bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Sepsis Bundle Compliance as a Predictor for Patient Outcomes at a Community Hospital
Authors: Lawrence John R. , Lee Ben Seiyon , Fadahunsi Adetokunbo I. , Mowery Bernice D.
Published: March 2024

Background:

Clinicians are encouraged to use the Centers for Medicare & Medicaid Services early management bundle for severe sepsis and septic shock (SEP-1); however, it is unclear whether this process measure improves patient outcomes.

Purpose:

The purpose of this study was to evaluate whether compliance with the SEP-1 bundle is a predictor of hospital mortality, length of stay (LOS), and intensive care unit LOS at a suburban community hospital.

Methods:

A retrospective observational study was conducted.

Results:

A total of 577 patients were included in the analysis. Compliance with the SEP-1 bundle was not a significant predictor for patient outcomes.

Conclusions:

SEP-1 compliance may not equate with quality of health care. Efforts to comply with SEP-1 may help organizations develop systems and structures that improve patient outcomes. Health care leaders should evaluate strategies beyond SEP-1 compliance to ensure continuous improvement of outcomes for patients experiencing sepsis.
The L-Shaped Zygomatic Reduction with Oblique or Vertical Resection: Which One Is the Optimal Choice?
Authors: He Yingyou , Wang Yu , Al-Watary Mohammed Qasem , Wang Yumo , Wu Yifan , Li Xiang , Ye Bin , Li Jihua
Published: March 2024

Background:

This study aimed to investigate the optimal surgical techniques in reduction malarplasty by comparing the difference between the L-shaped osteotomy with vertical and oblique bone resection.

Methods:

A total of 120 patients who visited the authors’ department for L-shaped osteotomy with either vertical (group I) or oblique bone resection (group II) from 2015 to 2021 were reviewed retrospectively. The preoperative and postoperative spiral computed tomographic data were analyzed. The preoperative computed tomographic data were also used to simulate the virtual and model surgery.

Results:

The results showed that a broken bridge–like structure with a bony gap of 2.86 ± 1.03 mm at the zygomatic arch root was observed in group I, and a mortice-and-tenon joint structure with a bone overlap of 2.28 ± 0.58 mm was formed in group II. The zygoma in group I displaced significantly in the vertical direction and horizontal direction during the follow-up. Simultaneously, the incidence of complications was higher in group I. In the mechanism analysis through virtual and model surgery, the zygomatic segment was shifted anteriorly and inferiorly in group I, and a bony gap was detected at the zygomatic arch root. Conversely, a superior and posterior movement was performed in group II and it maintained the zygomatic complex integral with bone overlap at the zygomatic arch root on repositioning.

Conclusion:

This study suggested that L-shaped osteotomy with oblique bone resection could be the optimal choice for reducing zygomatic prominence.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Predictive Power of Dependence and Clinical-Social Fragility Index and Risk of Fall in Hospitalized Adult Patients: A Case-Control Study
Authors: Cioce Marco , Grassi Simone , Borrelli Ivan , Grassi Vincenzo Maria , Ghisellini Renato , Nuzzo Carmen , Zega Maurizio , Laurenti Patrizia , Raponi Matteo , Rossi Riccardo , Boccia Stefania , Moscato Umberto , Oliva Antonio , Vetrugno Giuseppe
Published: March 2024

Objectives

Accidental falls are among the leading hospitals’ adverse events, with incidence ranging from 2 to 20 events per 1.000 days/patients. The objective of this study is to assess the relationship between in-hospital falls and the score of 3 DEPendence and Clinical-Social Fragility indexes.

Methods

A monocentric case-control study was conducted by retrieving data of in-hospital patients from the electronic health records.

Results

Significant differences between the mean scores at the hospital admission and discharge were found. The BRASS scale mean (SD) values at the admission and at the discharge were also significantly higher in cases of in-hospital falls: at the admission 10.2 (±7.7) in cases versus 7.0 (±8.0) in controls (P = 0.003); at the discharge 10.0 (±6.4) versus 6.7 (±7.5) (P = 0.001). Barthel index mean (SD) scores also presented statistically significant differences: at the admission 60.3 (±40.6) in cases versus 76.0 (±34.8) in controls (P = 0.003); at discharge 51.3 (±34.9) versus 73.3 (±35.2) (P = 0.000).

Odds ratios were as follows: for Barthel index 2.37 (95% CI, 1.28–4.39; P = 0.003); for Index of Caring Complexity 1.45 (95% CI, 0.72–2.91, P = 0. 255); for BRASS index 1.95 (95% CI, 1.03–3.70, P = 0.026). With BRASS index, the area under the curve was 0.667 (95% CI, 0.595–0.740), thus indicating a moderate predictive power of the scale.

Conclusions

The use of only Conley scale—despite its sensitivity and specificity—is not enough to fully address this need because of the multiple and heterogeneous factors that predispose to in-hospital falls. Therefore, the combination of multiple tools should be recommended.
A Case Report of Craniofacial Intraosseous Xanthoma in a Patient Seeking Facial Feminization Surgery
Authors: Nguyen Nghiem , Lee James , Liu Yuan
Published: March 2024

Background

Fibrous dysplasia (FD) is a benign developmental disorder of the bone that causes normal skeletal tissue to be replaced by excess fibrous tissue and poorly differentiated osteoblasts. Intraosseous xanthomas are benign intraosseous tumor growths characterized microscopically by the presence of lipid-laden foamy histiocytes, often with cortical expansion or disruption. Although FD commonly occurs in craniofacial bones, primary intraosseous xanthomas of the skull or facial skeleton are extremely rare. Although 2 distinct conditions, each may be difficult to differentiate on CT imaging when occurring in the facial skeleton.

