bluuebunny/crossref_metadata_2025 huggingface dataset:
Different nursing interventions on sleep quality among critically ill patients: A systematic review and network meta-analysis
Authors: Huang Daijin , Li Yumei , Ye Jing , Liu Chang , Shen Dongyan , Lv Yunhui
Published: January 2024

Background:

Critically ill patients in intensive care often struggle with disrupted sleep, a prevalent issue in this population. However, the question of which non-pharmacological intervention is most effective in enhancing sleep quality remains unanswered. This study was conducted to comprehensively evaluate and compare the efficacy of various non-pharmacological interventions aimed at improving sleep quality among critically ill individuals.

Methods:

We conducted a search of PubMed, Embase, and the Cochrane Library (Cochrane Central Register of Controlled Trials) without language restrictions to identify articles published until July 15, 2023. Randomized controlled trials (RCTs) that investigated various nursing interventions designed to improve sleep quality in critically ill patients were included in this network meta-analysis. All analyses were performed using R software (version 3.4.3) with the “gemtc” package.

Results:

A total of 2036 patients from 31 RCTs were included in the network meta-analysis, involving 11 different nursing interventions (routine care, relaxation combined with imagery (RI), nursel, music + earplugs + eye masks, music, eye masks, earplugs + eye masks, earplugs, aromatherapy, Warm footbath combined with acupoint exercise (WFA), Virtual reality meditation (VR)). Eye masks and earplugs + eye masks were associated with improved sleep quality compared to routine care intervention (P < .05).

Conclusions:

In summary, eye masks and earplugs + eye masks stand out as the most effective interventions for enhancing sleep quality in critically ill patients. Therefore, critical care nurses should consider incorporating the use of eye masks alone or combining music with eye masks into the sleep care regimen for critically ill patients.
Extracorporeal shock wave therapy for low back pain: A systematic review and meta-analysis
Authors: Wu Zhuorao , Zhou Tianqi , Ai Shuangchun
Published: January 2024

Background:

To provide high-quality evidence for extracorporeal shock wave therapy (ESWT) for low back pain (LBP).

Methods:

A computerized search screened trials of ESWT for LBP, and the time range was from the establishment of databases to August 2023, including CNKI, CBMdisc, Wanfang Data, VIP, PubMed, Web of Science, Embase, and Cochrane databases. The outcomes were extracted, including patients’ pain, physical and psychological conditions, and adverse reactions. Meta-analysis was completed using Revman 5.4 and Stata 15 software, and GRADEpro software quantitated rate the evidence and assigned a recommendation strength.

Results:

This meta-analysis included 22 studies involving 1749 patients. After treatment, patients in the ESWT group had lower scores in the visual analog scale (VAS) (mean difference [MD] = −1.14, 95% confidence interval [CI] (−1.47, −0.80), P < .00001), Oswestry disability index (ODI) [MD = −6.01, 95%CI (−7.97, −4.05), P < .00001], and Beck depression inventory [MD = −3.89, 95%CI (−6.59, −1.20), P = .005]; finger-floor distance [MD = −3.71, 95%CI (−5.26, −2.17), P < .00001] was shorter; Japanese orthopedic association scores [MD = 3.20, 95%CI (1.56, 4.85), P = .0001] were higher; at the 3-month follow-up, the VAS [MD = −1.29, 95%CI (−2.39, −0.19), P = .02] and ODI [MD = −5.95, 95%CI (−10.06, −1.84), P = .005] remained lower; adverse reactions [odds ratio = 0.19, 95%CI (0.07, 0.52), P = .001] were less, and the valid cases [odds ratio = 3.84, 95%CI (2.47, 5.96), P < .00001] were more. Sensitivity analyses revealed that the results were stable; Egger test found no publication bias in VAS (P = .270) and valid cases (P = .747); the trim and fill analysis tested the robustness of ODI scores due to the publication bias (P = .029), and the effect sizes before and after the trim and fill were consistent, which means the result was robust.

Conclusion:

ESWT for LBP has efficacy and safety in improving pain, dysfunction, and psychological conditions compared to other therapies. ESWT has shown advantages in terms of long-term efficacy. Randomized controlled trials with larger sample sizes and more objective outcomes are required.
Acquired isolated factor VII deficiency in a patient with myxoid pleomorphic liposarcoma, case report
Authors: Aljabry Mansour , Aleid Manar , Almutairi Shahad , AlSerhani Reema , Alsahil Shahad , Alotaibi Ghazi
Published: January 2024

Introduction:

Acquired factor VII (FVII) deficiency is a rare condition with various causes, including acquired inhibitors to FVII, liver disease, and malignancies. Myxoid pleomorphic liposarcoma is a rare and aggressive form of soft tissue sarcoma that can cause a range of clinical manifestations, including bleeding and clotting disorders.

Patient concerns and diagnosis:

We present a case report of a 21-year-old man with severe acquired FVII deficiency due to mediastinal myxoid pleomorphic liposarcoma. The patient presented with elevated International normalized ratio (INR) and a severe reduction in FVII coagulant activity, unresponsive to conventional therapy. While an acquired inhibitor to FVII was initially suspected, negative results from laboratory testing, including protein G sepharose adsorption and a Bethesda assay using Immunoglobulin G purified from patient plasma, made the diagnosis of an acquired inhibitor to FVII uncertain.

