bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive tests for alcohol-associated liver disease
Authors: Israelsen Mads , Rungratanawanich Wiramon , Thiele Maja , Liangpunsakul Suthat
Published: April 2024

Alcohol consumption is a global phenomenon and a major contributor to alcohol-associated liver disease (ALD). Detecting individuals at risk of ALD has been challenging, with only a small fraction of patients being identified at early stages compared to other chronic liver diseases. In response to this challenge, non-invasive tests (NITs) have become essential tools for the detection of ALD, offering opportunities for early identification and intervention to mitigate the disease burden. Noninvasive alcohol consumption biomarkers are crucial in estimating individuals’ recent alcohol intake, providing valuable insights into their drinking patterns. Various NITs have been investigated for the initial screening of asymptomatic individuals at risk of ALD, as well as for identifying specific stages of the disease. These NITs are applied in 2 main clinical scenarios: population-based stratification for identifying and predicting liver-related symptoms and diagnosing and prognosticating compensated cirrhosis or advanced chronic liver disease in secondary or tertiary care settings. Moreover, NITs play a significant role in the prognostic assessment of patients with various manifestations of ALD, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and metabolic-associated and ALD. These tests guide appropriate treatment decisions and predict outcomes. In this review, various NITs for the early detection and monitoring of alcohol consumption were discussed. Additionally, the evaluation of NITs for screening and predicting ALD and liver complications was addressed comprehensively. Future perspectives of NITs for ALD were explored, alongside a thorough discussion of the opportunities and challenges associated with NITs for ALD screening.
Incidence, clinical features, and risk factors of hemocoagulase-induced hypofibrinogenemia: A retrospective real-world study
Authors: Ma Wenming , Zhao Ting , Yu Lihong , Liu Wenyu , Wang Hang , Zhao Pengfei
Published: April 2024

The objective of this study was to explore the real-world incidence, severity, clinical features, and potential risk factors associated with hypofibrinogenemia induced by hemocoagulase. Based on Chinese Hospital Pharmacovigilance System, a retrospective case–control study was conducted, enrolling hospitalized patients who received hemocoagulase for the treatment or prevention of hemorrhage in Weifang People’s Hospital in China from January 2021 to May 2022. Univariate and multivariate logistic regression was performed to analyze the potential risk factors. Out of 10,397 hospitalized patients who received hemocoagulase, 341 patients showed positive triggers, with 235 patients ultimately conformed as hemocoagulase-associated hypofibrinogenemia. The system positive alarm rate was 68.91%, and the overall incidence of hemocoagulase-induced hypofibrinogenemia was 2.26%, predominantly characterized by mild to moderate severity levels. The incidence varied among the 4 types of hemocoagulase, with the highest incidence observed in hemocoagulaseAgkistrodon Halys Pallasat 4.59%. The incidence of hemocoagulase fromDeinagkistrodon acutus, Bothrops AtroxandAdderwere 0.97%, 0.44% and 0.12%, respectively. Multivariate logistic regression analysis revealed that age (odds ratios [OR] = 177.328,P < .001), source of snake venom (OR = 5.641,P < .05), albumin (OR = 2.487,P < .001), and cumulative dosage (OR = 1.106,P < .001) were independent risk factors. Increased risk of hemocoagulase-related hypofibrinogenemia may be associated with children, elderly patients, low albumin levels, high cumulative doses and hemocoagulase fromAgkistrodon Halys Pallas. Early recognition and close drug monitoring for these high-risk patients are vital in clinical practice.
Trending of small bowel adenocarcinoma research from 2000 to 2022: A bibliometric analysis
Authors: Li Li , Zhang Shao , Fu Guang
Published: April 2024

Small bowel adenocarcinoma (SBA) is a rare tumor entity with a relatively poor prognosis. Diagnosis and management of SBA are still challenging despite recent advancement of diagnostic methods and publication of guidelines. This study aimed to analyze and visualize the trending of SBA research in the past 22 years in the 21st century through bibliometric analysis. Our study collected 1270 publication records of SBA from 2000 Jan 1st to 2022 December 31 from Web of Science and used VOSviewer and CiteSpace to analyze countries, institutions, journals, authors, references and keywords to present the latest trends in SBA research. The USA was the most productive country in terms of the total number of publications (n = 418). The Mayo Clinic (n = 22) and University of Texas MD Cancer Center (n = 22) were the institutions with top publications. The “World Journal Of Gastroenterology” (n = 30) had the largest publications. Overman Michael J (n = 17) was the most active and prolific author. The “small bowel adenocarcinoma” was the most frequent keyword. Our bibliometric analysis provides a comprehensive overview of the trends and gaps in the research of SBA. Despite the challenges faced, researchers from USA, Japan and China have made significant contributions to the field of SBA research, and further research is necessary to develop evidence-based guidelines, and advance the understanding and management of SBA.
Thiazides for kidney stone recurrence prevention
Authors: Bargagli Matteo , Trelle Sven , Bonny Olivier , Fuster Daniel G.
Published: April 2024

Purpose of review

Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation.