Methods

We report a case of an incidental finding on craniofacial CT of a frontal bone lesion originally thought to be FD. The finding was in a 55-year-old transgender woman who was assigned male at birth before receiving multiprocedural facial feminization surgery.

Results

The clinical features, radiological findings, and treatment are discussed. Postoperatively, the patient had no sequelae secondary to facial feminization surgery or to the orbital lesion biopsy procedure. Bone graft appeared stable on CT imaging, although FD did not appear to resolve completely.

Conclusions

Diagnosis of such lesions is challenging and may require both radiographic and histopathologic assessment. As in the case of this patient, intraosseous xanthomas may also be misdiagnosed as other benign lesions such as FD. In most known cases, surgical intervention leads to complete resolution without recurrence of the lesion.
Free Tissue Transfer for Reconstruction After Bilateral Skin Sparing Mastectomy—A Systematic Review
Authors: Bucher Florian , Vogt Peter M. , Krezdorn Nicco , Dastagir Khaled
Published: March 2024

Background

Breast cancer is the most commonly diagnosed malignant neoplasia in females worldwide. Overall survival and patients' choice for bilateral mastectomy have increased. It is therefore important to offer breast reconstructive procedures to improve patient quality of life and self-esteem. The aim of this systematic literature review is to quantify the outcome and sustainability of bilateral breast reconstruction using autologous, vascularized free tissue transfer.

Methods

A systematic literature review of PubMed, Cochrane, and the Web of Science databases was performed. A total of 5879 citations were identified, and 12 studies met the inclusion criteria.

Results

A total of 1316 patients were included, with a mean age of 47.2 years. Overall, 32.5% of patients experienced a complication after breast reconstruction. If reported, 7.45% of patients experienced major complications, while 20.7% had minor complications.

The following flaps were used for breast reconstruction, in order of reducing frequency: DIEP (45.45%), TRAM (22.73%), SIEA (9.09%), SGAP (9.09%), TUG (4.55%), TMG (4.55%), and LD/MLD (4.55%).

Conclusions

Current studies indicate that bilateral breast reconstruction using autologous, vascularized free tissue transfer is a safe procedure for postmastectomy reconstruction and offers stable long-term results. This is particularly in comparison to implant-based breast reconstruction.
Indications, Techniques, and Barriers for Pancreas Transplant Biopsy: A Consensus Perspective From a Survey of US Centers
Authors: Singh Neeraj , Lentine Krista L. , Fleetwood Vidya A. , Woodside Kenneth J. , Odorico Jon , Axelrod David , Alhamad Tarek , Maher Kennan , Xiao Huiling , Fridell Jonathan , Kukla Aleksandra , Pavlakis Martha , Shokouh-Amiri Hosein M. , Zibari Gazi , Cooper Matthew , Parsons Ronald F.
Published: March 2024

Background.

Pancreas transplant biopsy practices for the diagnosis of rejection or other pathologies are not well described.

Methods.

We conducted a survey of staff at US pancreas transplant programs (March 22, 2022, to August 22, 2022) to assess current program practices and perceptions about the utility and challenges in the performance and interpretation of pancreas allograft biopsies.

Results.

Respondents represented 65% (76/117) of active adult pancreas transplant programs, capturing 66% of recent pancreas transplant volume in the United States. Participants were most often nephrologists (52%), followed by surgeons (46%), and other staff (4%). Pancreas allograft biopsies were performed mostly by interventional radiologists (74%), followed by surgeons (11%), nephrologists (8%), and gastroenterologists (1%). Limitations in the radiologist’s or biopsy performer’s comfort level or expertise to safely perform a biopsy, or to obtain sufficient/adequate samples were the two most common challenges with pancreas transplant biopsies. Pancreas transplant biopsies were read by local pathologists at a majority (86%) of centers. Challenges reported with pancreas biopsy interpretation included poor reliability, lack of reporting of C4d staining, lack of reporting of rejection grading, and inconclusive interpretation of the biopsy. Staff at a third of responding programs (34%) stated that they rarely or never perform pancreas allograft biopsies and treat presumed rejection empirically.

Conclusions.

This national survey identified significant variation in clinical practices related to pancreas allograft biopsies and potential barriers to pancreas transplant utilization across the United States. Consideration of strategies to improve program experience with percutaneous pancreas biopsy and to support optimal management of pancreas allograft rejection informed by histology is warranted.
Sequential Normothermic Regional Perfusion and End-ischemic Ex Situ Machine Perfusion Allow the Safe Use of Very Old DCD Donors in Liver Transplantation
Authors: Torri Francesco , Balzano Emanuele , Melandro Fabio , Maremmani Paolo , Bertini Pietro , Lo Pane Paolo , Masini Matilde , Rotondo Maria Isabella , Babboni Serena , Del Turco Serena , Antonelli Stefano , De Tata Vincenzo , Biancofiore Giandomenico , Guarracino Fabio , Paolicchi Aldo , De Simone Paolo , Basta Giuseppina , Ghinolfi Davide ,   for the DCDNet Study Group
Published: March 2024

Background.