Interventions and outcome:

The patient underwent surgical resection of the tumor, supported by recombinant FVII infusion, leading to the normalization of coagulation parameters. However, a relapse of the disease was detected 6 months later when he was noted to have a decline in FVII levels.

Conclusion:

This case highlights the importance of considering rare causes of bleeding and clotting disorders, particularly in unresponsive or atypical presentations. It also underscores the need for close monitoring and follow-up in patients with acquired FVII deficiency, even after successful treatment.
Neurosurgery for the rhinologist
Authors: Nizzola Mariagrazia , Leonel Luciano C.P.C. , Peris-Celda Maria
Published: January 2024

Purpose of review

The purpose of this review is to provide a comprehensive anatomical appraisal of the neurosurgical anatomy exposed through the endonasal and paranasal sinuses routes, focusing on the most common expanded endonasal approaches (EEAs) as well as recent advances in this surgical field.

Recent findings

The EEAs are redefining the management of skull base pathology. Neurovascular structures previously considered a limitation, can be now approached through these surgical corridors. Advances in this field include the development of new surgical techniques and routes that allow better visualization and access to pathologies located in the ventral skull base. Understanding the surgical anatomy related to EEAs is essential not only for neurosurgeons but also for rhinologists.

Knowledge of the surgical anatomy of the most common EEAs that utilize paranasal sinuses as a surgical corridor enables more effective management of complex skull base pathologies. Comprehensive anatomical knowledge of these corridors and the surrounding neurovascular structures is crucial to maximize benefits of EEAs and improve outcomes.
A 50-Year Review of Congressional Membership by Health Care Professionals: Is Surgical Representation Adequate?
Authors: Yau Alice , Lentskevich Marina A. , Yau Irene , Taritsa Iulianna , Ahmed Kaleem S. , Marlowe Teeba , Gosain Arun K.
Published: January 2024

Although 100% of congressional legislators vote on health care policy, only a minority have a background in health care. A review of the participation of health care professionals (HCPs) in Congress, highlighting participation by surgeons, is critical to the future policy-making endeavors in health care. This article seeks to better understand the characteristics of HCPs who engage in advocacy and describe the trends in their representation in Congress, with commentary on participation by surgeons and its impact on current health advocacy efforts.

A search of Congress.gov and the Biographical Directory of the United States Congress was performed to identify professional health care history for each congressperson, followed by review of official campaign websites for health advocacy work. Statistical analysis was performed using IBM SPSS Statistics Software for changes in representation of HCPs, physicians, and surgeons in Congress over time. Although there has been increasing representation of HCPs in Congress in the past 25 years, surgeons have the lowest increase in congressional membership. For health care reform to optimally address high costs, variable insurance coverage and reimbursement rates, and equal access to care, more physicians must make health care advocacy efforts an integral part of their careers. Incorporation of education in areas of health care advocacy and/or reform into undergraduate and graduate medical education curricula may help address deficiencies in knowledge of current health care–related events to further encourage involvement in health care legislation.
Photon-Counting Detector CT for Liver Lesion Detection—Optimal Virtual Monoenergetic Energy for Different Simulated Patient Sizes and Radiation Doses
Authors: Racine Damien , Mergen Victor , Viry Anaïs , Frauenfelder Thomas , Alkadhi Hatem , Vitzthum Veronika , Euler André
Published: January 2024

Objectives

The aim of this study was to evaluate the optimal energy level of virtual monoenergetic images (VMIs) from photon-counting detector computed tomography (CT) for the detection of liver lesions as a function of phantom size and radiation dose.

Materials and Methods

An anthropomorphic abdominal phantom with liver parenchyma and lesions was imaged on a dual-source photon-counting detector CT at 120 kVp. Five hypoattenuating lesions with a lesion-to-background contrast difference of −30 HU and −45 HU and 3 hyperattenuating lesions with +30 HU and +90 HU were used. The lesion diameter was 5–10 mm. Rings of fat-equivalent material were added to emulate medium- or large-sized patients. The medium size was imaged at a volume CT dose index of 5, 2.5, and 1.25 mGy and the large size at 5 and 2.5 mGy, respectively. Each setup was imaged 10 times. For each setup, VMIs from 40 to 80 keV at 5 keV increments were reconstructed with quantum iterative reconstruction at a strength level of 4 (QIR-4). Lesion detectability was measured as area under the receiver operating curve (AUC) using a channelized Hotelling model observer with 10 dense differences of Gaussian channels.

Results

Overall, highest detectability was found at 65 and 70 keV for both hypoattenuating and hyperattenuating lesions in the medium and large phantom independent of radiation dose (AUC range, 0.91–1.0 for the medium and 0.94–0.99 for the large phantom, respectively). The lowest detectability was found at 40 keV irrespective of the radiation dose and phantom size (AUC range, 0.78–0.99). A more pronounced reduction in detectability was apparent at 40–50 keV as compared with 65–75 keV when radiation dose was decreased. At equal radiation dose, detection as a function of VMI energy differed stronger for the large size as compared with the medium-sized phantom (12% vs 6%).

