system of heterogamety, or both—are frequent in some clades. In others, however, sex chromosome systems show long-term stability. Previous explanations of this stasis rely on evolutionary dynamics peculiar to sex linkage, such as the accumulation of deleterious mutations on the sex-specific chromosome or sexually antagonistic mutations on either sex chromosome. Here, I show that the ordinary operation of stabilizing selection on quantitative traits can, as a by-product, promote stability of sex chromosome systems. The reason is that stabilizing selection on a trait permits individual chromosomes’ genetic contributions to the trait to drift upwards or downwards, subject only to the constraint that they all sum to the trait optimum. This chromosome-specific drift causes reduced fitness in individuals with unusual chromosomal constitutions, such as the novel sexual genotypes that sex chromosome turnovers always produce. The theory can explain a suite of patterns in the phylogenetic distribution of sex determining systems. Applied to interspecific hybrids, it can also explain two key observations concerning their reduced fitness: Haldane’s rule and the large-X effect.
Rhythmic circuit function is more robust to changes in synaptic than intrinsic conductances
Authors: Fournier Zachary , Alonso Leandro M. , Marder Eve
Published: September 2024

Circuit function results from both intrinsic conductances of network neurons and the synaptic conductances that connect them. In models of neural circuits, different combinations of maximal conductances can give rise to similar activity. We compared the robustness of a neural circuit to changes in their intrinsic versus synaptic conductances. To address this, we performed a sensitivity analysis on a population of conductance-based models of the pyloric network from the crustacean stomatogastric ganglion (STG). The model network consists of three neurons with nine currents: a sodium current (Na), three potassium currents (Kd, KCa, A-type), two calcium currents (CaS and CaT), a hyperpolarization-activated current (H), a non-voltage-gated leak current (leak), and a neuromodulatory current (MI). The model cells are connected by seven synapses of two types, glutamatergic and cholinergic. We produced one hundred models of the pyloric network that displayed similar activities with values of maximal conductances distributed over wide ranges. We evaluated the robustness of each model to changes in their maximal conductances. We found that individual models have different sensitivities to changes in their maximal conductances, both in their intrinsic and synaptic conductances. As expected the models become less robust as the extent of the changes increase. Despite quantitative differences in their robustness, we found that in all cases, the model networks are more sensitive to the perturbation of their intrinsic conductances than their synaptic conductances.
A Common Longitudinal Intensive Care Unit data Format (CLIF) to enable multi-institutional federated critical illness research
Authors: Rojas Juan C. , Lyons Patrick G. , Chhikara Kaveri , Chaudhari Vaishvik , Bhavani Sivasubramanium V. , Nour Muna , Buell Kevin G. , Smith Kevin D. , Gao Catherine A. , Amagai Saki , Mao Chengsheng , Luo Yuan , Barker Anna K , Nuppnau Mark , Beck Haley , Baccile Rachel , Hermsen Michael , Liao Zewei , Park-Egan Brenna , Carey Kyle A , XuanHan  , Hochberg Chad H , Ingraham Nicholas E , Parker William F
Published: September 2024

Background

Critical illness, or acute organ failure requiring life support, threatens over five million American lives annually. Electronic health record (EHR) data are a source of granular information that could generate crucial insights into the nature and optimal treatment of critical illness. However, data management, security, and standardization are barriers to large-scale critical illness EHR studies.

Methods

A consortium of critical care physicians and data scientists from eight US healthcare systems developed the Common Longitudinal Intensive Care Unit (ICU) data Format (CLIF), an open-source database format that harmonizes a minimum set of ICU Data Elements for use in critical illness research. We created a pipeline to process adult ICU EHR data at each site. After development and iteration, we conducted two proof-of-concept studies with a federated research architecture: 1) an external validation of an in-hospital mortality prediction model for critically ill patients and 2) an assessment of 72-hour temperature trajectories and their association with mechanical ventilation and in-hospital mortality using group-based trajectory models.

Results

We converted longitudinal data from 94,356 critically ill patients treated in 2020-2021 (mean age 60.6 years [standard deviation 17.2], 30% Black, 7% Hispanic, 45% female) across 8 health systems and 33 hospitals into the CLIF format, The in-hospital mortality prediction model performed well in the health system where it was derived (0.81 AUC, 0.06 Brier score). Performance across CLIF consortium sites varied (AUCs: 0.74-0.83, Brier scores: 0.06-0.01), and demonstrated some degradation in predictive capability. Temperature trajectories were similar across health systems. Hypothermic and hyperthermic-slow-resolver patients consistently had the highest mortality.