Recent findings

The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence.

Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones.
Intralobar pulmonary sequestration: a rare cause of hemoptysis: a case report
Authors: Khandelwal Shreya , Mittal Aman , Sharma Shruti , Prasad Abhishek , Singh Roshan , Shah Anil , Lageju Nimesh
Published: April 2024

Overview and significance:

Pulmonary sequestration (PS) is a rare congenital anomaly characterized by aberrant formation of nonfunctional lung tissue with anomalous systemic blood supply. Despite its rarity, PS presents significant diagnostic and management challenges, often necessitating a multidisciplinary approach for optimal patient outcomes. This case report provides insights into the clinical presentation, diagnostic modalities, and management strategies for PS.

Case summary:

The authors present a case of a 30-year-old male who complained of chronic cough and hemoptysis and was eventually diagnosed with intralobar PS by computed tomography (CT) imaging. The patient underwent a surgical procedure, specifically a lobectomy, to address the lung tissue.

Clinical discussion:

The diagnosis of intralobar PS is confirmed by CT imaging, showing features of abnormalities, including irregular cystic communication. A large area with abnormal systemic arterial supply and variable venous fluid. This patient presented with symptoms consistent with PS, including chronic cough and hemoptysis, highlighting the importance of timely diagnosis and intervention to prevent life-threatening complications.

Conclusion:

Lung sequestration has diagnostic challenges due to its variable clinical presentation and potential for misdiagnosis. However, advances in technology, such as CT angiography, make accurate diagnosis and precise surgical planning easier. Prompt intervention via lobectomy or transarterial embolization is important to reduce the risk of life-threatening complications associated with PS. These data highlight the importance of multidisciplinary collaboration between physicians, radiologists, and surgeons to effectively manage PS and improve patient outcomes.
Bidirectional relationship between pancreatic cancer and diabetes mellitus: a comprehensive literature review
Authors: Sapoor Shady , Nageh Mahmoud , Shalma Noran Magdy , Sharaf Rana , Haroun Nooran , Salama Esraa , Pratama Umar Tungki , Sharma Sadish , Sayad Reem
Published: April 2024

Pancreatic cancer (PC) is a fatal malignant disease. It is well known that the relationship between PC and type 2 diabetes mellitus (T2DM) is a complicated bidirectional relationship. The most important factors causing increased risks of pancreatic cancer are hyperglycaemia, hyperinsulinemia, pancreatitis, and dyslipidemia. Genetics and the immune system also play an important role in the relationship between diabetes mellitus and pancreatic cancer. The primary contributors to this association involve insulin resistance and inflammatory processes within the tumour microenvironment. The combination of diabetes and obesity can contribute to PC by inducing hyperinsulinemia and influencing leptin and adiponectin levels. Given the heightened incidence of pancreatic cancer in diabetes patients compared to the general population, early screening for pancreatic cancer is recommended. Diabetes negatively impacts the survival of pancreatic cancer patients. Among patients receiving chemotherapy, it reduced their survival. The implementation of a healthy lifestyle, including weight management, serves as an initial preventive measure to mitigate the risk of disease development. The role of anti-diabetic drugs on survival is controversial; however, metformin may have a positive impact, especially in the early stages of cancer, while insulin therapy increases the risk of PC.
Neighborhood violent crime exposure is associated with preexposure prophylaxis nonuse among black sexually minoritized men and transgender women
Authors: Flores John M. , Moline Tyrone , Regan Seann D. , Chen Yen-Tyng , Shrader Cho-Hee , Schneider John A. , Duncan Dustin T. , Kim Byoungjun
Published: April 2024

Objective:

The objective of this study is to use GPS technology to determine if violent and property crime exposure to participants activity spaces affect outcomes of the HIV prevention and care continuum (PCC) among Young black sexually minoritized men (YBSMM) and transgender women (TGW), a subgroup at high vulnerability for new HIV diagnoses. Exposure to violent and property crime adversely affects a variety of acute and chronic medical conditions; however, the relationship between exposure to violent and property crime and HIV risk [e.g. preexposure prophylaxis (PrEP) nonuse] is unknown. Spatial analytic analysis using dynamic Global Position Systems (GPS) technology can accurately detect geospatial associations between the crime exposure and objective HIV-related outcomes.

Methods:

With the Neighborhoods and Networks (N2) Cohort Study, GPS technology to identify the activity space of 286 [123 people with HIV (PWH) and 163 people without HIV (PWoH)] YBSMM and TGW living in Chicago, Illinois, to identified spatial associations between violent and property crime exposures with HIV PCC outcomes.