Conclusions

Detectability of hypoattenuating and hyperattenuating liver lesions differed between VMI energies for different phantom sizes and radiation doses. Virtual monoenergetic images at 65 and 70 keV yielded highest detectability independent of phantom size and radiation dose.
Time-Restricted Feeding (16/8)
Authors: Kızıldağ Ayşen Yıldırım , Erge Sema , Haklıgil Umut
Published: January 2024

This study aimed to investigate the effects of 8-hour time-restricted feeding (TRF) on body weight, biochemical parameters, diet quality, and eating behavior in overweight females. In the TRF group, there was a statistically significant decrease in body weight, body mass index, and waist and hip circumference (P < .05). Furthermore, there was a statistically significant greater decrease in blood glucose, insulin, cholesterol, and low-density lipoprotein cholesterol in the TRF group (P < .05). TRF did not affect eating behavior or diet quality (P > .05), but it led to a decrease in fiber intake (P < .05). These findings suggest that consuming food within an 8-hour window may facilitate weight loss in individuals with obesity. Longitudinal studies with larger samples are needed to confirm this.
Impact of Prevascularization on Immunological Environment and Early Engraftment in Subcutaneous Islet Transplantation
Authors: Inoguchi Kenta , Anazawa Takayuki , Fujimoto Nanae , Tada Seiichiro , Yamane Kei , Emoto Norio , Izuwa Aya , Su Hang , Fujimoto Hiroyuki , Murakami Takaaki , Nagai Kazuyuki , Hatano Etsuro
Published: January 2024

Background.

The utilization of islet-like cells derived from pluripotent stem cells may resolve the scarcity of islet transplantation donors. The subcutaneous space is a promising transplantation site because of its capacity for graft observation and removal, thereby ensuring safety. To guarantee subcutaneous islet transplantation, physicians should ensure ample blood supply. Numerous methodologies, including prevascularization, have been investigated to augment blood flow, but the optimal approach remains undetermined.

Methods.

From C57BL/6 mice, 500 syngeneic islets were transplanted into the prevascularized subcutaneous site of recipient mice by implanting agarose rods with basic fibroblast growth factor at 1 and 2 wk. Before transplantation, the blood glucose levels, cell infiltration, and cytokine levels at the transplant site were evaluated. Furthermore, we examined the impact of the extracellular matrix capsule on graft function and the inflammatory response.

Results.

Compared with the 1-wk group, the 2-wk group exhibited improved glycemic control, indicating that longer prevascularization enhanced transplant success. Flow cytometry analysis detected immune cells, such as neutrophils and macrophages, in the extracellular matrix capsules, whereas cytometric bead array analysis indicated the release of inflammatory and proinflammatory cytokines. Treatment with antitumor necrosis factor and anti-interleukin-6R antibodies in the 1-wk group improved graft survival, similar to the 2-wk group.

Conclusions.

In early prevascularization before subcutaneous transplantation, neutrophil and macrophage accumulation prevented early engraftment owing to inflammatory cytokine production.
Vestibular syncope
Authors: Choi Jeong-Yoon , Lee Eek-Sung , Kim Ji-Soo
Published: January 2024

Purpose of review

This review considers recent observations on vestibular syncope in terms of clinical features, laboratory findings, and potential mechanisms.

Recent findings

Vestibular syncope, potentially associated with severe fall-related injuries, may develop multiple times in about one-third of patients. Meniere's disease and benign paroxysmal positional vertigo are the most common causes of vestibular syncope, but the underlying disorders remain elusive in 62% of cases with vestibular syncope. The postictal orthostatic blood pressure test exhibits a lower diagnostic yield. Vestibular function tests, such as cervical vestibular-evoked myogenic potentials and video head impulse tests, can reveal one or more abnormal findings, suggesting compensated or ongoing minor vestibular dysfunctions. The pathomechanism of syncope is assumed to be the erroneous interaction between the vestibulo-sympathetic reflex and the baroreflex that have different operating mechanisms and action latencies. The central vestibular system, which estimates gravity orientation and inertia motion may also play an important role in abnormal vestibulo-sympathetic reflex.

Vestibular disorders elicit erroneous cardiovascular responses by providing false vestibular information. The results include vertigo-induced hypertension or hypotension, which can ultimately lead to syncope in susceptible patients.
Association Between Magnetoencephalography-Localized Epileptogenic Zone, Surgical Resection Volume, and Postsurgical Seizure Outcome
Authors: Poghosyan Vahe , Algethami Hanin , Alshahrani Ashwaq , Asiri Safiyyah , Aldosari Mubarak M.
Published: January 2024

Purpose:

Surgical resection of magnetoencephalography (MEG) dipole clusters, reconstructed from interictal epileptiform discharges, is associated with favorable seizure outcomes. However, the relation of MEG cluster resection to the surgical resection volume is not known nor is it clear whether this association is direct and causal, or it may be mediated by the resection volume or other predictive factors. This study aims to clarify these open questions and assess the diagnostic accuracy of MEG in our center.

Methods:

We performed a retrospective cohort study of 68 patients with drug-resistant epilepsy who underwent MEG followed by resective epilepsy surgery and had at least 12 months of postsurgical follow-up.