Conclusions

CLIF facilitates efficient, rigorous, and reproducible critical care research. Our federated case studies showcase CLIF’s potential for disease sub-phenotyping and clinical decision-support evaluation. Future applications include pragmatic EHR-based trials, target trial emulations, foundational multi-modal AI models of critical illness, and real-time critical care quality dashboards.
The differential effects of common and rare genetic variants on cognitive performance across development
Authors: Malawsky Daniel S. , Koko Mahmoud , Danacek Petr , Huang Wei , Wootton Olivia , Huang Qin Qin , Wade Emma E. , Lindsay Sarah J. , Arden Rosalind , Hurles Matthew E. , Martin Hilary C.
Published: September 2024

Common and rare genetic variants that impact adult cognitive performance also predispose to rare neurodevelopmental conditions involving cognitive deficits in children. However, their influence on cognition across early life remains poorly understood. Here, we investigate the contribution of common genome-wide and rare exonic variation to cognitive performance across childhood and adolescence primarily using the Avon Longitudinal Study of Parents and Children (n=6,495 unrelated children). We show that the effect of common variants associated with educational attainment and adult cognitive performance increases as children age. Conversely, the negative effect of deleterious rare variants attenuates with age. Using trio analyses, we show that these age-related trends are driven by direct genetic effects on the individual who carries these variants rather than indirect genetic effects mediated via the family environment. We further find that the increasing effects of common variants are stronger in individuals at the upper end of the phenotype distribution, whereas the attenuating effects of rare variants are stronger in those at the lower end. Concordant results were observed in the Millenium Cohort Study (5,920 children) and UK Biobank (101,232 adults). The effects of common and rare genetic variation on childhood cognitive performance are broadly comparable in magnitude to those of other factors such as parental educational attainment, maternal illness and preterm birth. The effects of maternal illness and preterm birth on childhood cognitive performance also attenuate with age, whereas the effect of parental educational attainment does not. We show that the relative contribution of these various factors differs depending on whether one considers their contribution to phenotypic variance across the entire population or to the risk of poor outcomes. Our findings may help explain the apparent incomplete penetrance of rare damaging variants associated with neurodevelopmental conditions. More generally, they also show the importance of studying dynamic genetic influences across the life course and their differential effects across the phenotype distribution.
Assessing Cerebral Microvascular Volumetric Pulsatility with High-Resolution 4D CBV MRI at 7T
Authors: Guo Fanhua , Zhao Chenyang , Shou Qinyang , Jin Ning , Jann Kay , Shao Xingfeng , Wang Danny JJ
Published: September 2024

Arterial pulsation is crucial for promoting fluid circulation and for influencing neuronal activity. Previous studies assessed the pulsatility index based on blood flow velocity pulsatility in relatively large cerebral arteries of human. Here, we introduce a novel method to quantify the volumetric pulsatility of cerebral microvasculature across cortical layers and in white matter (WM), using high-resolution 4D vascular space occupancy (VASO) MRI with simultaneous recording of pulse signals at 7T. Microvascular volumetric pulsatility index (mvPI) and cerebral blood volume (CBV) changes across cardiac cycles are assessed through retrospective sorting of VASO signals into cardiac phases and estimating mean CBV in resting state (CBV0) by arterial spin labeling (ASL) MRI at 7T. Using data from 11 young (28.4±5.8 years) and 7 older (61.3±6.2 years) healthy participants, we investigated the aging effect on mvPI and compared microvascular pulsatility with large arterial pulsatility assessed by 4D-flow MRI. We observed the highest mvPI in the cerebrospinal fluid (CSF) on the cortical surface (0.19±0.06), which decreased towards the cortical layers as well as in larger arteries. In the deep WM, a significantly increased mvPI (p = 0.029) was observed in the older participants compared to younger ones. Additionally, mvPI in deep WM is significantly associated with the velocity pulsatility index (vePI) of large arteries (r = 0.5997, p = 0.0181). We further performed test-retest scans, non-parametric reliability test and simulations to demonstrate the reproducibility and accuracy of our method. To the best of our knowledge, our method offers the first in vivo measurement of microvascular volumetric pulsatility in human brain which has implications for cerebral microvascular health and its relationship research with glymphatic system, aging and neurodegenerative diseases.