Results:

We found that YBSMM and TGW with higher exposure areas with higher levels of violent crime were less likely to use HIV PrEP therapy [adjusted odds ratio (aOR) 0.76, 95% confidence interval (CI) 0.63–0.91, P = 0.03].

Conclusion:

This study demonstrates the importance of clinical providers to consider violent crime as a potential sociostructural barrier that may impact medication adherence and healthcare outcomes among vulnerable populations. Additionally, GPS technology offers an alternative data analytic process that may be used in future studies to assist in identifying barriers to ending the HIV epidemic.
The Role of High-Resolution Manometry Before and Following Antireflux Surgery
Authors: Salvador Renato , Pandolfino John E. , Costantini Mario , Gyawali Chandra Prakash , Keller Jutta , Mittal Sumeet , Roman Sabine , Savarino Edoardo V. , Tatum Roger , Tolone Salvatore , Zerbib Frank , Capovilla Giovanni , Jain Anand , Kathpalia Priya , Provenzano Luca , Yadlapati Rena ,   the HRM & Foregut Surgery International Working Group
Published: April 2024

Background:

In the last 2 decades the development of high-resolution manometry (HRM) has changed and revolutionized the diagnostic assessment of patients complain foregut symptoms. The role of HRM before and after antireflux procedure remains unclear, especially in surgical practice, where a clear understanding of esophageal physiology and hiatus anatomy is essential for optimal outcome of antireflux surgery (ARS). Surgeons and gastroenterologists (GIs) agree that assessing patients following antireflux procedures can be challenging. Although endoscopy and barium-swallow can reveal anatomic abnormalities, physiological information on HRM allowing insight into the cause of eventually recurrent symptoms could be key to clinical decision-making.

Methods:

A multidisciplinary international working group (14 surgeons and 15 GIs) collaborated to develop consensus on the role of HRM pre-ARS and post-ARS, and to develop a postoperative classification to interpret HRM findings. The method utilized was detailed literature review to develop statements, and the RAND/University of California, Los Angeles Appropriateness Methodology (RAM) to assess agreement with the statements. Only statements with an approval rate >80% or a final ranking with a median score of 7 were accepted in the consensus. The working groups evaluated the role of HRM before ARS and the role of HRM following ARS.

Conclusions:

This international initiative developed by surgeons and GIs together, summarizes the state of our knowledge of the use of HRM pre-ARS and post-ARS. The Padova Classification was developed to facilitate the interpretation of HRM studies of patients underwent ARS.
Development of a Large Animal Model of Ischemia-free Liver Transplantation in Pigs
Authors: Tang Yunhua , Li Jiahao , Wang Tielong , Zhang Zhiheng , Huang Shanzhou , Zhu Zebin , Wang Linhe , Zhao Qiang , Guo Zhiyong , He Xiaoshun
Published: April 2024

Background.

In organ transplantation, ischemia, and reperfusion injury (IRI) is considered as an inevitable event and the major contributor to graft failure. Ischemia-free liver transplantation (IFLT) is a novel transplant procedure that can prevent IRI and provide better transplant outcomes. However, a large animal model of IFLT has not been reported. Therefore, we develop a new, reproducible, and stable model of IFLT in pigs for investigating mechanisms of IFLT in IRI.

Methods.

Ten pigs were subjected to IFLT or conventional liver transplantation (CLT). Donor livers in IFLT underwent 6-h continuous normothermic machine perfusion (NMP) throughout graft procurement, preservation, and implantation, whereas livers in CLT were subjected to 6-h cold storage before implantation. The early reperfusion injury was compared between the 2 groups.

Results.

Continuous bile production, low lactate, and liver enzyme levels were observed during NMP in IFLT. All animals survived after liver transplantation. The posttransplant graft function was improved with IFLT when compared with CLT. Minimal histologic changes, fewer apoptotic hepatocytes, less sinusoidal endothelial cell injury, and proinflammatory cytokine (interleukin [IL]-1β, IL-6, and tumor necrosis factor-α) release after graft revascularization were documented in the IFLT group versus the CLT group.

Conclusions.

We report that the concept of IFLT is achievable in pigs. This innovation provides a potential strategy to investigate the mechanisms of IRI and provide better transplant outcomes for clinical practice.
Use of a Belatacept-based Immunosuppression for Kidney Transplantation From Donors After Circulatory Death: A Paired Kidney Analysis
Authors: Eid Rita , Scemla Anne , Giral Magali , Arzouk Nadia , Bertrand Dominique , Peraldi Marie-Noëlle , Mesnard Laurent , Longuet Helene , Maanaoui Mehdi , Desbuissons Geoffroy , Lefevre Edouard , Snanoudj Renaud
Published: April 2024

Background.

Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death.

Methods.

In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2).

Results.

There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed.

Conclusions.

The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.
Very Low Frequency of Pathological Findings in One-year Protocol Biopsies of Uneventful Standard Risk Kidney Transplant Recipients: Results From the Nordic Protocol Biopsy Study
Authors: Helanterä Ilkka , Dörje Christina , Ortiz Fernanda , Varberg Reisæter Anna , Hammarström Clara , Lauronen Jouni , Räisänen-Sokolowski Anne , Haugen Anders Johan , Lempinen Marko , Åsberg Anders , Mjøen Geir
Published: April 2024

Background.

The clinical significance of kidney transplant protocol biopsies has been debated. We studied the frequency of borderline changes and T cell–mediated rejection (TCMR) in 1-y protocol biopsies in standard risk kidney transplant recipients.

Methods.

Consecutive non-HLA-sensitized recipients of kidney transplants between 2006 and 2017, who underwent a protocol biopsy at 1 y in 2 national transplant centers were studied retrospectively (N = 1546). Donor-specific HLA antibodies (DSAs), graft function (plasma creatinine), and proteinuria were measured at the time of 1-y protocol biopsy. The occurrence of subclinical acute TCMR (i2t2v0 or higher) or borderline changes suspicious of TCMR (i1t1v0 or higher) in the protocol biopsy was studied, together with frequency of findings causing changes in the composite score iBox.

Results.

Subclinical acute TCMR was detected in 30 of 1546 (1.9%) of the protocol biopsies, and borderline or TCMR in 179 of 1546 (12%). Among patients with no history of acute rejection, and no proteinuria or DSA, TCMR was detected in only 1 of 974 (0.1%) and borderline or TCMR in only 48 of 974 (4.9%) patients at 1 y. In the absence of proteinuria (<30 mg/g, or equivalent as measured with a negative dipstick proteinuria) or DSA, or history of acute rejection, only 50 of 974 (5.1%) biopsies showed any lesions significant for the iBox score.

Conclusions.

The likelihood of pathological findings in 1-y protocol biopsies in non-HLA-sensitized patients without previous immunological events is low. Clinical usefulness of protocol biopsies seems limited in these patients.
Assessment and management of constipation in post-operative patients in the spinal surgery ward: a best practice implementation project
Authors: Luo Qin , Li Yanting , Guo Jia , Chen Jiarui , Chen Qirong , Sun Mei
Published: April 2024

Introduction and objective:

Constipation is a common complication following spinal surgery that can result in distension, abdominal pain, infection, and even intestinal perforation. This study reports on an evidence-based implementation project to reduce the incidence of constipation in spinal surgery wards.

Methods:

The project was conducted in the spinal surgery ward of a general tertiary hospital in Changsha City, China, from March to August 2022. We used the JBI Implementation Framework and the JBI Model of Evidence-Based Healthcare for audits and feedback. Data were collected and analyzed using JBI's Practical Application of Clinical Evidence System (PACES) software. Seven audit criteria were developed based on the best practice recommendations summarized by JBI. A baseline audit was conducted with 20 nurses and 50 patients in the spinal surgery ward, and a follow-up audit was conducted using the same sample size and setting.

Results:

The baseline audit revealed compliance below 46% for five of the seven criteria. Strategies developed to address poor compliance included educating nurses and patients, developing a post-operative constipation risk assessment sheet, organizing stakeholder focus group meetings, establishing a constipation management routine, and effective empowerment of nurses. The follow-up audit showed positive compliance results, with the highest rate for Criterion 7 (100%) and the greatest increase for Criterion 2 (from 0% to 78%). Furthermore, the incidence of post-operative constipation decreased from 48% to 16%.

Conclusion:

The project improved compliance with audit criteria, reduced the incidence of constipation, and enhanced the efficiency of quality management in the spinal surgery ward.

Spanish abstract:

http://links.lww.com/IJEBH/A186
Paenibacillus thermotolerans sp. nov., isolated from a hot spring in Yunnan Province, south-west China
Authors: Xiang Ming-Xian , Yin Min , Zhang Dian-Yan , Wang Juan , Miao Yong-Mei , Cai Man , Zhou Yu-Guang , Miao Cui-Ping , Tang Shu-Kun
Published: April 2024