Results:

Good seizure outcomes were associated with monofocal localization (χ2 = 6.94, P = 0.001; diagnostic odds ratio = 10.2) and complete resection of MEG clusters (χ2 = 22.1, P < 0.001; diagnostic odds ratio = 42.5). Resection volumes in patients with and without removal of MEG clusters were not significantly different (t = 0.18, P = 0.86; removed: M = 20,118 mm3, SD = 10,257; not removed: M = 19,566 mm3, SD = 10,703). Logistic regression showed that removal of MEG clusters predicts seizure-free outcome independent of the resection volume and other prognostic factors (P < 0.001).

Conclusions:

Complete resection of MEG clusters leads to favorable seizure outcomes without affecting the volume of surgical resection and independent of other prognostic factors. MEG can localize the epileptogenic zone with high accuracy. MEG interictal epileptiform discharges mapping should be used whenever feasible to improve postsurgical seizure outcomes.
National Trends and Clinical Outcomes after Scooter Injury in the US: 2016 to 2020
Authors: Cho Nam Yong , Kim Shineui , Tran Zachary , Hadaya Joseph , Ali Konmal , Kronen Elsa , Burruss Sigrid , Benharash Peyman
Published: January 2024

BACKGROUND:

In recent years, the adoption of electric scooters has been accompanied by a surge of scooter-related injuries in the US, raising concerns for their severity and associated healthcare costs. This study aimed to assess temporal trends and outcomes of scooter-related hospital admissions compared with bicycle-related hospitalizations.

STUDY DESIGN:

This was a retrospective cohort study using the 2016 to 2020 National Inpatient Sample for patients younger than 65 years who were hospitalized after bicycle- and scooter-related injuries. The Trauma Mortality Prediction Model was used to quantify injury severity. The primary outcomes of interest were temporal trends of micromobility injuries. In-hospital mortality, rates of long bone fracture, traumatic brain injury, paralysis, length of stay, hospitalization costs, and nonhome discharge were secondarily assessed.

RESULTS:

Among 92,815 patients included in the study, 6,125 (6.6%) had scooter-related injuries. Compared with patients with bicycle-related injuries, patients with scooter-related injuries were more commonly younger than 18 years (26.7% vs 16.4%, p < 0.001) and frequently underwent major operations (55.8% vs 48.1%, p < 0.001). After risk adjustment, scooter-related injuries were associated with greater risks of long bone fracture (adjusted odds ratio 1.40, 95% CI 1.15 to 1.70) and paralysis (adjusted odds ratio 2.06, 95% CI 1.16 to 3.69) compared with bicycle-related injuries. Additionally, patients with bicycle- or scooter-related injuries had comparable index hospitalization durations of stay and costs.

CONCLUSIONS:

The prevalence and severity of scooter-related injuries have significantly increased in the US, thereby attributing to a substantial cost burden on the healthcare system. Multidisciplinary efforts to inform safety policies and enact targeted interventions are warranted to reduce scooter-related injuries.
Adherence Rate to Alliance for Clinical Trials in Oncology Z0011 Trial Based on Breast Cancer Subtype
Authors: Maramara Taylor , Hsieh Mei-Chin , Janjua Mahin , Li Tingting , Wu Xiao-Cheng , Williams Mallory , Shoup Margo , Chu Quyen D
Published: January 2024

BACKGROUND:

The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011 or Z11) trial demonstrated no survival advantage with completion axillary lymph node dissection (ALND) for patients with T1-2 breast cancer, 1 to 2 positive SLNs who received adjuvant chemoradiation therapy. More than 70% of the cohort had estrogen receptor (ER)+ tumors. There is paucity of data on the adherence rate to Z11, as well as a dearth of data on the applicability of Z11 for the different subtypes. We conducted a large hospital-based study to evaluate the adherence rate to Z11 based on subtypes.

STUDY DESIGN:

The National Cancer Database was queried to evaluate 33,859 patients diagnosed with T1-2, N1, and M0 breast cancer treated with lumpectomy with negative margins, and adjuvant chemoradiation therapy between 2012 and 2018. Patients were classified into 3 groups: (1) ER+/HER2−, (2) ER−/HER2−, and (3) HER2+ regardless of ER status. The revised Scope of the Regional Lymph Node Surgery 2012 was used to classify patients into those who underwent an SLN or ALND. Differences in use of ALND by subtypes were compared. The Kaplan–Meier method and log-rank test were used to compare overall survival (OS). A p value of <0.05 was considered statistically significant.

RESULTS:

For ER+/human epidermal growth factor receptor 2 (HER2)−, ER−/HER2−, and HER2+ tumors, the rate of ALND was 43.6%, 50.2%, and 47.8%, respectively. The 5-year OS for SLN and ALND for the entire cohort was 94.0% and 93.1% (p = 0.0004); for ER+/HER2−, it was 95.4% and 94.7% (p = 0.04); for ER−/HER2−, it was 84.1% and 84.3% (p = 0.41); for HER2+, it was 94.2% and 93.2% (p = 0.20). Multivariable cox proportional hazard regression analysis demonstrated no significant survival differences between SLN and ALND (p = 0.776).