In Italy, 20 min of continuous, flat-line electrocardiogram are required for death declaration. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death (cDCD) liver transplantation by combining normothermic regional and end-ischemic machine perfusion (MP). The aim of this study was to evaluate the safety and feasibility of the use of septuagenarian and octogenarian cDCD donors with this approach.

Methods.

All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP.

Results.

In the period from April 2021 to December 2022, 17 cDCD older than 70 y were considered. In 6 cases (35%), the graft was not considered suitable for liver transplantation, whereas 11 (65%) were evaluated and eventually transplanted. The median donor age was 82 y, being 8 (73%) older than 80. Median functional warm ischemia and no-flow time were 36 and 28 min, respectively. Grafts were randomly assigned to ex situ dual hypothermic oxygenated MP in 6 cases (55%) and normothermic MP in 5 (45%). None was discarded during MP. There were no cases of primary nonfunction, 1 case of postreperfusion syndrome (9%) and 2 cases (18%) of early allograft dysfunction. At a median follow-up of 8 mo, no vascular complications or ischemic cholangiopathy were reported. No major differences were found in terms of postoperative hospitalization or complications based on the type of MP.

Conclusions.

The implementation of sequential normothermic regional and end-ischemic MP allows the safe use of very old donation after circulatory death donors.
Silymarin (Milk Thistle) Treatment of Adults With Gambling Disorder: A Double-Blind, Placebo-Controlled Trial
Authors: Grant Jon E. , Driessens Corine , Chamberlain Samuel R.
Published: March 2024

Objective

Data on the pharmacological treatment of gambling disorder are limited. Silymarin (derived from milk thistle) has antioxidant properties. The goal of the current study was to determine the efficacy and tolerability of silymarin in adults with gambling disorder.

Methods

Forty-three individuals (18 [41.9%] women; mean age=49.61 [±13.1] years) with gambling disorder entered an 8-week, double-blind, placebo-controlled study. Dosing of silymarin ranged from 150 to 300 mg twice a day. The primary outcome measure was the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS). Secondary outcome measures comprised the Gambling Symptom Assessment Scale and measures of depression and anxiety. Outcomes were examined using mixed-effect models.

Results

Silymarin did not statistically differentiate from the placebo on any of the outcome measures of interest, in terms of treatment group×time interactions. There was a robust response in the placebo group (57% reduction on the PG-YBOCS), and on average there was a 56% reduction in YBOCS score for the milk thistle.

Conclusions

The findings of this study do not support the use of silymarin/milk thistle in the treatment of gambling disorder but highlight the large placebo response seen in gambling disorder. Treatment interventions for gambling disorder need to better understand and address the placebo response.

Trial Registration

ClinicalTrials.gov identifier: NCT02337634
Collaborative Approach Toward Transplant Candidacy for Obese Patients with End-Stage Renal Disease
Authors: Levy Shauna , Attia Abdallah , Omar Mahmoud , Langford Nicole , Vijay Adarsh , Jeon Hoonbae , Galvani Carlos , Killackey Mary T , Paramesh Anil S
Published: March 2024

BACKGROUND:

An elevated BMI is a major cause of transplant preclusion for patients with end-stage renal disease (ESRD). This phenomenon exacerbates existing socioeconomic and racial disparities and increases the economic burden of maintaining patients on dialysis. Metabolic bariatric surgery (MBS) in such patients is not widely available. Our center created a collaborative program to undergo weight loss surgery before obtaining a kidney transplant.

STUDY DESIGN:

We studied the outcomes of these patients after MBS and transplant surgery. One hundred eighty-three patients with ESRD were referred to the bariatric team by the transplant team between January 2019 and June 2023. Of these, 36 patients underwent MBS (20 underwent Roux-en-Y gastric bypass and 16 underwent sleeve gastrectomy), and 10 underwent subsequent transplantation, with another 15 currently waitlisted. Both surgical teams shared resources, including dieticians, social workers, and a common database, for easy transition between teams.

RESULTS:

The mean starting BMI for all referrals was 46.4 kg/m2 and was 33.9 kg/m2 at the time of transplant. The average number of hypertension medications decreased from 2 (range 2 to 4) presurgery to 1 (range 1 to 3) postsurgery. Similarly, hemoglobin A1C levels improved, with preoperative averages at 6.2 (range 5.4 to 7.6) and postoperative levels at 5.2 (range 4.6 to 5.8) All transplants are currently functioning, with a median creatinine of 1.5 (1.2 to 1.6) mg/dL (glomerular filtration rate 46 [36.3 to 71]).

CONCLUSIONS:

A collaborative approach between bariatric and transplant surgery teams offers a pathway toward transplant for obese ESRD patients and potentially alleviates existing healthcare disparities. ESRD patients who undergo MBS have unique complications to be aware of. The improvement in comorbidities may lead to superior posttransplant outcomes.
Preventing functional decline in hospitalized older adults in medical ward: a best practice implementation project
Authors: Chen Chia-Te , Tung Heng-Hsin , Chen Chi-Wen , Yang Yea-Ru , Wang Jiun-Ling , Chang Chia-Ming , Chen Yen-Chin , Liang Shih-Hsin , Fan Chia-Hao
Published: March 2024

Introduction and objectives:

Functional decline frequently occurs in older adults in hospitals. The aim of this project was to promote evidence-based strategies for physical activity to prevent functional decline in hospitalized older adults in a medical center in southern Taiwan.