Two Gram-positive, rod-shaped, endospore-forming strains, YIM B05601 and YIM B05602T, were isolated from soil sampled at Hamazui hot spring, Tengchong City, Yunnan Province, PR China. Phylogenetic analysis based on 16S rRNA gene sequences suggested that the two strains fell within the genus Paenibacillus, appearing most closely related to Paenibacillus alkalitolerans YIM B00362T (96.9 % sequence similarity). Genome-based phylogenetic analysis confirmed that strains YIM B05601 and YIM B05602T formed a distinct phylogenetic cluster within the genus Paenibacillus. The average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values of strains YIM B05601 and YIM B05602T with the related species P. alkalitolerans YIM B00362T were within the ranges of 74.43–74.57 % and 12.1–18.5 %, respectively, which clearly indicated that strains YIM B05601, YIM B05602T represented a novel species. Strains YIM B05601 and YIM B05602T exhibited 99.6 % 16S rRNA gene sequence similarity. The ANI and dDDH values between the two strains were 99.8 and 100 %, respectively, suggesting that they belong to the same species. Optimum growth for both strains occurred at pH 7.0 and 45 °C. The diagnostic diamino acid in the cell-wall peptidoglycan of strains YIM B05601 and YIM B05602T was meso-diaminopimelic acid. MK-7 was the predominant menaquinone. The polar lipids of strain YIM B05602T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, four unidentified glycolipids, an unidentified polarlipid and phosphatidylinositol mannoside. The major fatty acids of the two stains were iso-C15 : 0 and anteiso-C15 : 0. Based on phylogenomic and phylogenetic analyses coupled with phenotypic and chemotaxonomic characterizations, strains YIM B05601 and YIM B05602T could be classified as a novel species of the genus Paenibacillus, for which the name Paenibacillus thermotolerans sp. nov. is proposed. The type strain is YIM B05602T (=CGMCC 1.60051T=KCTC 43460T=NBRC 115924T).
No Reliable Evidence Supports the Presence of Javan Tigers - Data Issues Related to the DNA Analysis of a Recent Hair Sample
Authors: Sui Zheng-Yan , Yamaguchi Nobuyuki , Liu Yue-Chen , Xue Hao-Ran , Sun Xin , Nyhus Philip , Luo Shu-Jin
Published: April 2024

A paper recently published inOryxby Wirdateti et al. (2024) suggests that the extinct Javan tiger may still survive on the Island of Java, Indonesia, based on mtDNA analysis of a single hair collected from a claimed tiger encounter site. After carefully re-analyzing the data presented in Wirdateti et al. (2024), we conclude that there is little support for the authors’ statements. Importantly, the sequences of the putative tiger hair and museum Javan tiger specimens generated by the authors are not from tiger cytoplasmic mitochondrial DNA but more likely the nuclear copies of mitochondrial DNA. In addition, the high mismatches found between the two “Javan tiger” sequences generated by the authors is unusual for homologous sequences that are both from tigers and hence indicative of data unreliability. Yet, too few details regarding the quality control were provided in Wirdateti et al. (2024) to rule out the possibility of contamination introduced during the data production process. In conclusion, it is inappropriate to use these unreliable sequences presented in Wirdateti et al. (2024) to infer the existence of the Javan tiger.
Reduction of right-hemispheric auditory cortex activity in response to speech in more experienced paediatric cochlear implant users
Authors: Kropf Björn , Rao Madhuri Sharma , Gutschalk Alexander , Andermann Martin , Praetorius Mark , Rupp André , Steinmetzger Kurt
Published: April 2024

In case of severe hearing loss early in life or congenital deafness, cochlear implants (CIs) represent the method of choice to restore hearing and enable language acquisition. While speech intelligibility has been shown to improve during the first year after implantation to then reach a plateau, the underlying neuroplastic changes are poorly understood. Here, we longitudinally compared the cortical processing of speech stimuli in a case-control design with two groups of pre-lingually deafened CI users (4.4 vs. 25.8 months of CI experience) and an age-matched control group with normal hearing (NH; mean group ages ∼9 years). In two experiments, participants were presented with running speech and vowel sequences while fNIRS and EEG data were obtained simultaneously. Despite trends in this direction, cortical activity did not increase significantly with more CI experience and did not approach the higher levels observed in the NH controls. However, in the speech experiment, the less experienced CI group showed an abnormal shift of activity to the right hemisphere not observed in the other two groups. These results hence imply that adaptation to CI-based hearing is not characterised by a gradual increase of activity in left-hemispheric language network, but a reduction of abnormal activity elsewhere.
Optimised control of adaptive evolution with competing selective pressures
Authors: Corrao Marco , Abrahams Gabriel , Steel Harrison
Published: April 2024

The development of methods to understand and control the population dynamics of microbial evolution remains an outstanding question in synthetic biology and biotechnology more broadly. Due to the stochastic nature of evolution, its limited observability, and complex intra-population dynamics, this presents a significant challenge. In this paper, we explore techniques to control the evolutionary dynamics of a population, based on manipulation of one or two orthogonal selective pressures, which may in turn be coupled to mutagenesis. Our approach builds on past research in evolutionary biology that developed frameworks to study intra-population variant competition during asexual adaptive processes (i.e. clonal interference). Extending this theory, we design optimal control strategies for one (or more) selective pressures that can be used to maximise the rate of adaptation across a population as a whole. We introduce a theoretical modelling framework for this process, which we support with both simulations and preliminary experimental data, providing a concrete basis for emerging control approaches to directed evolution and evolution-aware design.
Connectome caricatures: removing large-amplitude co-activation patterns in resting-state fMRI emphasizes individual differences
Authors: Rodriguez Raimundo X. , Noble Stephanie , Camp Chris C. , Scheinost Dustin
Published: April 2024