CONCLUSIONS:

Z11 is applicable for women with early N1 disease, regardless of subtypes. ALND did not confer a survival advantage over SLN. Despite this, up to 50% of patients who fit Z11 criteria continue to undergo ALND.
Structural Changes in Depressed Patients Directly After Treatment With Electroconvulsive Therapy and 3 Months Later
Authors: Jaarsveld Stevie , Mulders Peter , Tendolkar Indira , van Eijndhoven Philip
Published: January 2024

Objectives

It is assumed that neuroplasticity plays a central role in the effect of electroconvulsive therapy (ECT) on patients with major depressive disorder. We carried out an explorative study to map out the extent in which gray matter volume changes could be found directly after ECT treatment and after follow-up.

Methods

Initially, 12 patients with treatment-resistant depression were recruited from the Radboud Medical Center. Magnetic resonance imaging scans were conducted at the following 3 time points: before ECT (n = 12), after ECT (n = 10), and at 3-month follow-up (n = 8). Subcortical volume, hippocampal subfield volume, and cortical thickness were analyzed using FreeSurfer.

Results

The extensive, generalized changes in gray matter volume are largely transient after treatment with ECT, with the noted exceptions being a sustained increase in volume of the right amygdala and a part of the left cornu ammonis. Post hoc testing revealed no significant correlation with clinical response.

Discussion

Our results suggest that the neuroplastic effects of ECT may not be mediators of clinical response and could be transient epiphenomena.
MoCoLo: a testing framework for motif co-localization
Authors: Xu Qi , del Mundo Imee M.A. , Zewail-Foote Maha , Luke Brian T. , Vasquez Karen M. , Kowalski Jeanne
Published: January 2024

Sequence-level data offers insights into biological processes through the interaction of two or more genomic features from the same or different molecular data types. Within motifs, this interaction is often explored via the co-occurrence of feature genomic tracks using fixed-segments or analytical tests that respectively require window size determination and risk of false positives from over-simplified models. Moreover, methods for robustly examining the co-localization of genomic features, and thereby understanding their spatial interaction, have been elusive. We present a new analytical method for examining feature interaction by introducing the notion of reciprocal co-occurrence, define statistics to estimate it, and hypotheses to test for it. Our approach leverages conditional motif co-occurrence events between features to infer their co-localization. Using reverse conditional probabilities and introducing a novel simulation approach that retains motif properties (e.g., length, guanine-content), our method further accounts for potential confounders in testing. As a proof-of-concept, MoCoLo confirmed the co-occurrence of histone markers in a breast cancer cell line. As a novel analysis, MoCoLo identified significant co-localization of oxidative DNA damage within non-B DNA forming regions that significantly differed between non-B DNA structures. Altogether, these findings demonstrate the potential utility of MoCoLo for testing spatial interactions between genomic features via their co-localization.
Interferon Regulatory Factor 6 Determines Intestinal Epithelial Cell Development and Immunity
Authors: Wright Austin P. , Harris Sydney , Madden Shelby , Reyes Bryan Ramirez , Mulamula Ethan , Gibson Alexis , Rauch Isabella , Constant David A. , Nice Timothy J.
Published: January 2024

Intestinal epithelial cell (IEC) responses to interferon (IFN) favor antiviral defense with minimal cytotoxicity, but IEC-specific factors that regulate these responses remain poorly understood. Interferon regulatory factors (IRFs) are a family of nine related transcription factors, and IRF6 is preferentially expressed by epithelial cells, but its roles in IEC immunity are unknown. In this study, CRISPR screens found thatIrf6deficiency enhanced IFN-stimulated antiviral responses in transformed mouse IECs but not macrophages. Furthermore, KO ofIrf6in IEC organoids resulted in profound changes to homeostasis and immunity gene expression.Irf6KO organoids grew more slowly, and single-cell RNA sequencing indicated reduced expression of genes in epithelial differentiation and immunity pathways. IFN-stimulated gene expression was also significantly different inIrf6KO organoids, with increased expression of stress and apoptosis-associated genes. Functionally, the transcriptional changes inIrf6KO organoids were associated with increased cytotoxicity upon IFN treatment or inflammasome activation. These data indicate a previously unappreciated role for IRF6 in IEC biology, including regulation of epithelial development and moderation of innate immune responses to minimize cytotoxicity and maintain barrier function.
Pathogen and host adapt pH responses during enteric infection
Authors: Woodward Sarah E. , Neufeld Laurel M.P. , Peña-Díaz Jorge , Feng Wenny , Serapio-Palacios Antonio , Tarrant Isabel , Finlay B. Brett
Published: January 2024

Enteric pathogens navigate distinct regional micro-environments within the intestine which cue important adaptive behaviours. We investigated the response ofCitrobacter rodentium, a model of human pathogenicEscherichia coliinfection, to regional gastrointestinal pH. We found that small intestinal pH (4.4-4.8) triggered virulence gene expression and altered cell morphology, supporting initial intestinal attachment, while higher pH, representative ofC. rodentium’s replicative niches further along the intestine, supported pathogen growth. Gastric pH, a key barrier to intestinal colonization, caused significant accumulation of intra-bacterial reactive oxygen species, inhibiting growth ofC. rodentiumand related human pathogens. Within-host adaptation increased gastric acid survival, which may be due to a robust acid tolerance response induced at colonic pH. However, we also found that host gastric pH decreases post-infection, corresponding to increased serum gastrin levels and altered host expression of acid secretion-related genes. Similar responses followingSalmonellainfection may indicate a protective host response to limit further pathogen ingestion. Together, we highlight adaptive pH responses as an important component of host-pathogen co-evolution.
An ecological investigation of the effect of background noise on speech processing in a Virtual Classroom
Authors: Levy Orel , Korisky Adi , Zvilichovsky Yair , Zion Golumbic Elana
Published: January 2024

Many real-life situations can be extremely noisy. Psychoacoustic studies have shown that background noise can have a detrimental effect on the ability to process and understand speech. However, most studies use stimuli and task designs that are highly artificial, limiting their generalization to more realistic contexts. Moreover, to date, we do not fully understand the neurophysiological consequences of trying to pay attention to speech in a noisy place.