Methods:

This project was guided by the JBI Evidence Implementation Framework. Seven audit criteria were derived from a JBI evidence summary and a baseline audit involving 25 nurses and 30 hospitalized older adults was conducted to compare current practice with best practice recommendations. The JBI Getting Research into Practice (GRiP) approach was used to identify barriers to implementation, and strategies were developed to overcome those barriers. A follow-up audit was conducted to measure any changes in compliance.

Results:

After implementing the strategies, the pass rate of nursing staff improved in the physical activity knowledge test, rising from 56% to 88%. Compliance of nursing staff with providing physical activity instructions using evidence-based guidelines to hospitalized older adults reached 80%. The incidence of functional decline among hospitalized older adults decreased from 36.7% to 20%.

Conclusions:

The results of this best practice implementation project suggest that initiating physical activity as early as possible for hospitalized older adults once their medical condition has stabilized can help prevent functional decline.

Spanish abstract:

http://links.lww.com/IJEBH/A171
Prevention and management of enteral nutrition-related diarrhea among adult inpatients: a best practice implementation project
Authors: Zhang Xinyue , Du Meijie , He Mei , Wang Mei , Jiang Mengyao , Cai Yue , Cui Mengying , Wang Ying
Published: March 2024

Introduction:

Diarrhea, the most common complication for patients during enteral nutrition, poses a range of risks and care burdens. Medical staff are aware of the importance of proactively preventing and managing enteral nutrition-related diarrhea. However, clinical prevention and management methods are not standardized, and the scientific basis and effectiveness of these methods need to be further verified.

Objectives:

This project aimed to promote evidence-based practices for the prevention and management of enteral nutrition-related diarrhea among adult inpatients in a public tertiary hospital in China.

Methods:

This project was guided by the JBI Evidence Implementation Framework and used the JBI Practical Application of Clinical Evidence System (PACES) and the JBI Getting Research into Practice (GRiP) tools. Twelve audit criteria were developed to conduct a baseline audit to measure compliance with best practices. A barrier analysis was conducted, and strategies were implemented to overcome the barriers. The project was finalized with a follow-up audit to determine any changes in compliance with best practices.

Results:

The overall compliance rate for the audit criteria increased from 27.37% at baseline to 89.62% in the follow-up audit, with six criteria achieving a compliance rate of 100%.

Conclusions:

The implementation of evidence-based practices can effectively narrow the gap between current practice and best practice. This project improved the ability of medical staff to prevent and manage enteral nutrition-related diarrhea, as well as promoting evidence-based practice in the hospital.

Spanish abstract:

http://links.lww.com/IJEBH/A168
The wake- and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimer’s disease
Authors: Satpati Abhijit , Pereira Felipe L. , Soloviev Alexander V. , Mladinov Mihovil , Larsen Eva , Li Song Hua , Tu Chia-Ling , Leite Renata E. P. , Suemoto Claudia K. , Rodriguez Roberta D. , Paes Vitor R. , Walsh Christine , Spina Salvatore , Seeley William W. , Pasqualucci Carlos A. , Filho Wilson Jacob , Chang Wenhan , Neylan Thomas C. , Grinberg Lea T.
Published: March 2024

Background

Sleep-wake dysfunction is an early and common event in Alzheimer’s disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic neurons (OrxN) and sleep-promoting melanin-concentrating hormone or MCHergic neurons (MCHN). These neurons share close anatomical proximity with functional reciprocity. This study investigated LHA OrxNand MCHNloss patterns in AD individuals. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD.

Methods

Postmortem human brain tissue from donors with AD (across progressive stages) and controls were examined using unbiased stereology. Formalin-fixed, celloidin-embedded hypothalamic sections were stained with Orx-A/MCH, p-tau (CP13), and counterstained with gallocyanin. Orx or MCH-positive neurons with or without CP13 inclusions and gallocyanin-stained neurons were considered for stereology counting. Additionally, we extracted RNA from the LHA using conventional techniques. We used customized Neuropathology and Glia nCounter®(Nanostring) panels to study gene expression. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <.05.

Results

We observed a progressive decline in OrxNalongside a relative preservation of MCHN. OrxNdecreased by 58% (p=.03) by Braak stages (BB) 1-2 and further declined to 81% (p=.03) by BB 5-6. Conversely, MCHNdemonstrated a non-statistical significant decline (27%, p=.1088) by BB 6. We observed a progressive increase in differentially expressed genes (DEGs), starting with glial profile changes in BB2. While OrxNloss was observed, Orx-related genes showed upregulation in BB 3-4 compared to BB 0-1. GO and KEGG terms related to neuroinflammatory pathways were mainly enriched.

Conclusions

To date, OrxNloss in the LHA represents the first neuronal population to die preceding the loss of LC neurons. Conversely, MCHN shows resilience to AD p-tau accumulation across Braak stages. The initial loss of OrxNcorrelates with specific neuroinflammation, glial profile changes, and overexpression of HCRT, possibly due to hyperexcitation following compensation mechanisms. Interventions preventing OrxNloss and inhibiting p-tau accumulation in the LHA could prevent neuronal loss in AD and, perhaps, the progression of the disease.
Sendai virus persistence questions the transient naive reprogramming method for iPSC generation
Authors: De Los Angeles Alejandro , Hug Clemens B. , Gladyshev Vadim N. , Church George M. , Velychko Sergiy
Published: March 2024

Since the revolutionary discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka, the comparison between iPSCs and embryonic stem cells (ESCs) has revealed significant differences in their epigenetic states and developmental potential. A recent compelling study published inNatureby Buckberry et al.1demonstrated that a transient-naive-treatment (TNT) could facilitate epigenetic reprogramming and improve the developmental potential of human iPSCs (hiPSCs). However, the study characterized bulk hiPSCs instead of isolating clonal lines and overlooked the persistent expression of Sendai virus carrying exogenous Yamanaka factors. Our analyses revealed that Sendai genes were expressed in most control PSC samples, including hESCs, which were not intentionally infected. The highest levels of Sendai expression were detected in samples continuously treated with naive media, where it led to overexpression of exogenous MYC, SOX2, and KLF4, altering both the expression levels and ratios of reprogramming factors. Our findings call for further research to verify the effectiveness of the TNT method in the context of delivery methods that ensure prompt elimination of exogenous factors, leading to the generation of bona fide transgene-independent iPSCs.
Molecular mechanism of parental H3/H4 recycling at a replication fork
Authors: Nagae Fritz , Murayama Yasuto , Terakawa Tsuyoshi
Published: March 2024

In eukaryotic chromatin replication, faithful recycling of histones from parental DNA to replicated leading and lagging strands is essential for maintaining epigenetic information across generations. A recent experimental study has revealed that disrupting interactions between the N-terminal disordered tail of Mcm2, a subunit in DNA replication machinery, and a histone H3/H4 tetramer, a carrier of epigenetic modifications, perturbs their faithful recycling. However, the molecular pathways via which the H3/H4 tetramer attached to Mcm2 is recycled to the replicated strands have yet to be deciphered. Furthermore, the factors that regulate the ratio recycled to each strand and the destination location still need to be discovered. The elucidation requires visualization of a structural trajectory from H3/H4 bound to Mcm2 until recycled to the replicated strands. In this study, we performed molecular dynamics simulations of yeast DNA replication machinery (Mcm2-7, Cdc45, GINS, Pol ε, and RPA), an H3/H4 tetramer, and replicated DNA strands. The simulations demonstrated that histones are recycled via Cdc45-mediated and unmediated pathways even without histone chaperones, as ourin vitrobiochemical assays supported. Also, RPA binding to the ssDNA portion of the lagging strand regulated the ratio recycled to each strand, whereas DNA bending by Pol ε modulated the destination location. Together, the simulations in this study provided testable hypotheses, which are vital for clarifying intracellular histone recycling controlled by the cooperation of many histone chaperones.
The unexplored diversity of wild lupins provides rich genomic resources and insights into lupin evolution
Authors: Susek Karolina , Franco Edoardo , Tomaszewska Magdalena , Kroc Magdalena , Jamil Humaira , Tanwar Umesh , Nelson Matthew N. , Papa Roberto , Delledonne Massimo , Jackson Scott A.
Published: March 2024

Lupin crops provide nutritious seeds as an excellent source of dietary protein. However, extensive genomic resources are needed for the adaptation of lupin crops, particularly to improve their nutritional value and facilitate their adaptation to harsh environments caused by the changing climate. Such resources can be derived from crop wild relatives, which represent a large untapped source of genetic variation for crop improvement. Here we describe the first whole-genome sequences of the cross-compatible speciesLupinus cosentinii(Mediterranean) and its pan-Saharan wild relativeL. digitatus, which are well adapted to drought-prone environments and partially domesticated. We found that both species are tetraploids, with similar genome structures, distributions of gene duplications, and numbers of expanded and contracted gene families. The expansion and contraction of gene families that determine seed size, a paradigmatic domestication trait, indicates that gene duplication may have led to morphological adaptations inL. cosentiniiandL. digitatusdiffering from those inL. albus, a domesticated lupin used as a reference. Seed size may therefore reflect convergent evolution mechanisms that play a key role in lupin domestication.
PGBTR: A powerful and general method for inferring bacterial transcriptional regulatory networks
Authors: Gu Wei-Cheng , Ma Bin-Guang
Published: March 2024

Predicting bacterial transcriptional regulatory networks (TRNs) through computational methods is a core challenge in systems biology, and there is still a long way to go. Here we propose a powerful, general, and stable computational framework called PGBTR, which employs Convolutional Neural Networks (CNN) to predict bacterial transcriptional regulatory relationships from gene expression data and genomic information. PGBTR consists of two main components: the input generation step PDGD and the deep learning model CNNBTR. On the realEscherichia coliandBacillus subtilisdatasets, PGBTR outperforms other advanced supervised and unsupervised learning methods in terms of AUROC, AUPR, and F1-score. Moreover, PGBTR exhibits greater stability in identifying real transcriptional regulatory interactions compared to existing methods. PGBTR provides a new software tool for bacterial TRNs inference, and its core ideas can be further extended to other molecular network inference tasks and other biological problems using gene expression data.
Development of alcoholic liver disease model for drug evaluation from human induced pluripotent stem cell derived liver organoids
Authors: Feng Zhiwei , Zhou Bingrui , Shuai Qizhi , Wei Yunliang , Jin Ning , Wang Xiaoling , Zhao Hong , Liu Zhizhen , Xu Jun , Mu Jianbing , Xie Jun
Published: March 2024

Alcoholic liver disease (ALD) poses a significant health challenge, demanding comprehensive research efforts to enhance our comprehension and treatment strategies. However, the development of effective treatments is hindered by the limitations of existing liver disease models. Liver organoids, characterized by their cellular complexity and three-dimensional (3D) tissue structure closely resembling the human liver, hold promise as ideal models for liver disease research. In this study, we employ a meticulously designed protocol involving the differentiation of human induced pluripotent stem cells (hiPSCs) into liver organoids. This process incorporates a precise combination of cytokines and small molecule compounds within a 3D culture system to guide the differentiation process. Subsequently, these differentiated liver organoids are subjected to ethanol treatment to induce ALD, thus establishing a disease model. Rigorous assessment through a series of experiments reveals that this model partially replicates key pathological features observed in clinical ALD, including cellular mitochondrial damage, elevated cellular reactive oxygen species (ROS) levels, fatty liver, and hepatocyte necrosis. In addition, this model offers potential utility in screening drugs for ALD treatment. Taken together, the liver organoids model of ALD, derived from hiPSCs differentiation, emerges as an invaluable platform for advancing our understanding and management of ALD in clinical settings.
Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells
Authors: Myers Chloe G , Viswambharan Hema , Haywood Natalie J , Bridge Katherine , Turvey Samuel , Armstrong Tom , Lunn Lydia , Meakin Paul J , Clavane Eva M , Beech David J , Cubbon Richard M , Wheatcroft Stephen B , McPhillie Martin J , Issad Tarik , Fishwick Colin WG , Kearney Mark T , Simmons Katie J
Published: March 2024

Objectives

The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear. We sought insight by developing a small molecule capable of reducing hybrid formation in endothelial cells.

Methods

We performed a high-throughput small molecule screening, based on a homology model of hybrid structure. Endothelial cells were studied using western blotting and qPCR to determine the effects of small molecules that reduced hybrid formation.

Results

Our studies unveil a first-in-class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells (HUVECs) with no effects on insulin or insulin like growth factor-1 receptors. This small molecule reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, increased basal phosphorylation of the downstream target Akt and enhanced insulin/insulin-like growth factor-1 and shear stress-induced serine phosphorylation of Akt. In primary saphenous vein endothelial cells (SVEC) from patients with type 2 diabetes mellitus undergoing coronary artery bypass (CABG) surgery, hybrid receptor expression was greater than in patients without type 2 diabetes mellitus. The small molecule significantly reduced hybrid expression in SVEC from patients with type 2 diabetes mellitus.

Conclusions

We identified a small molecule that decreases the formation of IR: IGF-1R hybrid receptors in human endothelial cells, without significant impact on the overall expression of IR or IGF-1R. In HUVECs, reduction of IR: IGF-1R hybrid receptors leads to an increase in insulin-induced serine phosphorylation of the critical downstream signalling kinase, Akt. The underpinning mechanism appears, at least in part to involve the attenuation of the adverse effect of IR: IGF-1R hybrid receptors on PI3-kinase signalling.

Highlights

We have discovered a small molecule (HI) that inhibits insulin receptor/IGF-1 receptor hybrid formation.

HI reveals previously unrecognised actions of insulin receptor/IGF-1 receptor hybrids distinct to insulin and IGF-1 receptors in endothelial cells.

Treatment of endothelial cells with HI enhances activity of the downstream signalling kinase Akt due to inhibitory regulation via PI3-K.
MULTIMODAL GRADIENTS UNIFY LOCAL AND GLOBAL CORTICAL ORGANIZATION
Authors: Wang Yezhou , Eichert Nicole , Paquola Casey , Rodriguez-Cruces Raul , DeKraker Jordan , Royer Jessica , Cabalo Donna Gift , Auer Hans , Ngo Alexander , Leppert Ilana , Tardif Christine L. , Rudko David A. , Amunts Katrin , Smallwood Jonathan , Evans Alan C. , Bernhardt Boris C.
Published: March 2024

Specialization of brain areas and subregions, as well as their integration into large-scale networks are key principles in neuroscience. Consolidating both local and global cortical organization, however, remains challenging. Our study developed a new approach to map global, cortex-wise similarities of microstructure, structural connectivity, and functional interactions, and integrate these patterns with maps of cortical arealization. Our analysis combined repeated high-field in-vivo 7 tesla (T) Magnetic Resonance Imaging (MRI) data collected in 10 healthy adults with a recently introduced probabilistic post-mortem atlas of cortical cytoarchitecture. We obtained multimodal eigenvectors describing cortex-wide gradients at the level of microstructural covariance, structural connectivity, and intrinsic functional interactions, and then assessed inter- and intra-area differences in cortex-wide embedding based on these multimodal eigenvectors. Inter-area similarities followed a canonical sensory-fugal gradient, with primary sensorimotor cortex being the most distinctive from all other areas, while paralimbic regions were least distinctive. This pattern largely corresponded to functional connectivity variations across different tasks collected in the same participants, suggesting that the degree of global cortical integration mirrors the functional diversity of brain areas across contexts. When studying heterogeneity within areas, we did not observe a similar relationship, despite overall higher heterogeneity in association cortices relative to paralimbic and idiotypic cortices. Findings could be replicated in a different dataset. Our findings highlight a close coupling between cortical arealization and global cortical motifs in shaping specialized versus integrative human brain function.
A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions
Authors: Fang Jennifer S. , Hatch Christopher J. , Andrejecsk Jillian , Trigt William Van , Juat Damie J. , Chen Yu-Hsi , Matsumoto Satomi , Lee Abe P. , Hughes Christopher C.W.
Published: March 2024

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and may rupture leading to frequent, uncontrolled bleeding. There are few treatment options and no cure for HHT. Most HHT patients are heterozygous for loss-of-function mutations for Endoglin (ENG) or Alk1 (ACVRL1), however, why loss of these genes manifests as vascular malformations remains poorly understood. To complement ongoing work in animal models, we have developed a microphysiological system model of HHT. Based on our existing vessel-on-a-chip (VMO) platform, our fully human cell-based HHT-VMO recapitulates HHT patient vascular lesions. Using inducibleACVRL1(Alk1)-knockdown, we control timing and extent of endogenous Alk1 expression in primary human endothelial cells (EC) in the HHT-VMO. HHT-VMO vascular lesions develop over several days, and are dependent upon timing of Alk1 knockdown. Interestingly, in chimera experiments AVM-like lesions can be comprised of both Alk1-intact and Alk1-deficient EC, suggesting possible cell non-autonomous effects. Single cell RNA sequencing data are consistent with microvessel pruning/regression as contributing to AVM formation, while loss of PDGFB expression implicates mural cell recruitment. Finally, lesion formation is blocked by the VEGFR inhibitor pazopanib, mirroring the positive effects of this drug in patients. In summary, we have developed a novel HHT-on-a-chip model that faithfully reproduces HHT patient lesions and that is sensitive to a treatment effective in patients. The VMO-HHT can be used to better understand HHT disease biology and identify potential new HHT drugs.

Significance

This manuscript describes development of an organ-on-a-chip model of Hereditary Hemorrhagic Telangiectasia (HHT), a rare genetic disease involving development of vascular malformations. Our VMO-HHT model produces vascular malformations similar to those seen in human HHT patients, including small (telangiectasias) and large (arteriovenous malformations) lesions. We show that VMO-HHT lesions are sensitive to a drug, pazopanib, that appears to be effective in HHT human patients. We further use the VMO-HHT platform to demonstrate that there is a critical window during vessel formation in which the HHT gene, Alk1, is required to prevent vascular malformation. Lastly, we show that lesions in the VMO-HHT model are comprised of both Alk1-deficient and Alk1-intact endothelial cells.
Mycobacterium tuberculosisFtsB and PerM interact via a C-terminal helix in FtsB to modulate cell division
Authors: Hensel Zach , Xu Ruilan , Ferreira João Ramalheira
Published: March 2024

Latent infection byMycobacterium tuberculosis(Mtb) impedes effective tuberculosis therapy and eradication. The protein PerM is essential for chronic Mtb infections in mice and acts via the divisome protein FtsB to modulate cell division. Using transgenic co-expression inEscherichia coli, we studied the Mtb PerM-FtsB interaction in isolation from other Mtb proteins, engineering PerM to enhance expression in theE. colimembrane. We confirmed the reported instability of Mtb FtsB, and we linked FtsB instability to a segment of FtsB predicted to bind cell-division proteins FtsL and FtsQ. Using fluorescence microscopy, we found that PerM stability hinged on its interaction with a C-terminal helix in FtsB. Molecular dynamics results supported the observation that FtsB stabilized PerM, and suggested that interactions at the PerM-FtsB interface differ from our initial structure prediction in a way that is consistent with PerM sequence conservation. Though narrowly conserved, the PerM-FtsB interaction emerges as a potential target for therapy targeting persistent infections by disrupting regulation of cell division. Integrating protein structure prediction, molecular dynamics and single-molecule microscopy, our approach is primed to screen potential inhibitors of the PerM-FtsB interaction and can be straightforwardly adapted to explore other putative interactions.
AMPA receptor desensitization shapes gain control in the lateral geniculate nucleus
Authors: Ruggieri Sonia , Gollisch Tim , von Engelhardt Jakob
Published: March 2024

Synaptic short-term plasticity and EPSP summation determine the processing of visual information by dLGN relay cells.In vitrostudies suggested that desensitization of AMPA receptor results in pronounced short-term depression in retinogeniculate synapses thereby influencing activation of relay cells by retinal ganglion cell spikes. However, whether retinogeniculate synapses depress and whether AMPA receptors desensitizein vivois controversial. We here tested the role of AMPA receptor desensitization in processing of visual information by generating a computational model of a dLGN relay cell containing AMPA receptors with different levels of desensitization. In addition, we investigated thein vivoactivity of dLGN relay cells in wildtype and CKAMP44−/−mice. CKAMP44 is an auxiliary subunit that increases desensitization of AMPA receptors in retinogeniculate synapses. The comparison of responses of relay cells in the two genotypes therefore allowed us to obtain information about the contribution of AMPA receptor desensitization in processing of visual information. The simulations and thein vivodata show that AMPA receptor desensitization affects relay cell activity by decreasing input gain and response gain. In addition, desensitization sharpens the response of relay neurons to moving gratings in the temporal domain by decreasing the firing rate when the non-preferred stimulus is presented. Altogether, we uncover a complex role of CKAMP44 and AMPA receptor desensitization in information processing of dLGN relay neuronsin vivo.
Approaching the conformal WZW behavior in the infrared limit of two-dimensional massless QCD: A lattice study
Authors: Karthik Nikhil , Narayanan Rajamani , Narayanan Sruthi A.
Published: March 2024

Two-dimensional QCD with Nc colors and Nf flavors of massless fermions in the fundamental representation is expected to exhibit conformal behavior in the infrared governed by a u(Nf) Wess–Zumino–Witten model with level Nc. Using numerical analysis within the lattice formalism with exactly massless overlap fermions, we show the emergence of such behavior in the infrared limit. Both the continuum extrapolated low-lying eigenvalues of the massless Dirac operator and the propagator of scalar mesons exhibit a flow from the ultraviolet to the infrared. We find that the amplitude of the conserved current correlator remains invariant under the flow, while the amplitude of the scalar correlator approaches Nf-independent values in the infrared.

Published by the American Physical Society
2024
Neutrino window to scalar leptoquarks: From low energy to colliders
Authors: De Romeri Valentina , Lozano Víctor Martín , Garcia G. Sanchez
Published: March 2024

Leptoquarks are theorized particles of either scalar or vector nature that couple simultaneously to quarks and leptons. Motivated by recent measurements of coherent elastic neutrino-nucleus scattering, we consider the impact of scalar leptoquarks coupling to neutrinos on a few complementary processes, from low energy to colliders. In particular, we set competitive constraints on the typical mass and coupling of scalar leptoquarks by analyzing recent COHERENT data. We compare these constraints with bounds from atomic parity violation experiments, deep inelastic neutrino-nucleon scattering and collider data. Our results highlight a strong complementarity between different facilities and demonstrate the power of coherent elastic neutrino-nucleus scattering experiments to probe leptoquark masses in the sub-TeV range. Finally, we also present prospects for improving current bounds with future upgrades of the COHERENT detectors and the planned European Spallation Source.

Published by the American Physical Society
2024
Hints of neutrino dark matter scattering in the CMB? Constraints from the marginalized and profile distributions
Authors: Giarè William , Gómez-Valent Adrià , Di Valentino Eleonora , van de Bruck Carsten
Published: March 2024

We study scatterlike interactions between neutrinos and dark matter in light of different combinations of temperature, polarization and lensing data released by three independent CMB experiments—the Planck satellite, the Atacama Cosmology Telescope (ACT), and the South Pole Telescope (SPT)—in conjunction with baryon acoustic oscillation (BAO) measurements. We apply two different statistical methodologies. Alongside the usual marginalization technique, we cross-check all the results through a profile likelihood analysis. As a first step, working under the assumption of massless neutrinos, we perform a comprehensive (re)analysis aimed at assessing the validity of some recent results hinting at a mild preference for nonvanishing interactions from small-scale CMB data. We find compelling resilience in the results already documented in the literature, confirming that interactions with a strength uνDM∼10−5–10−4 appear to be globally favored by ACT (both alone and in combination with Planck). This result is corroborated by the inclusion of additional data, such as the recent ACT-DR6 lensing likelihood, as well as by the profile likelihood analysis. Interestingly, a fully consistent preference for interactions emerges from SPT, as well, although it is weaker than the one obtained from ACT. As a second step, we repeat the same analysis considering neutrinos as massive particles. Despite the larger parameter space, all the hints pointing towards interactions are confirmed also in this more realistic case. In addition, we report a very mild preference for interactions in Planck+BAO alone (not found in the massless case) which aligns with small-scale data. While this latter result is not fully confirmed by the profile likelihood analysis, the profile distribution does confirm that interactions are not disfavored by Planck.

Published by the American Physical Society
2024
Bootstrapping Deconfined Quantum Tricriticality
Authors: Chester Shai M. , Su Ning
Published: March 2024

The paradigmatic example of deconfined quantum criticality is the Neel to valence bond solid phase transition. The continuum description of this transition is the N=2 case of the CPN−1 model, which is a field theory of N complex scalars in 3D coupled to an Abelian gauge field with SU(N)×U(1) global symmetry. Lattice studies and duality arguments suggest the global symmetry of the

C

P

1

model is enhanced to SO(5). We perform a conformal bootstrap study of SO(5) invariant fixed points with one relevant SO(5) singlet operator, which would correspond to two relevant SU(2)×U(1) singlets, i.e., a tricritical point. We find that the bootstrap bounds are saturated by four different predictions from the large N computation of monopole operator scaling dimensions, which were recently shown to be very accurate even for small N. This suggests that the Neel to valence bond solid phase transition is described by this bootstrap bound, which predicts that the second relevant singlet has dimension ≈2.36.

Published by the American Physical Society
2024