High-amplitude co-activation patterns are sparsely present during resting-state fMRI but drive functional connectivity1–5. Further, they resemble task activation patterns and are well-studied3,5–10. However, little research has characterized the remaining majority of the resting-state signal. In this work, we introduced caricaturing—a method to project resting-state data to a subspace orthogonal to a manifold of co-activation patterns estimated from the task fMRI data. Projecting to this subspace removes linear combinations of these co-activation patterns from the resting-state data to create Caricatured connectomes. We used rich task data from the Human Connectome Project (HCP)11and the UCLA Consortium for Neuropsychiatric Phenomics12to construct a manifold of task co-activation patterns. Caricatured connectomes were created by projecting resting-state data from the HCP and the Yale Test-Retest13datasets away from this manifold. Like caricatures, these connectomes emphasized individual differences by reducing between-individual similarity and increasing individual identification14. They also improved predictive modeling of brain-phenotype associations. As caricaturing removes group-relevant task variance, it is an initial attempt to remove task-like co-activations from rest. Therefore, our results suggest that there is a useful signal beyond the dominating co-activations that drive resting-state functional connectivity, which may better characterize the brain’s intrinsic functional architecture.
Abnormal morphology and synaptogenic signaling in astrocytes following prenatal opioid exposure
Authors: Niebergall Ethan B. , Weekley Daron , Mazur Anna , Olszewski Nathan A. , DeSchepper Kayla M. , Radant N. , Vijay Aishwarya S. , Risher W. Christopher
Published: April 2024

In recent decades, there has been a dramatic rise in the rates of children being born afterin uteroexposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a strong influence on synaptic development, secreting factors that both promote and inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist, buprenorphine, on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, suggestive of a complex neuroadaptive response that maintains synaptogenic pathways in the face of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LD), suggestive of a maladaptive stress response in the developing nervous system.
Adjacent Neuronal Fascicle Guides Motoneuron 24 Dendritic Branching and Axonal Routing Decisions through Dscam1 Signaling
Authors: Bui Kathy Clara , Kamiyama Daichi
Published: April 2024

The formation and precise positioning of axons and dendrites are crucial for the development of neural circuits. Although juxtracrine signaling via cell-cell contact is known to influence these processes, the specific structures and mechanisms regulating neuronal process positioning within the central nervous system (CNS) remain to be fully identified. Our study investigates motoneuron 24 (MN24) in theDrosophilaembryonic CNS, which is characterized by a complex yet stereotyped axon projection pattern, known as ‘axonal routing.’ In this motoneuron, the primary dendritic branches project laterally toward the midline, specifically emerging at the sites where axons turn. We observed that Scp2-positive neurons contribute to the lateral fascicle structure in the ventral nerve cord (VNC) near MN24 dendrites. Notably, the knockout of the Down syndrome cell adhesion molecule (dscam1) results in the loss of dendrites and disruption of proper axonal routing in MN24, while not affecting the formation of the fascicle structure. Through cell-type specific knockdown and rescue experiments of dscam1, we have determined that the interaction between MN24 and Scp2-positive fascicle, mediated by Dscam1, promotes the development of both dendrites and axonal routing. Our findings demonstrate that the holistic configuration of neuronal structures, such as axons and dendrites, within single motoneurons can be governed by local contact with the adjacent neuron fascicle, a novel reference structure for neural circuitry wiring.

Significance Summary

We uncover a key neuronal structure serving as a guiding reference for neural circuitry within theDrosophilaembryonic CNS, highlighting the essential role of an adjacent axonal fascicle in precisely coordinating axon and dendrite positioning in motoneuron 24 (MN24). Our investigation of cell-cell interactions between motoneurons and adjacent axonal fascicles— crucial for initiating dendrite formation, soma migration, and axonal pathfinding in MN24— emphasizes the neuronal fascicle’s significance in neural circuit formation through Dscam1-mediated inter-neuronal communication. This enhances our understanding of the molecular underpinnings of motoneuron morphogenesis inDrosophila. Given the occurrence of analogous axon fascicle formations within the vertebrate spinal cord, such structures may play a conserved role in the morphogenesis of motoneurons via Dscam1 across phyla.
Using Eye Gaze to Train an Adaptive Myoelectric Interface
Authors: Chou Amber H.Y. , Madduri Maneeshika , Li Si Jia , Isa Jason , Christensen Andrew , Hutchison Finley (Liya) , Burden Samuel A. , Orsborn Amy L.
Published: April 2024