To address this lab to real-life gap and increase the ecological validity of speech in noise research, here we introduce a novel audiovisual Virtual Reality (VR) experimental platform. Combined with neurophysiological measurements of neural activity (EEG), eye-gaze and skin conductance (GSR) we studied the effects of background noise in a realistic context where the ability to process and understand continuous speech is especially important: A VR Classroom.

Participants (n=32) sat in a VR Classroom and were told to pay attention to mini-lecture segments by a virtual teacher. Trials were either Quiet or contained background construction noise, emitted from outside the classroom window, which was either Continuous (drilling) or Intermittent (air hammers).

Result show that background noise had a detrimental effect on learning outcomes, which was also accompanied by reduced neural tracking of the teacher’s speech. Comparison of the two noise types showed that the intermittent construction noise was more disruptive than continuous noise, as index by both behavioral and neural measures, and it also elicited higher skin-conductance levels, reflecting heightened arousal. Interesting, eye-gaze dynamics were not affected by the presence of noise.

This study advances our understanding of the neurophysiological effects of background noise and extends it to more ecologically relevant contexts. It also emphasizes the role that temporal dynamics play for processing speech in noise, highlighting the need to consider the features of realistic noises, as we expand speech in noise research to increasingly realistic circumstances.
A polymer-physics view of peripheral chromatin: de Gennes’ self-similar carpet
Authors: Sarıyer Ozan S. , Erbaş Aykut
Published: January 2024

Using scaling arguments to model peripheral chromatin localized near the inner surface of the nuclear envelope (NE) as a flexible polymer chain, we discuss the structural properties of the peripheral chromatin composed of alternating lamin-associated domains (LADs) and inter-LADs. Modeling the attraction of LADs to NE by de Gennes’ self-similar carpet, which treats the chromatin layer as a polymer fractal, explains two major experimental observations: (i) The high density of chromatin close to the nuclear periphery decays to a constant density as the distance to the periphery increases. (ii) Due to the decreasing mesh size towards the nuclear periphery, the chromatin carpet inside NE excludes molecules (vianon-specific interactions) above a threshold size that depends on the distance from the nuclear periphery.
Cardiac stress leads to regulation of Filamin C dimerisation via an ancient phosphorylation-modulated interaction with HSPB7
Authors: Wang Zihao , Cao Guodong , Collier Miranda P. , Qiu Xingyu , Broadway-Stringer Sophie , Šaman Dominik , Ng Jediael Z.Y. , Sen Navoneel , Azad Amar J. , Hooper Charlotte , Zimmermann Johannes , McDonough Michael , Brem Jürgen , Rabe Patrick , Song Haigang , Reid Alderson T. , Schofield Christopher J. , Bolla Jani R. , Djinovic-Carugo Kristina , Fürst Dieter O. , Warscheid Bettina , Degiacomi Matteo T. , Allison Timothy M. , Hochberg Georg K.A. , Robinson Carol V. , Gehmlich Katja , Benesch Justin L.P.
Published: January 2024

The biomechanical properties and responses of tissues underpin a variety of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. Seemingly a multi-functional protein that interacts with a variety of partners, how FLNC is regulated at the molecular level is not well understood. Here we have investigated its interaction with HSPB7, a cardiac-specific molecular chaperone whose absence is embryonically lethal. We found that FLNC and HSPB7 interact in cardiac tissue under biomechanical stress, forming a strong hetero-dimer whose structure we have solved by means of X-ray crystallography. Our quantitative analyses show that the hetero-dimer out-competes the FLNC homo-dimer interface, potentially acting to abrogate the ability of the protein to cross-link the actin cytoskeleton, and to enhance its diffusive mobility. We show that phosphorylation of FLNC at threonine 2677, located at the dimer interface and associated with cardiac stress, acts to favour the homo-dimer. Conversely, phosphorylation at tyrosine 2683, also at the dimer interface, has the opposite effect and shifts the equilibrium towards the hetero-dimer. Evolutionary analysis and ancestral sequence reconstruction reveals this interaction and its mechanisms of regulation to date around the time primitive hearts evolved in chordates. Our work rationalises on the molecular level how FLNC might switch between stabilising functions in the cell, and reveals how HSPB7 acts as a specific molecular chaperone that regulates FLNC.
Genetically encoded Boolean logic operators to sense and integrate phenylpropanoid metabolite levels in plants
Authors: Ferreira Savio S. , Antunes Mauricio S.
Published: January 2024

Synthetic biology has the potential to revolutionize biotechnology, public health and agriculture. Recent studies have shown the enormous potential of plants as chassis for synthetic biology applications. However, tools to precisely manipulate metabolic pathways for bioproduction in plants are still needed.

