bluuebunny/crossref_metadata_2025 huggingface dataset:
Factor XI as a therapeutic target in neuroinflammatory disease
Authors: Taskin Berk , Kohs Tia C.L. , Shatzel Joseph J. , Puy Cristina , McCarty Owen J.T.
Published: September 2023

Purpose of review

This review summarizes the pathophysiology and potential therapeutic options for treatment of multiple sclerosis, a common neuronal demyelinating disorder affecting 2.2 million people worldwide. As an autoimmune disorder, multiple sclerosis is associated with neuroinflammation and increased permeability of the blood–brain barrier (BBB), although the cause linking multiple sclerosis with compromised barrier function remains ill-defined. It has been previously shown that coagulation factors, including thrombin and fibrin, exacerbate the inflammatory processes and permeability of the BBB.

Recent findings

Increased levels of the coagulation factor (F) XII have been found in patients presenting with relapsing–remitting multiple sclerosis, with a deleterious role for FXII being validated in murine model of multiple sclerosis, experimental autoimmune encephalitis (EAE). Recent work has uncovered a role for the major substrate activated by FXII and thrombin, FXI, in the disorder of EAE. The study found that pharmacological targeting of FXI decreased clinical symptoms, lymphocyte invasion, and white matter destruction in a multiple sclerosis model.

This review emphasizes the role of FXII and FXI in regulating barrier function and the immune response in neuroinflammation. These new findings broaden the potential for therapeutic utility of FXI inhibitors beyond thrombosis to include neuroinflammatory diseases associated with compromised BBB function, including multiple sclerosis.
Identifying Barriers to HPV Vaccination for Patients With Sickle Cell Disease and Childhood Cancer Survivors
Authors: Rahim Mahvish Q. , Jacob Seethal A. , Coven Scott L. , Miller Meagan , Meagher Carolyn G. , Lozano Gabriella , Zimet Gregory , Ott Mary A.
Published: September 2023

Human papillomavirus (HPV) vaccination prevents the development of HPV-associated malignancies. Adolescent and young adult survivors of childhood cancers and patients with sickle cell disease (SCD) are vulnerable patient populations who would significantly benefit from HPV vaccination. In this multimethod study, a retrospective chart review found a notable difference between the rate of HPV vaccinations and other age-appropriate vaccinations in 177 childhood cancer survivors and in 70 patients with SCD. We then sought to describe patient and caregiver beliefs regarding HPV vaccination, through semistructured interviews with 21 patients and 48 caregivers. Interviews were analyzed with a thematic content approach to understand attitudes regarding the HPV vaccination. Qualitative interviews noted that many caregivers and adolescents had baseline misconceptions regarding the HPV vaccination in general and in context with their chronic illness. It was found that a strong recommendation from a trusted subspecialty provider would create reassurance about vaccination and reduce misconceptions and concerns about side effects in the context of a chronic illness. Counseling from subspecialists could have a strong impact on understanding the HPV vaccine in the context of chronic illness. This would likely help overcome many of the barriers to vaccination that are encountered by patients with SCD or oncology survivors.
The Effect of Simulation on Nursing Student Perceptions of Readiness to Provide End-of-Life Care
Authors: Dias Rebecca , Robinson Kathryn , Poirier Patricia
Published: September 2023

Evidence suggests that nursing students in a prelicensure nursing program lack the required preparation to care for patients at the end of life (EOL), causing feelings of inadequacy and stress. New graduate nurses (years 0-5) struggle to address the needs of this patient population, leading to considering career changes. Nursing simulation has been shown to enhance competency and is gaining increasing favor in prelicensure nursing education. Little research has been conducted on the application of simulation using standardized patients in EOL patient scenarios. This study used live standardized patients who simulated a home health patient encounter with the nursing student acting as a home health hospice nurse. Watson's theory of caring and interpretive phenomenological analysis guided the qualitative research method and analysis. Five students chose to participate in this simulation and completed 6 reflective questions. After simulation, they felt more comfortable having difficult discussions about EOL care, treatment options, and patient fears. Participants noted the importance of communication in a team setting, which included the caregiver as an integral member. The use of standardized patient-simulated experiences increases realism and provides students the opportunity to bridge the gap between didactic education and clinical practice. This will enhance their readiness and confidence in providing EOL care.
The Association Between Magnet® Recognition and Patient Outcomes
Authors: Connor Linda , Beckett Cindy , Zadvinskis Inga , Melnyk Bernadette Mazurek , Brown Roy , Messinger Jeffery , Gallagher-Ford Lynn
Published: September 2023

BACKGROUND

Previous systematic reviews have explored nurse, patient, and organizational outcomes in Magnet®-recognized hospitals compared with non-Magnet hospitals, yet these did not comprehensively review a wide variety of patient outcomes.

AIM

The purpose of this scoping review was to describe the findings from published research evaluating patient outcomes in Magnet-recognized hospitals compared with non-Magnet hospitals.

METHODS

A medical librarian conducted a systematic search for published peer-reviewed, English-language literature and a search of the reference lists for retrieved publications to identify articles addressing Magnet compared with non-Magnet hospitals related to patient outcomes.

RESULTS

Four patient outcomes improved in Magnet-designated hospitals: mortality, patient satisfaction, failure to rescue, and falls. Four patient outcomes showed undesirable or mixed outcomes. Five patient outcomes had insufficient evidence regarding patient outcomes when treated at Magnet-recognized hospitals.

CONCLUSION

Magnet Recognition® is associated with improvement in a distinct set of patient outcomes, but not all key outcome measures. Standardized outcomes and rigorous study designs are needed to further explore the impact of Magnet Recognition on a wide variety of patient outcomes.
Celebrating Nursing Professional Development Week
Authors: Fox Naomi , Smith Mary
Published: September 2023

As we celebrate Nursing Professional Development Week, September 10–16, 2023, individually, as a team, and collectively as a specialty, let us reflect on the road traversed, the present path, and the future course of nursing professional development. Celebrate your personal history, evolvement, and commitment to a future where nursing professional development practitioners continue to collaborate, innovate, and drive quality health care.
Utility of Hospital Failure to Rescue for Analyzing Variation in Pediatric Postoperative Mortality
Authors: Mehl Steven C. , Portuondo Jorge I. , Tian Yao , Raval Mehul V. , Shah Sohail R. , Vogel Adam M. , Wesson David , Massarweh Nader N.
Published: September 2023

OBJECTIVES:

To evaluate the association between pediatric hospital performances in terms of failure to rescue (FTR), defined as postoperative mortality after a surgical complication, and mortality among patients without a surgical complication.

DESIGN:

Retrospective cohort study.

SETTING:

Forty-eight academic, pediatric hospitals; data obtained from Pediatric Health Information System database (Child Health Corporation of America, Shawnee Mission, KS) (2012–2020).

PATIENTS:

Children who underwent at least one of 57 high-risk operations associated with significant postoperative mortality.

EXPOSURES:

Hospitals were stratified into quintiles of reliability adjusted FTR (lower than average FTR in quintile 1 [Q1], higher than average FTR in quintile 5 [Q5]). Multivariable hierarchical regression was used to evaluate the association between hospital FTR performance and mortality among patients who did not have a surgical complication.

MEASUREMENTS AND MAIN RESULTS:

Among 203,242 children treated across 48 academic hospitals, the complication and overall postoperative mortality rates were 8.8% and 2.3%, respectively. Among patients who had a complication, the FTR rate was 8.8%. Among patients who did not have a complication, the mortality rate was 1.7%. There was a 6.5-fold increase in reliability adjusted FTR between the lowest and highest performing hospitals (lowest FTR hospital—2.7%; 95% CI [1.6–3.9]; highest FTR hospital—17.8% [16.8–18.8]). Complex chronic conditions were highly prevalent across hospitals (Q1, 72.7%; Q2, 73.8%; Q3, 72.2%; Q4, 74.0%; Q5, 74.8%; trend test p < 0.01). Relative to Q1 hospitals, the odds of mortality in the absence of a postoperative complication significantly increased by 33% at Q5 hospitals (odds ratio 1.33; 95% CI [1.07–1.66]). This association was consistent when limited to patients with a complex chronic condition and neonates.

CONCLUSION:

FTR may be a useful and valid surgical quality measure for pediatric surgery, even when considering patients without a postoperative complication. These findings suggest practices and processes for preventing FTR at high performing pediatric hospitals might help mitigate the risk of postoperative mortality even in the absence of a postoperative complication.
Review of Traditional First Aid for Burn Injuries in the 21st Century
Authors: Hafizurrachman Muhammad , Menna Clara , Lesmana Elvira
Published: September 2023

Introduction

This review aims to investigate data on traditional burn first aid materials used in different countries.

Methods

A systematic search was performed through 8 databases for studies on traditional burn first aid published in the 21st century. Data regarding study demographics, burn first aid, first aid materials, water irrigation, and source of knowledge were summarized, and the use of each material was discussed.

Results

A total of 28 studies including 20,150 subjects were identified. An average of 29% of the study population applied water irrigation, whereas 46% used various traditional materials, and 30% did not administer first aid. People with higher education and socioeconomy class tend to choose correct first aid actions.

Discussion

The single best treatment as burn first aid is cool-water irrigation. Despite that, various other materials have been used, most of which are not suitable for first aid. Some materials possess healing abilities and can be used as wound dressing, whereas others are harmful. Inappropriate materials are mostly used in underdeveloped regions lacking water access and hygiene. Mass media and community knowledge have a large influence in burn first aid practices.

Conclusion

Raising public health awareness on burn first aid is crucial along with providing the people access to water, basic hygiene, and health care.
Undiagnosed Lambert-Eaton Myasthenic Syndrome in the Era of Sugammadex: A Case Report
Authors: Yoon Jenny J. , Anderson Alexandra L. , Niesen Adam D.
Published: September 2023

Objective

In this case report, we discuss the rare manifestation of prolonged neuromuscular blockade in a patient with history of small cell lung cancer and undiagnosed Lambert-Eaton myasthenic syndrome (LEMS) who had previously received succinylcholine for general anesthesia without incident but subsequently exhibited prolonged neuromuscular blockade during a laparoscopic procedure. We aimed to emphasize the importance of reversal agent safety and precision as well as vigilant perioperative and postoperative care.

Methods

We used the patient's electronic medical record, direct patient care experiences, and comprehensive literature review for this case report.

Results

Sugammadex was administered with mild improvement. Suspecting undiagnosed LEMS, neostigmine was administered, yielding satisfactory muscle strength and successful extubation. In retrospect, the patient reported history of weakness when lifting weights that improved upon exertion.

Conclusions

Sugammadex is an efficient and effective agent for reversal of neuromuscular blockade. However, proper monitoring of the depth and recovery of blockade is imperative to when using sugammadex with optimal safety and precision in all patients. Perioperative care teams must remain vigilant with a high index of suspicion for neuromuscular junction pathology to properly plan perioperative care for patients at risk, especially those with small cell lung cancer who may have undiagnosed LEMS.
Activation of autophagy after blast-induced traumatic brain injury in mice
Authors: Zhou Yuan , Song Yue , Zhu Lin
Published: September 2023

Injury mechanism and treatment of blast-induced traumatic brain injury (bTBI) has not made a breakthrough so far. Previous reports demonstrate autophagy is involved in regulating the pathophysiological process after TBI. Therefore, this study explored whether autophagy was activated after bTBI. A total of 108 mice were divided randomly into six groups: 6 h, 1 d, 3 d, 7 d, 14 d after bTBI groups and sham group. The protein levels of anti-microtubule associated protein 1 light chain 3B (LC3B, hereafter referred to as LC3), beclin1 and p62 were detected using western blot. Moreover, HO-1 and Nrf2 were localized using histologic staining. Immunofluorescence of LC3 and immunohistochemistry of beclin1 were performed. The autophagy-related ultrastructure was observed by TEM. LC3-II and beclin1 reached their peak on day 3 after bTBI, while p62 showed a continuous downward trend. Immunofluorescence and immunohistochemistry also confirmed that the expression levels of LC3 and beclin1 were the highest at 3 days after bTBI. Autophagic vesicles containing lysosomes or digestive residual structures were observed then. Autophagy was induced in the frontal lobe tissues of bTBI mice induced by moderate-intensity explosion, with a peak at 3d and a gradual decline thereafter.
Plasma MMP-9/TIMP-1 ratio serves as a novel potential biomarker in Alzheimer’s disease
Authors: Liu Jingfeng , Li Xing , Qu Ji
Published: September 2023

This study aimed to explore the diagnostic potential of plasma MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for Alzheimer's disease (AD). This retrospective study was performed in a cohort consisting of patients with AD (AD group) and cognitive normal subjects (HC group). Cerebrospinal fluid (CSF) classic biomarkers including Aβ42, Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) levels, and plasma MMP-9 and TIMP-1 levels were measured by commercially available ELISA kits, respectively. The differential diagnostic potential of plasma MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio was evaluated using the receiver operating characteristic curve analysis. It was observed that significantly elevated levels of plasma MMP-9 and MMP-9/TIMP-1 ratio in patients with AD than HC. Both MMP-9 and MMP-9/TIMP-1 ratios were negatively correlated with CSF Aβ42/Aβ40 ratio and positively correlated with CSF p-tau in AD group. ROC curve analysis showed better diagnostic accuracy of MMP-9/TIMP-1 ratio than MMP-9 for AD at a cutoff value of 1.35 with an area under the curve of 0.906 and sensitivity and specificity of 95.8% and 75%, respectively. Our findings encourage the use of plasma MMP-9/TIMP-1 ratio as a biomarker in the diagnosis of AD.
Recursive structures modulate the electrophysiological correlates of visual perspective taking
Authors: Xiao Feng , He Feng-Qi , Zhong Yu-Huan , Deng Jie , Zhang Chao
Published: September 2023

An increasing number of studies have focused on the neural basis of complex mental inferences, which requires an understanding of the recursive nature of thought; however, the precise electrophysiological response to a recursive structure remains unclear. The present event-related potential (ERP) study investigated the recursive structure effect on the neural correlates of visual perspective taking by modifying a third-person visual perspective-taking task. Participants were required to determine how many dots in the presented scenes could be seen from the cued perspective, including the perspectives in the self, other, and recursive (one avatar’s belief of another avatar) conditions. The ERP results showed that the N100 and P200 components specific to the recursive-perspective condition showed greater attentional allocation; the N200 component increased in the recursive condition and was related to the conflict process; and larger late slow waves were found in the other- and recursive-perspective conditions compared with those in the self-perspective condition, which reflected the decoupling mechanism. The results suggested that high-order perspective taking requires more attentional resources and conflict processing for further decoupling from the self-perspective.
Valbenazine for tardive dyskinesia: a systematic review and network meta-analysis
Authors: Kishi Taro , Sakuma Kenji , Iwata Nakao
Published: September 2023

To date, the role of valbenazine (VAL) in a dose-dependent increase in efficacy for tardive dyskinesia (TD) and in the worsening of acceptability and tolerability in a dose-dependent manner remains to be elucidated. Thus, in this systematic review and frequentist network meta-analysis, we compared 16 outcomes of VAL80 mg/d (VAL80) with VAL40 mg/d (VAL40) related to the efficacy, acceptability, tolerability, and safety in the treatment of patients with TD. Using a 95% confidence interval, we calculated the standardized mean difference for continuous variables and the risk ratio for dichotomous variables. Our results demonstrated that both VAL80 and VAL40 were superior to the placebo in terms of Abnormal Involuntary Movement Scale (AIMS) total score, Clinical Global Impression of Change–TD, and response to treatment, but VAL80 outperformed VAL40 in terms of AIMS score and response to treatment. However, any active therapy and placebo treatment groups did not have significant differences in acceptability, tolerability, and safety outcomes and similarly between VAL80 and VAL40 in any other outcomes. In conclusions, VAL could be increased from VAL40 to VAL80 if a patient with TD adequately tolerates VAL40 but treatment response is poor.
Amphoteric dissolution of two-dimensional polytriazine imide carbon nitrides in water
Authors: Lisowska Karolina , Purser Will , Chang Fuqiang , Suter Theo M. , Miller Thomas S. , Sella Andrea , Howard Christopher A. , McMillan Paul F. , Corà Furio , Clancy Adam J.
Published: September 2023

Crystalline two-dimensional carbon nitrides with polytriazine imide (PTI) structure are shown to act amphoterically, buffering both HCl and NaOH aqueous solutions, resulting in charged PTI layers that dissolve spontaneously in their aqueous media, particularly for the alkaline solutions. This provides a low energy, green route to their scalable solution processing. Protonation in acid is shown to occur at pyridinic nitrogens, stabilized by adjacent triazines, whereas deprotonation in base occurs primarily at basal plane NH bridges, although NH
2
edge deprotonation is competitive. We conclude that mildly acidic or basic pHs are necessary to provide sufficient net charge on the nanosheets to promote dissolution, while avoiding high ion concentrations which screen the repulsion of like-charged PTI sheets in solution.

This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 2)'.
WITHDRAWN: Mechanism of the microRNA-4677-3p/LDHB axis in the regulation of paclitaxel resistance of breast cancer cells
Authors: Chen Ying , Dong Qinzuo , Xing Liwei , Yang Jun , Sun Yuhuan , Zhang Junbao , Zhao Rong
Published: September 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to the statistical analysis using the original database was found to have some problems. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Adeno-to-squamous transition drives resistance to KRAS inhibition inLKB1mutant lung cancer
Authors: Tong Xinyuan , Patel Ayushi S. , Kim Eejung , Li Hongjun , Chen Yueqing , Li Shuai , Liu Shengwu , Dilly Julien , Kapner Kevin S. , Xue Yun , Hover Laura , Mukhopadhyay Suman , Sherman Fiona , Mynzdar Khrystyna , Gao Yijun , Li Fei , Li Fuming , Fang Zhaoyuan , Jin Yujuan , Gao Juntao , Shi Minglei , Chen Luonan , Chen Yang , Kheoh Thian , Yang Wenjing , Yanai Itai , Moriera Andre L. , Velcheti Vamsidhar , Neel Benjamin G. , Hu Liang , Christensen James G. , Olson Peter , Gao Dong , Zhang Michael Q. , Aguirre Andrew J. , Wong Kwok-Kin , Ji Hongbin
Published: September 2023

KRASG12Cinhibitors including adagrasib and sortorasib have shown clinical promise in targetingKRASG12C-mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurringKRASG12CandSTK11/LKB1mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies ofLkb1-deficientKRASG12CandKrasG12Dlung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed ΔNp63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked byKrt6aupregulation. Notably, higherKRT6Aexpression at baseline correlated with shorter overall survival inKRAS-mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.
Key Proteins for Regeneration inA. mexicanum: Transcriptomic Insights from Aged and Juvenile Limbs
Authors: del Moral-Morales Aylin , Sámano Cynthia , Ocampo-Cervantes José Antonio , Topf Maya , Baumbach Jan , González-Barrios Rodrigo , Soto-Reyes Ernesto
Published: September 2023

The axolotl is an animal with remarkable regenerative abilities, making it an ideal model for studying potential regenerative therapies in mammals, including humans. However, the molecular mechanisms involved in regeneration remain unclear. We conducted a transcriptomic analysis of juvenile axolotls’ limbs and their blastema and compared the results with aged axolotls that failed to regenerate after amputation. We identified a set of genes involved in cell differentiation, transcriptional regulation, cartilage development, bone morphogenesis, and extracellular matrix remodeling. Four highly expressed genes (FSTL1, ADAMTS17, GPX7, andCTHRC1) were identified in regenerating tissue, but underexpressed in aged axolotls. Structural and homology analysis showed that these genes are conserved and have important roles in development, bone morphogenesis, and cartilage formation. Our findings propose a novel set of axolotl genes involved in tissue regeneration that could be a starting point for further studies in other vertebrates.

Graphical abstract
Reduced S-nitrosylation of TGFβ1 elevates its binding affinity towards the receptor and promotes fibrogenic signaling in the breast
Authors: Letson Joshua , Furuta Saori
Published: September 2023

Transforming Growth Factor β (TGFβ) is a pleiotropic cytokine closely linked to tumors. TGFβ is often elevated in precancerous breast lesions in association with epithelial-to-mesenchymal transition (EMT), indicating its contribution to precancerous progression. We previously reported that basal nitric oxide (NO) levels declined along with breast cancer progression. We then pharmacologically inhibited NO production in healthy mammary glands of wild-type mice and found that this induced precancerous progression accompanied by desmoplasia and upregulation of TGFβ activity. In the present study, we tested our hypothesis that NO directly S-nitrosylates (forms an NO-adduct at a cysteine residue) TGFβ to inhibit the activity, whereas the reduction of NO denitrosylates TGFβ and de-represses the activity. We introduced mutations to three C-terminal cysteines of TGFβ1 which were predicted to be S-nitrosylated. We found that these mutations indeed impaired S-nitrosylation of TGFβ1 and shifted the binding affinity towards the receptor from the latent complex. Furthermore,in silicostructural analyses predicted that these S-nitrosylation-defective mutations strengthen the dimerization of mature protein, whereas S-nitrosylation-mimetic mutations weaken the dimerization. Such differences in dimerization dynamics of TGFβ1 by denitrosylation/S-nitrosylation likely account for the shift of the binding affinities towards the receptor vs. latent complex. Our findings, for the first time, unravel a novel mode of TGFβ regulation based on S-nitrosylation or denitrosylation of the protein.

Significance statement

Transforming Growth Factor β (TGFβ) is a widely studied cytokine associated with tumors. Because of its pleiotropic functions and dichotomous roles in tumorigenesis, the development of therapeutics targeted to TGFβ for cancer treatment has been challenging. In the present study, we report that TGFβ is indeed S-nitrosylated at specific sites for repressing its functions, whereas it is denitrosylated to derepress its activity. Such covalent modification-based regulation of TGFβ activity could potentially be utilized to design a new type of inhibitor or activator of the protein.
Multi-population dissolution in confined active fluids
Authors: Fylling Cayce , Tamayo Joshua , Gopinath Arvind , Theillard Maxime
Published: September 2023

Autonomous out-of-equilibrium agents or cells in suspension are ubiquitous in biology and engineering. Turning chemical energy into mechanical stress, they generate activity in their environment, which may trigger spontaneous large-scale dynamics. Often, these systems are composed of multiple populations that may reflect the coexistence of multiple species, differing phenotypes, or chemically varying agents in engineered settings. Here, we present a new method for modeling such multi-population active fluids subject to confinement. We use a continuum multi-scale mean-field approach to represent each phase by its first three orientational moments and couple their evolution with those of the suspending fluid. The resulting coupled system is solved using a parallel adaptive level-set-based solver for high computational efficiency and maximal flexibility in the confinement geometry. Motivated by recent experimental work, we employ our method to study the spatiotemporal dynamics of confined bacterial suspensions and swarms dominated by fluid hydrodynamic effects. Our computational explorations reproduce observed emergent collective patterns, including features of active dissolution in two-population active-passive swarms, with results clearly suggesting that hydrodynamic effects dominate dissolution dynamics. Our work lays the foundation for a systematic characterization of natural and synthetic multi-population systems such as bacterial colonies, bird flocks, fish schools, colloidal swimmers, or programmable active matter.
UCLA’s Competitive Edge Program Provides an Advantage to STEM Doctoral Students from Historically Excluded and Underrepresented Groups
Authors: Del Carpio Christina A. , Azurdia Diana E.
Published: September 2023

Universities benefit from recruiting and retaining diverse students, as it leads to more creative and rigorous problem solving. Efforts to improve the diversity, equity, and inclusion of graduate education have historically been focused on recruitment but are now shifting to retaining enrolled students. A low percentage of doctoral students, particularly those from historically underrepresented groups (URGs), complete their PhD within 10 years. To increase support of incoming doctoral students from URGs, UCLA established the Competitive Edge (CE) bridge program. CE provides six weeks of professional development and research training at the start of the PhD program. We surveyed 55+ first-year doctoral students (14 CE students, eight non-CE students from URGs, and 34 well-represented (WR) students) in STEM fields to understand CE’s effectiveness. We found that the CE program aided students in four areas that influence graduate student attrition: mentor/mentee relationship, socialization, finances, and preparedness. At the end of their first academic year, CE students reported that the program helped them in multiple areas relating to student success, such as mental wellbeing and sense of belonging. CE students reported a larger mean growth in seven of eight skills needed in graduate school compared to NonCE URG and WR students. Short answer responses revealed that NonCE students wished for more support in areas covered by the CE program, such as managing advising relationships and protecting mental health. Additionally, CE students received significant funding during the program. The CE program’s successful model at UCLA can be adapted to improve support for underrepresented doctoral students at other institutions.
ZZZ3 protects human embryonic stem cells from nucleolar stress by boosting mTOR/ribosome pathway
Authors: Conte Michela Lo , Lucchino Valeria , Scalise Stefania , Zannino Clara , Murfuni Maria Stella , Cicconetti Chiara , Scaramuzzino Luana , Matassa Danilo Swann , Procopio Anna , Cuda Giovanni , Parrotta Elvira Immacolata
Published: September 2023

Embryonic stem cells (ESCs) are defined as stem cells with self-renewing and differentiation capabilities. These unique properties are tightly regulated and controlled by complex genetic and molecular mechanisms whose understanding is essential for both basic and translational research. A large number of studies have mostly focused on understanding the molecular mechanisms governing pluripotency and differentiation of ESCs, while the regulation of proliferation has received comparably less attention. In mouse ESCs, pluripotency and proliferation can be independent processes meaning that it is possible for mouse ESCs to maintain their pluripotent state without actively proliferating. Here, we investigate the role of ZZZ3 (Zinc Finger ZZ-Type Containing 3) function in human ESCs homeostasis. We found that knockdown of ZZZ3 strongly decreases ribosome biogenesis, translation, and mTOR signaling leading to nucleolar stress and significant reduction of cell proliferation. This process occurs without affecting pluripotency, suggesting that ZZZ3-depleted ESCs enter a dormant-like state and that proliferation and pluripotency can be uncoupled also in human ESCs.
Spatial and temporal control of lysis by the lambda holin
Authors: Cahill Jesse , Holt Ashley , Theodore Matthew , Moreland Russell , O’Leary Chandler , Martin Cody , Bettridge Kelsey , Xiao Jie , Young Ry
Published: September 2023

The infection cycle of phage λ terminates in lysis mediated by three types of lysis proteins, each disrupting a layer in the bacterial envelope: the S105 holin, the R endolysin, and the Rz/Rz1 spanin complex targeting the inner membrane (IM), cell wall or peptidoglycan (PG), and the outer membrane (OM), respectively. Video microscopy has shown that in most infections lysis occurs as a sudden, explosive event at a cell pole, such that the initial product is a less refractile ghost that retains rod-shaped morphology. Here, we investigate the molecular basis of polar lysis using time lapse fluorescence microscopy. The results indicate that the holin determines the morphology of lysis by suddenly forming two-dimensional rafts at the poles about 100 seconds prior to lysis. Given the physiological and biochemical similarities between the lambda holin and other class I holins, dynamic redistribution and sudden concentration may be common features of holins, probably reflecting the fitness advantage of all-or-nothing lysis regulation.
C4 induces pathological synaptic loss by impairing AMPAR trafficking
Authors: Phadke Rhushikesh A. , Kruzich Ezra , Fournier Luke A. , Brack Alison , Sha Mingqi , Picard Ines , Johnson Connor , Stroumbakis Dimitri , Salgado Maria , Yeung Charlotte , Escude Velasco Berta , Liu Yen Yu , Cruz-Martín Alberto
Published: September 2023

During development, activation of the complement pathway, an extracellular proteolytic cascade, results in microglia-dependent synaptic elimination via complement receptor 3 (CR3). Here, we report that decreased connectivity caused by overexpression ofC4(C4-OE), a schizophrenia-associated gene, is CR3 independent. Instead, C4-OE triggers GluR1 degradation through an intracellular mechanism involving endosomal trafficking protein SNX27, resulting in pathological synaptic loss. Moreover, the connectivity deficits associated with C4-OE were rescued by increasing levels of SNX27, linking excessive complement activity to an intracellular endolysosomal recycling pathway affecting synapses.
Cellular gibberellin dynamics govern indeterminate nodule development, morphology and function
Authors: Drapek Colleen , Radzman-Mohd Nadiatul , Rizza Annalisa , Schiessl Katharina , Barbosa Fabio Dos Santos , Wen Jiangqi , Oldroyd Giles E.D. , Jones Alexander M.
Published: September 2023

During nutrient scarcity, plants can adapt their developmental strategy to maximize their chance of survival. Such plasticity in development is underpinned by hormonal regulation, which mediates the relationship between environmental cues and developmental outputs. In legumes, endosymbiosis with nitrogen fixing bacteria (rhizobia) is a key adaptation for supplying the plant with nitrogen in the form of ammonium. Rhizobia are housed in lateral root-derived organs termed nodules that maintain an environment conducive to Nitrogenase in these bacteria. Several phytohormones are important for regulating the formation of nodules, with both positive and negative roles proposed for gibberellin (GA). In this study, we determined the cellular location and function of bioactive GA during nodule organogenesis using a genetically-encoded second generation GA biosensor, GPS2. We found endogenous bioactive GA accumulates locally at the site of nodule primordia, increasing dramatically in the cortical cell layers, persisting through cell divisions and maintaining accumulation in the mature nodule meristem. We show, through mis-expression of GA catabolic enzymes that suppress GA accumulation, that GA acts as a positive regulator of nodule growth and development. Furthermore, increasing or decreasing GA through perturbation of biosynthesis gene expression can increase or decrease the size of nodules, respectively. This is unique from lateral root formation, a developmental program that shares common organogenesis regulators. We link GA to a wider gene regulatory program by showing that cytokinin as well as nodule-identity genes induce and sustain GA accumulation necessary for nodule function.
A minimum threshold for myelination of pyramidal cells in human and mouse neocortex
Authors: Pascual-García M. , Unkel M. , Slotman J. A. , Bolleboom A. , Bouwen B. , Houtsmuller A. B. , Dirven C. , Gao Z. , Hijazi S. , Kushner S.A.
Published: September 2023

Neocortical pyramidal neurons are frequently myelinated. Diversity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and calibre are critical determinants of fast-spiking interneuron myelination (Stedehouder, J. etal(2019). However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy and cell type-specific manipulations to examine the extent to which axonal morphology determines the topography of axonal myelination in mouse neocortical pyramidal neurons. We found that, unlike what was determined for fast-spiking interneurons, the joint combination of axonal calibre and interbranch distance does not predict axonal myelination in pyramidal neurons, rather it provides a minimum threshold for myelination; pyramidal neurons with an axon calibre and interbranch distance lower than 0.24 µm and 19 µm, respectively, are almost never myelinated. Moreover, we further confirmed that these findings in mice also extend to human neocortical pyramidal cell myelination, suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is highly deterministic of the topography and cell-type specificity of neocortical myelination.
Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED
Authors: Bu G , Danelius E , Wieske L.H , Gonen T
Published: September 2023

Paritaprevir is an orally bioavailable, macrocyclic drug used for treating chronic Hepatitis C virus infection. Its structures had been elusive to the public until recently when one of the crystal forms was solved by MicroED. In this work, we report the MicroED structures of two distinct polymorphic crystal forms of paritaprevir from the same experiment. The different polymorphs show conformational changes in the macrocyclic core, as well as the cyclopropylsulfonamide and methylpyrazinamide substituents. Molecular docking shows that one of the conformations fits well into the active site pocket of the NS3/4A serine protease target, and can interact with the pocket and catalytic triad via hydrophobic interactions and hydrogen bonds. These results can provide further insight for optimization of the binding of acylsulfonamide inhibitors to the NS3/4A serine protease. In addition, this also demonstrate the opportunity of deriving different polymorphs and distinct macrocycle conformations from the same experiments using MicroED.
Malaria trends in districts that were targeted and not-targeted for seasonal malaria chemoprevention in children under five years of age in Guinea, 2014–2021
Authors: Bisanzio D , Keita MS , Camara A , Guilavogui T , Diallo T , Barry H , Preston A , Bangoura L , Mbounga E , Florey L , Taton JL , Fofana A , Reithinger R
Published: September 2023

Background

Seasonal malaria chemoprevention (SMC) is one of the main interventions recommended by WHO to prevent and reduce childhood malaria. Since 2015, Guinea has implemented SMC targeting children aged 3–59 months (CU5) in districts with high and seasonal malaria transmission.

Objective

We assessed the programmatic impact of SMC in Guinea’s context of scaled-up malaria intervention programming by comparing malaria-related outcomes in 14 districts that had (n = 8) or had not (n = 6) been targeted for SMC.

Method

Using routine health management information system data, we calculated the district-level monthly test positivity rate (TPR) and monthly uncomplicated and severe malaria incidence for the whole population and disaggregated age groups (<5yrs and ≥5yrs of age). Changes in malaria indicators through time were analyzed by calculating the district-level compound annual growth rate (CAGR) from 2014 to 2021; we used statistical analyses to describe the time trend of the number of tested clinical cases, TPR, uncomplicated malaria incidence, and severe malaria incidence.

Result

The CAGR of TPR of all age groups was statistically lower in SMC (median = −7.8%, range [IQR] = −9.7%, −5.5%) compared to non-SMC (median = −3.0%, IQR = −3.0%, −1.2%) districts. Similarly, the CAGR in uncomplicated malaria incidence was significantly lower in SMC (median = 1.8%, IQR = −0.9%, 3.5%) compared to non-SMC (median = 11.5%, IQR = 8.8%, 14.0%) districts. For both TPR and uncomplicated malaria incidence the observed difference was also significant age disaggregated. The CAGR of severe malaria incidence showed that all age groups experienced a decline in severe malaria in both SMC and non-SMC districts. However, this decline was significantly higher in SMC (median = −22.3%, IQR= −27.6%, −18.2%) than in non-SMC (median = −5.1%, IQR= - 7.7; −3.6) districts for the entire population, as well as both CU5 and people over 5 years of age.

Conclusion

Our results provide evidence to support that—even in an operational programming context—adding SMC to the comprehensive package of malaria interventions yields a positive epidemiological impact and results in greater reduction in TPR, as well as the incidence of uncomplicated and severe malaria in CU5.
Genomic Insights into the Population History and Adaptive Traits of Latin American Criollo Cattle
Authors: Ward James A. , Ng’ang’a Said I. , Randhawa Imtiaz A. S. , McHugo Gillian P. , O’Grady John F. , Flórez Julio M. , Browne John A. , Pérez O’Brien Ana M. , Landaeta-Hernández Antonio J. , Garcia José F. , Sonstegard Tad S. , Frantz Laurent A. F. , Salter-Townshend Michael , MacHugh David E.
Published: September 2023

Criollo cattle, descendants of animals brought by Iberian colonists to the Americas, have been subject to centuries of natural and human-mediated selection in novel tropical agroecological zones. Consequently, these breeds have evolved distinct characteristics such as resistance to disease and exceptional heat tolerance. In addition to European taurine (Bos taurus) ancestry, it has been proposed that gene flow from African taurine and Asian indicine (Bos indicus) cattle has shaped the ancestry of Criollo cattle. In this study, we analysed Criollo breeds from Colombia and Venezuela using whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) array data to examine population structure and admixture at high resolution. Analysis of genetic structure and ancestry components provided evidence for African taurine and Asian indicine admixture in Criollo cattle. In addition, using WGS data, we detected selection signatures associated with a myriad of adaptive traits, revealing genes linked to thermotolerance, reproduction, fertility, immunity, and distinct coat and skin coloration traits. This study underscores the remarkable adaptability of Criollo cattle and highlights the genetic richness and potential of these breeds in the face of climate change, habitat flux, and disease challenges. Further research is warranted to leverage these findings for more effective and sustainable cattle breeding programmes.
Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils
Authors: Soeda Yoshiyuki , Yoshimura Hideaki , Bannai Hiroko , Koike Riki , Shiiba Isshin , Takashima Akihiko
Published: September 2023

Intracellular tau aggregation requires a local protein concentration increase, referred to as "droplets". However, the cellular mechanism for droplet formation is poorly understood. Here, we expressed OptoTau, a P301L mutant tau fused with CRY2olig, a light-sensitive protein that can form homo-oligomers. Under blue light exposure, OptoTau increased tau phosphorylation and was sequestered in aggresomes. Suppressing aggresome formation by nocodazole formed tau granular clusters in the cytoplasm. The granular clusters disappeared by discontinuing blue light exposure or 1,6-hexanediol treatment suggesting that intracellular tau droplet formation requires microtubule collapse. Expressing OptoTau-ΔN, a species of N-terminal cleaved tau observed in the Alzheimer’s disease brain, formed 1,6-hexanediol and detergent-resistant tau clusters in the cytoplasm with blue light stimulation. This intracellular stable tau clusters acted as a seed for tau fibrils in vitro. These results suggest that tau droplet formation and N-terminal cleavage are necessary for neurofibrillary tangles formation in neurodegenerative diseases.
Dysfunctional parvalbumin interneurons in a genetic mouse model of schizophrenia
Authors: Hijazi S. , Pascual-García M. , Tolido A. , Pham A. , Kushner S.A.
Published: September 2023

The 22q11 deletion syndrome (22q11DS) is an interstitial microdeletion associated to an increased risk of developing schizophrenia. In this disorder, there is a dysfunction in the overall connectivity of the brain. Parvalbumin-expressing (PV+) interneurons have been associated with multiple pre- and post-synaptic impairments that affect various brain regions. Specifically, previous results have suggested that alterations in hippocampal networks may be related to PV+interneurons dysfunction. In this study, we used the Df1 mouse model that carries the 22q11 deletion to examine the excitability of PV+cells in the dorsal CA1 region of the hippocampus, due to its importance in memory and cognition. We found that PV+interneurons were hyperexcitable in this region. To understand the source of the altered excitability, we measured potassium currents, highly involved in the intrinsic firing properties of neurons. We observed that voltage-gated potassium channel subfamily A member 1 (Kv1.1) was impaired in PV+cells. Specific activation of this channel recovered some of the excitability disturbances observed in Df1 mice. Furthermore, blockade of synaptic inputs also restored PV+interneuron’s excitability. Taken together, these results suggest that PV excitability is increased in the CA1 region of the hippocampus and it is partially mediated by Kv1.1 in a mouse model of 22q11DS.
Collaborative and privacy-preserving workflows on a clinical data warehouse: an example developing natural language processing pipelines to detect medical conditions
Authors: Petit-Jean Thomas , Gérardin Christel , Berthelot Emmanuelle , Chatellier Gilles , Frank Marie , Tannier Xavier , Kempf Emmanuelle , Bey Romain
Published: September 2023

Abstract

Objective

To develop and validate advanced natural language processing pipelines that detect 18 conditions in clinical notes written in French, among which 16 comorbidities of the Charlson index, while exploring a collaborative and privacy-preserving workflow.

Materials and methods

The detection pipelines relied both on rule-based and machine learning algorithms for named entity recognition and entity qualification, respectively. We used a large language model pre-trained on millions of clinical notes along with clinical notes annotated in the context of three cohort studies related to oncology, cardiology and rheumatology, respectively. The overall workflow was conceived to foster collaboration between studies while complying to the privacy constraints of the data warehouse. We estimated the added values of both the advanced technologies and the collaborative setting.

Results

The 18 pipelines reached macro-averaged F1-score positive predictive value, sensitivity and specificity of 95.7 (95%CI 94.5 - 96.3), 95.4 (95%CI 94.0 - 96.3), 96.0 (95%CI 94.0 - 96.7) and 99.2 (95%CI 99.0 - 99.4), respectively. F1-scores were superior to those observed using either alternative technologies or non-collaborative settings. The models were shared through a secured registry.

Conclusions

We demonstrated that a community of investigators working on a common clinical data warehouse could efficiently and securely collaborate to develop, validate and use sensitive artificial intelligence models. In particular, we provided efficient and robust natural language processing pipelines that detect conditions mentioned in clinical notes.