Myoelectric interfaces hold promise in consumer and health applications, but they are currently limited by variable performance across users and poor generalizability across tasks. To address these limitations, we consider interfaces that continually adapt during operation. Although current adaptive interfaces can reduce inter-subject variability, they still generalize poorly between tasks because they make use of task-specific data during training. To address this limitation, we propose a new paradigm to adapt myoelectric interfaces using natural eye gaze as training data. We recruited 11 subjects to test our proposed method on a 2D computer cursor control task using high-density surface EMG signals measured from forearm muscles. We find comparable task performance between our gaze-trained paradigm and the current task-dependent method. This result demonstrates the feasibility of using eye gaze to replace task-specific training data in adaptive myoelectric interfaces, holding promise for generalization across diverse computer tasks.

CCS Concepts

• Human-centered computing → Interaction devices; Empirical studies in HCI.
A tale of two tumors: differential, but detrimental, effects of glioblastoma extracellular vesicles (EVs) on normal human brain cells
Authors: Wang Mary , Graner Arin N. , Knowles Bryne , McRae Charlotte , Fringuello Anthony , Paucek Petr , Gavrilovic Michael , Redwine McKenna , Hanson Caleb , Coughlan Christina , Metzger Brooke , Bolus Vince , Kopper Timothy , Smith Marie , Zhou Wenbo , Lenz Morgan , Abosch Aviva , Ojemann Steven , Lillehei Kevin O. , Yu Xiaoli , Graner Michael W.
Published: April 2024

Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM EVs dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). EVs from different patient-derived GBM spheroids induced differential transcriptomic, secretomic, and proteomic effects on cultured astrocytes/brain tissue slices as GBM EV recipients. The net outcome of brain cell differential changes nonetheless converges on increased tumorigenicity. GBM spheroids and brain slices were derived from neurosurgical patient tissues following informed consent. Astrocytes were commercially obtained. EVs were isolated from conditioned culture media by ultrafiltration, ultraconcentration, and ultracentrifugation. EVs were characterized by nanoparticle tracking analysis, electron microscopy, biochemical markers, and proteomics. Astrocytes/brain tissues were treated with GBM EVs before downstream analyses. EVs from different GBMs induced brain cells to alter secretomes with pro-inflammatory or TME-modifying (proteolytic) effects. Astrocyte responses ranged from anti-viral gene/protein expression and cytokine release to altered extracellular signal-regulated protein kinase (ERK1/2) signaling pathways, and conditioned media from EV-treated cells increased GBM cell proliferation. Thus, astrocytes/brain slices treated with different GBM EVs underwent non-identical changes in various ‘omics readouts and other assays, indicating “personalized” tumor-specific GBM EV effects on the TME. This raises concern regarding reliance on “model” systems as a sole basis for translational direction. Nonetheless, net downstream impacts from differential cellular and TME effects still led to increased tumorigenic capacities for the different GBMs.
Realized flower constancy in bumble bees: optimal foraging strategy balancing cognitive and travel costs and its possible consequences for floral diversity
Authors: Takagi Kentaro , Ohashi Kazuharu
Published: April 2024

Pollinating insects often exhibit flower constancy, i.e., the tendency to make consecutive visits to the same flower species while disregarding others. This behaviour is commonly attributed to the cost of retrieving visual or motor memories from long-term storage while switching between flowers with distinct colours and shapes. Accordingly, researchers often predict co-flowering species to exhibit significantly greater phenotypic diversity than random expectation, thereby minimizing heterospecific pollen transfer. However, field observations have not consistently supported this notion.

The observed inconsistencies may arise from variations in travel costs, which depend on the interaction between the forager’s constancy level and the spatial mixing of plant species. If species are evenly mixed, constant pollinators incur higher levels of travel cost due to frequent skipping of neighbouring flowers. In contrast, if species are patchily distributed, constant pollinators experience lower levels of travel cost, as most neighbours are of the same species. Considering this, ‘realized flower constancy’ may be determined as an optimal strategy for balancing cognitive and travel costs, which dynamically vary across different degrees of spatial species mixing. Here we test this possibility in indoor experiments with bumble bees foraging from two differently coloured artificial flowers (’species’) arranged at three mixing levels.

First, bees dramatically reduced flower constancy as species mixing increased, irrespective of flower spacing. Second, bees were less inclined to switch species after accumulating consecutive visits to one species, suggesting a rapid decay of another species’ information in short-term memory back to long-term storage. This effect may have additionally contributed to the increased flower constancy observed in species with patchy distributions. Third, bees showed minimal constancy for similarly coloured, evenly mixed flower species, suggesting that these flowers were operated with shared short-term memory. The constancy level was hardly affected by colour similarity when species were patchily distributed.