We have adapted bacterial allosteric transcription factors (aTFs) to control gene expression in plants in a ligand-specific manner. The aTFs used here function as transcription repressors of semi-synthetic promoters, and aTF activity is regulated by specific plant metabolites, especially phenylpropanoid-related molecules. Using these aTFs, we also designed synthetic genetic circuits capable of computing Boolean logic operations.

Three aTFs, CouR, FapR and TtgR, were able to achieve ∼95% repression of their respective target promoters. For TtgR, a 6-fold de-repression could be triggered by inducing its ligand (naringenin) accumulation, showing its use as biosensor. Moreover, we designed synthetic genetic circuits that use AND, NAND, IMPLY and NIMPLY Boolean logic operations and integrate metabolite levels as input to the circuit.

We showed that biosensors can be implemented in plants to detect phenylpropanoid-related metabolites and activate a genetic circuit that follows a pre-defined logic, demonstrating their potential as tools for exerting control over plant metabolic pathways and facilitating the bioproduction of natural products.
Using FINDeM for rapid, CRISPR-based detection of the emerging salamandrid fungal pathogen,Batrachochytrium salamandrivorans
Authors: Hoenig Brandon D. , Böning Philipp , Plewnia Amadeus , Richards-Zawacki Corinne L.
Published: January 2024

Abstract

The fungal pathogenBatrachochytrium salamandrivorans(Bsal) is one of two species (the other,B. dendrobatidis/Bd) that cause amphibian chytridiomycosis, an emerging infectious disease that has been indicated in the declines of hundreds of amphibian species worldwide. WhileBdhas been near-globally distributed for well over a century,Bsalis a more recently emerged pathogen, having been identified just over a decade ago with current impacts localized to salamandrids in parts of Europe. However, because there is concern thatBsalwill cause widespread declines if introduced to naïve regions – such as the Americas where the greatest diversity of salamandrids exist – it is imperative that widespread testing and monitoring strategies be implemented to mitigate the spread ofBsal. As standard diagnostic approaches tend to be expensive, time-consuming, or require specialized instrumentation and training, we have developed a simplified, rapid, CRISPR-based approach forBsal-DNA identification and provide suggestions for its future application.
Cell type specific long non-coding RNA targets identified by integrative analysis of single-cell and bulk colorectal cancer transcriptomes
Authors: Mihaljevic Ante , Rubin Philip , Chouvardas Panagiotis , Esposito Roberta
Published: January 2024

Long non-coding RNAs (lncRNAs) represent an emerging class of genes which play significant and diverse roles in human cancers. Nevertheless, the functional repertoires of lncRNAs in cancer cell subtypes remains unknown since most studies are focused on protein coding genes. Here, we explored the contribution of lncRNAs in Colorectal Cancer (CRC) heterogeneity. We analyzed 49,436 single-cells from 29 CRC patients and showed that lncRNAs are significantly more cell type specific compared to protein-coding genes. We identified 996 lncRNAs strongly enriched in epithelial cells. Among these, 98 were found to be differentially expressed in tumor samples compared to normal controls, when integrating 270 bulk CRC profiles. We validated the upregulation of two of them (CASC19 and LINC00460) in CRC cell lines and showed their involvement in CRC proliferation by CRISPR-Cas9 knock down experiments. This study highlights a list of novel RNA targets for potential CRC therapeutics, substantiated through experimental validation.
Large-scale computational analyses of gut microbial CAZyme repertoires enabled by Cayman
Authors: Ducarmon Q. R. , Karcher N. , Tytgat H.L.P. , Delannoy-Bruno O. , Pekel S. , Springer F. , Schudoma C. , Zeller G.
Published: January 2024

Carbohydrate-active enzymes (CAZymes) are crucial for digesting glycans, but bioinformatics tools for CAZyme profiling and interpretation of substrate preferences in microbial community data are lacking. To address this, we developed a CAZyme profiler (Cayman) and a hierarchical substrate annotation scheme. Leveraging these, we genomically survey CAZymes in human gut microbes (n=107,683 genomes), which suggests novel mucin-foraging species. In a subsequent meta-analysis of CAZyme repertoires in Western versus non-Western gut metagenomes (n=4,281) we find that non-Western metagenomes are richer in fibre-degrading CAZymes despite lower overall CAZyme richness. We additionally pinpoint the taxonomic drivers underlying these CAZyme community shifts. A second meta-analysis comparing colorectal cancer patients (CRC) to controls (n=1,998) shows that CRC metagenomes are deprived of dietary fibre-targeting, but enriched in glycosaminoglycan-targeting CAZymes. A genomic analysis of co-localizing CAZyme domains predicts novel substrates for CRC-enriched CAZymes. Cayman is broadly applicable across microbial communities and freely available fromhttps://github.com/zellerlab/cayman.
Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency
Authors: Nithianadam Vanitha , Sarkar Souvarish , Feany Mel B.
Published: January 2024

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in theDrosophilaretina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.
Testis Specific Serine Kinase 6 (TSSK6) is abnormally expressed in colorectal cancer and promotes oncogenic behaviors
Authors: Delgado Magdalena , Gallegos Zachary , Stippec Steve , McGlynn Kathleen , Cobb Melanie H. , Whitehurst Angelique W.
Published: January 2024

Cancer testis antigens (CTAs) are a collection of proteins whose expression is normally restricted to the gamete, but abnormally activated in a wide variety of tumors. The CTA, Testis specific serine kinase 6 (TSSK6), is essential for male fertility in mice. Functional relevance of TSSK6 to cancer, if any, has not previously been investigated. Here we find that TSSK6 is frequently anomalously expressed in colorectal cancer and patients with elevated TSSK6 expression have reduced relapse free survival. Depletion of TSSK6 from colorectal cancer cells attenuates anchorage independent growth, invasion and growth in vivo. Conversely, overexpression of TSSK6 enhances anchorage independence and invasion in vitro as well as in vivo tumor growth. Notably, ectopic expression of TSSK6 in semi-transformed human colonic epithelial cells is sufficient to confer anchorage independence and enhance invasion. In somatic cells, TSSK6 co-localizes with and enhances the formation of paxillin and tensin positive foci at the cell periphery, suggesting a function in focal adhesion formation. Importantly, TSSK6 kinase activity is essential to induce these tumorigenic behaviors. Our findings establish that TSSK6 exhibits oncogenic activity when abnormally expressed in colorectal cancer cells. Thus, TSSK6 is a previously unrecognized intervention target for therapy, which could exhibit an exceptionally broad therapeutic window.
ImagingGiardia intestinaliscellular organisation using expansion microscopy revealed atypical centrin localisation
Authors: Soukup J. , Zelená M. , Weisz F. , Kostelanská M. , Nohýnková E. , Tůmová P.
Published: January 2024

Advanced imaging of microorganisms, including protists, is challenging due to their small size. Specimen expansion prior to imaging is thus beneficial to increase resolution and cellular details. Here, we present a sample preparation workflow for improved observations of the single-celled eukaryotic pathogenGiardia intestinalis(Excavata, Metamonada). The binucleated trophozoites colonize the small intestine of humans and animals and cause a diarrhoeal disease. Their remarkable morphology includes two nuclei and a pronounced microtubular cytoskeleton enabling cell motility, attachment and proliferation. By use of expansion and confocal microscopy, we resolved in a great detail subcellular structures and organelles of the parasite cell. The acquired spatial resolution of 43 nm enabled novel observations of centrin localisation atGiardiabasal bodies. Interestingly, non-luminal centrin localization between theGiardiabasal bodies was observed, which is an atypical eukaryotic arrangement. Our protocol includes antibody staining and can be used for the localisation of epitope-tagged proteins, as well as for differential organelle labelling by amino reactive esters. This fast and simple protocol is suitable for routine use without a superresolution microscopy equipment.
Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren’s disease
Authors: Son Ga-Yeon , Zou Anna , Wahl Amanda , Huang Kai Ting , Vinu Manikandan , Zorgit Saruul , Zhou Fang , Wagner Larry , Idaghdour Youssef , Yule David I. , Feske Stefan , Lacruz Rodrigo S.
Published: January 2024

Sjogren’s disease (SjD) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been involved in the development of SjD. Saliva production is regulated by parasympathetic input into the glands initiating intracellular Ca2+signals that activate the store operated Ca2+entry (SOCE) pathway eliciting sustained Ca2+influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca2+channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models and its impact on SjD. Here we report that male and female mice lackingStim1andStim2(Stim1/2K14Cre) in salivary glands showed reduced intracellular Ca2+levels via SOCE in parotid acini and hyposalivate upon pilocarpine stimulation. Bulk RNASeq of the parotid glands ofStim1/2K14Cremice showed a decrease in the expression ofStim1/2but no other Ca2+associated genes mediating saliva fluid secretion. SOCE was however functionally required for the activation of the Ca2+activated chloride channel ANO1. Despite hyposalivation, ageingStim1/2K14Cremice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum, which may be linked to the downregulation of the toll-like receptor 8 (Tlr8). By contrast, salivary gland biopsies of SjD patients showed increasedSTIM1andTLR8expression, and induction of SOCE in a salivary gland cell line increased the expression ofTLR8. Our data demonstrate that SOCE is an important activator of ANO1 function and saliva fluid secretion in salivary glands. They also provide a novel link between SOCE and TLR8 signaling which may explain why loss of SOCE does not result in SjD.
Novel approach to the global analysis of proton form factors in elastic electron-proton scattering
Authors: McRae C. , Blunden P. G.
Published: January 2024

We present a method for the global analysis of elastic electron-proton scattering when combining data sets from experiments with different overall normalization uncertainties. The method is a modification of one employed by the NNPDF collaboration in the fitting of parton distribution data. This method is an alternative to the ‘penalty trick’ method traditionally employed in global fits to proton electric and magnetic form factors, while avoiding the statistical biases inherent in that approach. We discuss issues that arise when extending the method to nonlinear models. For data with Q2>1GeV2 we find relatively minor differences to traditional model fits when the normalization uncertainties from different experiments are correctly accounted for. We discuss implications of this method for the well-known discrepancy between the form factor ratio GE/GM extracted from the Rosenbluth and polarization transfer techniques.

Published by the American Physical Society
2024