Results support our initial hypothesis that realized flower constancy reflects an optimal foraging strategy rather than a fixed outcome of cognitive limitation. Notably, bees’ constancy increased significantly with greater colour difference only when species were evenly mixed, suggesting a novel perspective: spatial mixing promotes the evolution and maintenance of floral diversity.
Empirical Bayes spline model learns multi-way genomic interactions from single cell 3D genome data
Authors: Park Kwangmoon , Keleş Sündüz
Published: April 2024

A number of foundational analysis methods have emerged for single cell chromatin conformation (scHi-C) datasets capturing 3D organizations of genomes at the single cell resolution; however, these scHi-C datasets are currently under-utilized. The canonical uses of the existing scHi-C data encompass, beyond standard cell type identification through clustering and trajectory analysis, inference of chromosomal structures such as topologically associated domains, A/B compartments, and pairwise interactions. However, multi-way interactions, e.g., looping among multiple genomic elements such as multiple enhancers of a gene, are entirely overlooked. We introduceELECT, an empirical Bayes modelling framework toExtract muLti-way gEnomiCinTeractions by leveraging scHi-C data. ELECT builds on a dirichlet-multinomial spline model, incorporates well-known genomic distance bias of the chromatin conformation capture data, and yields multi-way interaction scores by leveraging corresponding pairwise interactions across cells of the same type. The multinomial-poisson transformation enables parameter estimation and inference for ELECT in a computationally feasible way for both low and high resolution single cell chromatin conformation data. ELECT yields well-calibrated p-values for controlling the false discovery rate and inferring multi-way interactions. We applied ELECT to both low and high resolution scHi-C datasets and carried out evaluations with external genomic and epigenomic data including data from DNA methylation, SPIRITE, scNanoHi-C, and DNA seqFISH+ assays. Application of ELECT to scHi-C data from human prefrontal cortex revealed multi-way interactions that involved GWAS SNPs associated with psychiatric disorders including autism and major depressive disorder, suggesting ELECT’s potential for interrogating genomewide association studies for epistasis. ELECT is publicly available athttps://github.com/keleslab/elect.
Silybin A fromSilybum marianumreprograms lipid metabolism to induce a cell fate-dependent class switch from triglycerides to phospholipids
Authors: Koeberle Solveigh C. , Thürmer Maria , Werner Markus , Grander Julia , Hofer Laura , Gollowitzer André , Su Fengting , Le Xuan Loc , Benscheid Felix J. , Bonyadi Rad Ehsan , Zarrelli Armando , Di Fabio Giovanni , Werz Oliver , Romanucci Valeria , Lupp Amelie , Koeberle Andreas
Published: April 2024

Silybum marianumis used to protect against degenerative liver damage. The molecular mechanisms of its bioactive component, silybin, remained enigmatic, although membrane-stabilizing properties, modulation of membrane protein function, and metabolic regulation have been discussed for decades. Here, we show that specifically the stereoisomer silybin A decreases triglyceride levels and lipid droplet content, while enriching major phospholipid classes and maintaining a homeostatic phospholipid composition in human hepatocytesin vitroand in mouse liverin vivounder normal and pre-disease conditions. Conversely, in cell-based disease models of lipid overload and lipotoxic stress, silybin treatment primarily depletes triglycerides. Mechanistically, silymarin/silybin suppresses phospholipid-degrading enzymes, induces phospholipid biosynthesis to varying degrees depending on the conditions, and down-regulates triglyceride biosynthesis, while inducing complex changes in sterol and fatty acid metabolism. Structure-activity relationship studies highlight the importance of the 1,4-benzodioxane ring configuration of silybin A in triglyceride reduction and the saturated 2,3-bond of the flavanonol moiety in phospholipid accumulation. Enrichment of hepatic phospholipids and intracellular membrane expansion are associated with an heightened biotransformation capacity. In conclusion, our study deciphers the structural features of silybin contributing to hepatic lipid reorganization and offers insights into its liver-protective mechanism, potentially involving a context-dependent lipid class switch from triglycerides to phospholipids.
An integrative single-cell atlas to explore the cellular and temporal specificity of neurological disorder genes during human brain development
Authors: Kim Seoyeon , Lee Jihae , Koh In Gyeong , Ji Jungeun , Kim Hyun Jung , Kim Eunha , Park Jihwan , Park Jong-Eun , An Joon-Yong
Published: April 2024

Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to the developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expressions under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of developing human brains, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder genes. Lineages of non-neuronal cells determined by molecular profiles also showed temporal-specific expressions, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types for neuronal disorders, indicative of the prenatal stage’s influence on disease determination. Our findings facilitate unbiased comparisons of cell type-disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders.