bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations Between Inactivity and Cognitive Function in Older Intensive Care Unit Survivors
Authors: Elias Maya N. , Ahrens Emily A. , Schumacher Farah A. , Liang Zhan , Munro Cindy L.
Published: December 2023

Background/Introduction

Critically ill older adults are profoundly inactive while in the intensive care unit (ICU), and this inactivity persists after discharge from the ICU. Older ICU survivors who were mechanically ventilated are at high risk for post-ICU cognitive impairment.

Objectives/Aims

The present study examined the relationship between the ratio of daytime to nighttime activity and executive function in older ICU survivors.

Methods

This was a secondary analysis of pooled data from 2 primary studies of older adults who were functionally independent prior to hospitalization, mechanically ventilated while in ICU, and within 24 to 48 hours post-ICU discharge. Actigraphy recorded daytime activity (mean activity counts per minute, 6 am to 9:59 pm) and nighttime activity (mean activity counts per minute, 10 pm to 5:59 am). A daytime-to-nighttime activity ratio was calculated by dividing daytime activity by nighttime activity. The NIH Toolbox Dimensional Change Card Sort Test assessed cognitive flexibility (DCCST: fully corrected T score). Multivariate regression examined the association between the daytime-to-nighttime activity ratio and DCCST scores, adjusting for 2 covariates (age in years and NIH Toolbox Grip Strength fully corrected T score).

Results

The mean daytime-to-nighttime activity ratio was 2.10 ± 1.17 (interquartile range, 1.42). Ratios for 6 participants (13.6%) were less than 1, revealing higher activity during nighttime hours rather than daytime hours. Higher daytime-to-nighttime ratios were associated with better DCCST scores (β = .364, P = .005).

Conclusions

The proportion of daytime activity versus nighttime activity was considerably low, indicating severe alterations in the rest/activity cycle. Higher daytime-to-nighttime activity ratios were associated with better executive function scores, suggesting that assessment of daytime activity could identify at-risk older ICU survivors during the early post-ICU transition period. Promotion of daytime activity and nighttime sleep may accelerate recovery and improve cognitive function.
Impact of COVID-19 on Quality of Life After Hospital Discharge in Patients Treated With Noninvasive Ventilation/Continuous Positive Airway Pressure
Authors: Bolgeo Tatiana , Di Matteo Roberta , Gatti Denise , Cassinari Antonella , Damico Vincenzo , Ruta Federico , Gambalunga Francesca , Maconi Antonio
Published: December 2023

Background

COVID-19 has caused a worldwide pandemic that has significantly affected people's health and daily lives. Patients hospitalized with COVID-19 have impaired physical and psychological conditions. Despite this, few studies have examined the physical and psychological health of COVID-19 patients after discharge from the hospital.

Aims

To assess the impact of COVID-19 pneumonia on quality of life and residual disability, anxiety, and insomnia at 4 and 8 months after hospital discharge in patients treated with continuous positive airway pressure and noninvasive ventilation.

Methods

This is a prospective, multicenter, longitudinal observational study. The STROBE checklist was observed. We administered the Post–COVID-19 Functional Status scale to identify and objectively quantify the degree of residual disability and the impact on the patient's functional status. Simultaneously, we used the EuroQOL-5D scale to measure the quality of life, the 7-item Generalized Anxiety Disorder Scale to monitor anxiety, and the Insomnia Severity Index to monitor insomnia.

Results

The study enrolled 199 patients 4 months after discharge; 145 completed the 8-month follow-up. The quality of life, insomnia, pain, and movement ability seem to worsen over time in our cohort of patients. The quality of life deteriorated significantly between 4 and 8 months after discharge especially in terms of mobility (27.6% of the patients interviewed) and pain (31% of the patients interviewed). There was a significant correlation between COVID-19 symptoms and comorbidities present at admission and inadequate quality-of-life perception.

Discussion

The recognition of early signs and symptoms in patients who have already experienced COVID-19 disease is essential for early detection and prevention of chronicity. Health care professionals need to pay more attention to the physical and psychological rehabilitation of COVID-19 patients after hospital discharge. To determine the long-term impacts of COVID-19, a long-term follow-up of COVID-19 patients after discharge is required.
Kintsugi
Authors: Ruth-Sahd Lisa A. , Deibler Aarin
Published: December 2023

Kintsugi serves as a powerful metaphor for nurse externs and residents to identify lessons learned from the pandemic and to refocus on the golden cracks to foster respect, resilience, and rebuilding. Kintsugi encourages nurses to embrace their challenges, find strength in their vulnerabilities, and grow from their experiences.
Longitudinal Analysis of Local Recurrence and Survival After Transanal Abdominal Transanal Radical Proctosigmoidectomy for Low Rectal Cancer Treated With Neoadjuvant Chemoradiation
Authors: Marks John H. , Reif de Paula Thais , Saidi Hela , Ikner Taylor P , Schoonyoung Henry , Marks Gerald , Keller Deborah S
Published: December 2023

BACKGROUND:

The transanal abdominal transanal radical proctosigmoidectomy was developed in 1984 as a sphincter preservation surgery in low rectal cancers after preoperative radiation. While serving as a catalyst for disruptive sphincter preservation surgery, it continues to be used and evolve. With the controversy over safety and local recurrence in other sphincter preserving surgery, review of transanal abdominal transanal radical proctosigmoidectomy long-term oncologic outcomes is warranted.

OBJECTIVE:

To assess local after transanal abdominal transanal radical proctosigmoidectomy after neoadjuvant chemoradiation.

DESIGN:

Retrospective cohort study of a prospectively maintained database.

SETTINGS:

Tertiary rectal cancer referral center.

PATIENTS:

Low adenocarcinoma (≤5 cm anorectal ring) receiving neoadjuvant chemoradiation then transanal abdominal transanal radical proctosigmoidectomy for curative resection between 1998-2021.

MAIN OUTCOME MEASURES:

Local recurrence rates and overall survival rates.

RESULTS:

Of 255 included, 67.8% were male (n = 173), mean 58.7 years old (standard deviation 11.5), with mean body mass index 27.1 kg/m2 (standard deviation, 5.4) and 50.2% (n = 128) American Society of Anesthesiology II. The mean tumor size was 4.8 cm (standard deviation 1.9), majority clinical T3 (81.8%, n = 184) and 52.1% had nodal disease (n = 100). The median radiation dose was 5400 cGy, with 73.7% (n = 149) achieving good response. 90.2% (n = 230) had minimally invasive surgery. Complete total mesorectal excision rate was 94.3% (n = 83/87) and 100% (n = 255) had negative distal margins. The mean examined lymph nodes were 13.9 (standard deviation, 10.7). After median follow-up of 55.4 months, 5.1% (n = 13) patients developed local recurrence, at median time of 29.6 months. The 5-year overall survival was 84.1% (95% CI 78.8-89.4).

LIMITATIONS:

Retrospective review with risk of bias and lack of generalizability.

CONCLUSIONS:

In this longitudinal study, the transanal abdominal transanal radical proctosigmoidectomy demonstrated excellent long-term locoregional control and survival in very low rectal cancers. The superior transanal abdominal transanal radical proctosigmoidectomy outcomes are durable over time, warranting expansion of the sphincter preserving surgery technique.
Localization of Central Breast Lymphatics and Predefined Separation of Lobes along the Horizontal Septum
Authors: Würinger Elisabeth
Published: December 2023

Background:

The predictable localization of the neurovascular supply along the ligamentous suspension, composed of the horizontal septum, vertical ligaments, and superficial fascia, has increased safety in breast reduction. Lymphatic drainage of the breast has always been described as running close to vascular supply. However, the correlation between the lymphatic course and ligamentous suspension has not yet been considered. This study aimed to visualize the relationship, direction of lymphatic flow, and predefined separation of lobes along the horizontal septum.

Methods:

To investigate central drainage, methylene blue was injected subareolarly in five breasts of female cadavers before blunt preparation of the horizontal septum in anatomical studies. To visualize central and peripheral drainage, lymphographin was injected into one of the three different sites in 14 breasts; the dynamic flow of drainage was observed during subsequent septum-based breast reductions in clinical settings.

Results:

In all anatomical studies, a predefined section of the glandular layers allowed access to central clearance along the stained horizontal septum. Clinical investigations similarly showed clearance along the corresponding part of the ligamentous suspension, most reliably along the horizontal septum. The affected quadrant of the breast, its relation to the nipple-areola complex, and the anterior-posterior axis toward the thoracic wall mainly determine the direction of lymphatic flow. Interconnections along the ligaments may explain the unpredictability of final clearance directions.

Conclusions:

This study shows the horizontal septum as a guiding structure for central mammary drainage. This may encourage a septum-based approach for refinement of procedures such as oncoplastic, irradiation, and lymphedema treatments.
Quantifying Improvement in V˙o 2peak and Exercise Thresholds in Cardiovascular Disease Using Reliable Change Indices
Authors: Faricier Robin , Keltz Randi R. , Hartley Tim , McKelvie Robert S. , Suskin Neville G. , Prior Peter L. , Keir Daniel A.
Published: December 2023

Purpose:

Improving aerobic fitness through exercise training is recommended for the treatment of cardiovascular disease (CVD). However, strong justifications for the criteria of assessing improvement in key parameters of aerobic function including estimated lactate threshold (θLT), respiratory compensation point (RCP), and peak oxygen uptake (V˙o
2peak) at the individual level are not established. We applied reliable change index (RCI) statistics to determine minimal meaningful change (MMCRCI) cutoffs of θLT, RCP, and V˙o
2peak for individual patients with CVD.

Methods:

Sixty-six stable patients post-cardiac event performed three exhaustive treadmill-based incremental exercise tests (modified Bruce) ∼1 wk apart (T1-T3). Breath-by-breath gas exchange and ventilatory variables were measured by metabolic cart and used to identify θLT, RCP, and V˙o
2peak. Using test-retest reliability and mean difference scores to estimate error and test practice/exposure, respectively, MMCRCI values were calculated for V˙o
2 (mL·min−1.kg−1) at θLT, RCP, and V˙o
2peak.

Results:

There were no significant between-trial differences in V˙o
2 at θLT (P = .78), RCP (P = .08), or V˙o
2peak (P = .74) and each variable exhibited excellent test-retest variability (intraclass correlation: 0.97, 0.98, and 0.99; coefficient of variation: 6.5, 5.4, and 4.9% for θLT, RCP, and V˙o
2peak, respectively). Derived from comparing T1-T2, T1-T3, and T2-T3, the MMCRCI for θLT were 3.91, 3.56, and 2.64 mL·min−1.kg−1; 4.01, 2.80, and 2.79 mL·min−1.kg−1 for RCP; and 3.61, 3.83, and 2.81 mL·min−1.kg−1 for V˙o
2peak. For each variable, MMCRCI scores were lowest for T2-T3 comparisons.

Conclusion:

These MMCRCI scores may be used to establish cutoff criteria for determining meaningful changes for interventions designed to improve aerobic function in individuals with CVD.
Broad Vitreomacular Attachment Induced Macular Hole: Structural Changes and Surgical Outcome
Authors: Cheng Chia-Yi , Hsieh Yi-Ting , Yang Chung-May
Published: December 2023

Purpose:

This study aims to describe the structural changes and surgical outcomes of full-thickness macular holes (FTMHs) induced by vitreomacular traction (VMT) with broad vitreomacular attachment (VMA).

Methods:

A retrospective analysis of idiopathic FTMHs from October 2010 to May 2022 was conducted. Patients with FTMHs and no retinal detachment (RD) induced by broad VMA (the study group) were compared to a control group consisting of typical FTMHs with focal VMA.

Results:

31 eyes had broad VMA associated FTMH and among which 7 eyes (22%) were with concurrent RD. Among the total of 24 cases without RD, 8 (33%) exhibited schisis. The incidence of lamellar holes associated epithelial proliferation (LHEP) and multiple membrane traction was significantly higher in the study group. 100% FTMH closure was observed postoperatively in both groups. While the postoperative visual acuity was not significantly different, the study group showed greater ellipsoid zone disruption length.

Conclusion:

Broad VMA-induced FTMHs are characterized by diverse macular structural changes, including schisis and macular detachment. These FTMHs are associated with a higher incidence of LHEP and multiple membrane traction. Surgical outcomes for FTMHs induced by broad VMA are similar to those induced by typical focal VMA, with both groups demonstrating a 100% hole closure rate.
US nurse practitioner voluntary turnover: Development of a framework for analysis
Authors: Strobehn Patricia K. , Barnes Hilary , Bellury Lanell M. , Randolph Justus J.
Published: December 2023

Background:

There is growing interest in nurse practitioner (NP) turnover with some reports indicating it is as high as 15% annually. However, there is a lack of generalizability and other conceptual weaknesses in the literature. These weaknesses support the development of a framework to operationalize NP turnover for administrators to develop workplace initiatives to reduce turnover.

Purpose:

To describe the demographic and job characteristics of four NP voluntary turnover groups (i.e., dynamic leavers, static leavers, dynamic stayers, and static stayers) representing voluntary turnover intention and actual turnover among US NPs.

Methodology:

A cross-sectional, descriptive secondary analysis of NPs (N = 86,632) from the 2018 National Sample Survey of Registered Nurses (NSSRN) was used to delineate and describe four NP voluntary turnover groups.

Results:

Nurse practitioners who left nursing (static leavers) were older and had the most work experience. Nurse practitioners who changed jobs and stayed in nursing (dynamic leavers) were younger, less experienced, and reported the least job satisfaction. Nurse practitioners who remained in their positions (stayers) regardless of whether they reported turnover intentions or not earned the most and reported the most job satisfaction.

Conclusions:

Four NP voluntary turnover groups were defined and described to distinguish voluntary turnover intentions from actual turnover.

Implications:

Characterizing NP voluntary turnover can help administrators mitigate losses and project organizational needs associated with NP turnover. A framework developed from the 2018 NSSRN can be used to research and develop key initiatives to strengthen the NP workforce.
Diversity, Equity, and Inclusion Curriculum Embedded in a Physical Medicine and Rehabilitation Residency Program
Authors: Nnoromele Chinenye C. , Chen Ya-Ting , Olezene Cameron S. , Blauwet Cheri A. , Brady Wagner Lynne C. , Katz Nicole B. , Hunter Tracey , Silver Julie K.
Published: December 2023

Diversity, Equity, and Inclusion (DEI) initiatives are continuing to have increased importance in medical training, including rehabilitation medicine. Although resident-led curricula have been integrated into medical education in other training programs, to our knowledge, this the first report focusing on integrating these topics into resident education for a Physical Medicine and Rehabilitation (PM&R) program. We created a didactic curriculum for our rehabilitation residents that included: quarterly lectures on DEI topics followed by small group discussions. Each session also included an article that was included in the discussion. The sessions utilized both anonymous pre and post-survey data to assess the efficacy of our initiative. Our initial data showed that our quarterly sessions created a safe and comfortable environment for discussing DEI topics. In addition, our session specific data supported that increased awareness of DEI disparities with rehabilitation and medicine was achieved. Our committee used the data and feedback to create further iterations of this initiative within our program, and we believe that this is a model that can be adopted by other PM&R residencies.
Post-ERCP Pancreatitis Risk Factors: Is Post-Sphincterotomy Bleeding Another Risk Factor?
Authors: Altunpak Burak , Aydin Husnu , Cebi Fevzi , Seyit Hakan , Kones Osman , Akarsu Cevher , Kabuli Hamit , Gumusoglu Alpen , Karabulut Mehmet
Published: December 2023

Background:

Despite advancements in technology and expertise, ERCP carries risks of significant complications, such as pancreatitis, bleeding, and perforation. Post-ERCP pancreatitis is the most common and important complication following ERCP. In our study, we aimed to examine the relationship between patient and procedure-related parameters and the development of pancreatitis.

Methods:

Four hundred patients who underwent ERCP between January 1, 2019 and December 31, 2020, at the General Surgery Clinic of the Bakirköy Dr. Sadi Konuk Health Application and Research Center of the University of Health Sciences Faculty of Medicine were retrospectively evaluated. Patient and procedure-related factors were analyzed statistically through univariate and multivariate analyses.

Results:

Age, urgent indication, ERCP history, cholangitis, precut sphincterotomy, common bile duct diameter, pancreatic cannulation, pancreatic stent, and bleeding were statistically significant risk factors for post-ERCP pancreatitis (+). In multivariate analysis, the effects of urgent indication, ERCP history, cholangitis, precut sphincterotomy, common bile duct diameter, and pancreatic cannulation on post-ERCP pancreatitis were statistically significant risk factors (P<0.05).

Discussion:

This study demonstrates that emergency indication, ERCP history, cholangitis, precut sphincterotomy, and pancreatic cannulation are significant risk factors for the development of post- ERCP pancreatitis. One notable contribution of our study to the existing literature is the unique analysis of post-sphincterotomy bleeding as an independent factor.
Inhibition of human cytomegalovirus replication by interferon alpha can involve multiple anti-viral factors
Authors: Chowdhury Shabab , Latham Katie A. , Tran Andy C. , Carroll Christopher J. , Stanton Richard J. , Weekes Michael P. , Neil Stuart J. D. , Swanson Chad M. , Strang Blair L.
Published: December 2023

The shortcomings of current direct-acting anti-viral therapy against human cytomegalovirus (HCMV) has led to interest in host-directed therapy. Here we re-examine the use of interferon proteins to inhibit HCMV replication utilizing both high and low passage strains of HCMV. Pre-treatment of cells with interferon alpha (IFNα) was required for robust and prolonged inhibition of both low and high passage HCMV strains, with no obvious toxicity, and was associated with an increased anti-viral state in HCMV-infected cells. Pre-treatment of cells with IFNα led to poor expression of HCMV immediate-early proteins from both high and low passage strains, which was associated with the presence of the anti-viral factor SUMO-PML. Inhibition of HCMV replication in the presence of IFNα involving ZAP proteins was HCMV strain-dependent, wherein a high passage HCMV strain was obviously restricted by ZAP and a low passage strain was not. This suggested that strain-specific combinations of anti-viral factors were involved in inhibition of HCMV replication in the presence of IFNα. Overall, this work further supports the development of strategies involving IFNα that may be useful to inhibit HCMV replication and highlights the complexity of the anti-viral response to HCMV in the presence of IFNα.
Comprehensive Genomic Features indicative for Notch Responsiveness
Authors: Giaimo Benedetto Daniele , Friedrich Tobias , Ferrante Francesca , Bartkuhn Marek , Borggrefe Tilman
Published: December 2023

Transcriptional specificity is often determined by transcription factor levels and/or chromatin context. In the Notch signal transduction pathway, transcription factor RBPJ is the central component and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While the RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated RBPJ occupancy by ChIP-Seq making use of Notch-dependent T cells. Surprisingly, only a small set of the total RBPJ sites show a dynamic binding behavior in response to Notch signaling. Compared to static RBPJ sites, dynamic sites differ in regard to their chromatin state, binding strength and enhancer positioning. Dynamic RBPJ sites are predominantly located distal to transcriptional start sites (TSS), while most static sites are found in promoter-proximal regions. Importantly, gene responsiveness is preferentially associated with dynamic RBPJ binding sites and this static and dynamic binding behavior is repeatedly observed in different cell types and species. Based on the above findings we used a machine-learning algorithm to predict Notch responsiveness with high confidence in different cellular contexts. This approach is potentially applicable to other transcription factors regulating signal-induced gene sets. Our results strongly support the notion that the combination of binding strength and enhancer positioning are indicative of Notch responsiveness.
Shared Genetic Susceptibility between Abdominal Aortic Aneurysm and Cardiometabolic Traits
Authors: Zheng Shufen , Tsao Philip S. , Pan Cuiping
Published: December 2023

Abdominal aortic aneurysm (AAA) presents abnormal metabolism and co-occurs with cardiometabolic disorders, suggesting a shared genetic susceptibility. We investigated this commonality leveraging recent GWAS studies of AAA and 32 cardiometabolic traits (CMTs). Significant genetic correlations are found between AAA and 21 CMTs, among which are causal relationship with coronary artery disease, hypertension, lipid traits, and blood pressure. For each trait pair, we identified shared causal variants, genes, and pathways, which revealed cholesterol metabolism and immune responses were the shared most prominently. Additionally, we uncovered the tissue and cell type specificity in the shared signals, with strong enrichment across traits in liver, arteries, adipose tissues, macrophages, adipocytes, and fibroblasts. Finally, we leveraged drug-gene databases and identified several lipid-lowering drugs and antioxidants with high potential to treat AAA with comorbidities. Our study provides insight into the shared genetic mechanism for AAA and cardiometabolic traits and potential targets for pharmacological intervention.
Advancing bee conservation in the US: gaps and opportunities in data collection and reporting
Authors: Rousseau Josée S. , Woodard S. Hollis , Jepsen Sarina , Du Clos Brianne , Johnston Alison , Danforth Bryan N. , Rodewald Amanda D.
Published: December 2023

Bee conservation in the U.S. is currently hindered by challenges associated with assessing the status and trends of a diverse group of >3000 species, many of which are rare, endemic to small areas, and/or exhibit high inter-annual variation in population size. Fundamental information about the distribution of most species across space and time, thus, is lacking yet urgently needed to assess population status, guide conservation plans, and prioritize actions among species and geographies. Using wild bee data from two public data repositories representing the contiguous U.S., we evaluated the availability and sufficiency of data for use in species assessments of wild bees. We also examined the number of bee species recorded in each U.S. state and the proportion of species with recent records (2012-2021). Although efforts to monitor bees continue to grow, there remains a massive paucity of data. Exceedingly few records (0.04%) reported both sampling protocol and effort, greatly limiting the usefulness of the data. Few species or locations have adequate publicly available data to support analyses of population status or trends, and fewer than half of species have sufficient data to delineate geographic range. Despite an exponential increase in data submissions since the 2000s, only 47% of species were reported within the last decade, which may be driven by how data are collected, reported, and shared, or may reflect troubling patterns of local or large-scale declines and extirpations. Based on our analysis, we provide recommendations to improve the quality and quantity of data that can be used to detect, understand, and respond to changes in wild bee populations.
The temporal recovery of contralateral and ipsilateral knee extensor torque following a bout of unilateral knee extensor resistance exercise in young, healthy resistance-trained men
Authors: Davies Robert W. , Barnes Harley L. , Carson Brian P. , Jakeman Philip M.
Published: December 2023

The present study aimed to characterise the temporal recovery pattern of contralateral-homologous torque following a bout of unilateral resistance exercise (RE). Ten young, healthy, recreationally active, resistance-trained men performed 10 sets of 10 repetitions of knee extensor (KE) contractions at 50 % 1RM with 1 min rest between sets. Isometric maximal voluntary contraction (MVC) peak torque (PT), surface electromyography (sEMG), muscle soreness and serum creatine kinase (CK) levels were assessed immediately before and 5 min after RE cessation, and then +4 h, +24 h, +48 h and +72 h later. Data are presented as mean [95 % CI] % change from pre-exercise values. RE evoked a minor increase in CK and pain in the late recovery period (+24 h to +72 h) (P < 0.034) and decreases in ipsilateral KE PT were observed immediately post-exercise (-26 [-33, -18] %, P < 0.001) and up to +48 h (-12 [-19, -4] %, P = 0.006). Measurable decreases in PT were also observed in the non-exercised contralateral KE immediately post-exercise (-8 [-13, -3] %, P = 0.006) up to +24 h (-8 [-15, 0] %, P = 0.020), but were significantly lower than the ipsilateral KE PT (P < 0.05). These findings suggest the presence of crossover fatigue following RE in young, healthy, active, resistance-trained men, however, the magnitude and temporal recovery are substantially less severe and protracted in the contralateral homologous KE.
Sex-specific role for the long noncoding RNAPnkyin mouse behavior
Authors: Saha Parna , Andersen Rebecca E. , Hong Sung Jun , Gil Eugene , Simms Jeffrey , Lim Daniel A.
Published: December 2023

The human brain expresses thousands of different long noncoding RNAs (lncRNAs), and aberrant expression of specific lncRNAs has been associated with cognitive and psychiatric disorders. While a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few have been shown to underlie animal behavior, particularly with genetic strategies that establish lncRNA function intrans.Pnkyis an evolutionarily conserved, neural lncRNA that regulates brain development. Using mouse genetic strategies, we show thatPnkyhas sex-specific roles in mouse behavior and that this lncRNA underlies specific behavior by functioning intrans. MalePnky-knockout (KO) mice have deficits in cued fear recall, a type of Pavlovian associative memory. In femalePnky-KO mice, the acoustic startle response (ASR) is increased and accompanied by a decrease in prepulse inhibition (PPI), both of which are behaviors altered in affective disorders. Remarkably, expression ofPnkyfrom a bacterial artificial chromosome (BAC) transgene reverses the ASR phenotype of femalePnky-KO mice, demonstrating thatPnkyunderlies specific animal behavior by functioning intrans. More broadly, these data provide genetic evidence that a lncRNA gene and its function intranscan play a key role in the behavior of adult mammals, contributing fundamental knowledge to our growing understanding of the association between specific lncRNAs and disorders of cognition and mood.
Key phosphorylation sites for robust β-arrestin2 binding at the MOR revisited
Authors: Underwood Owen , Fritzwanker Sebastian , Glenn Jaqueline , Batista-Gondin Arisbel , Drube Julia , Hoffman Carsten , Briddon Stephen J , Schulz Stefan , Canals Meritxell
Published: December 2023

Abstract Figure

Desensitisation of the mu-opioid receptor (MOR) is proposed to underlie the initiation of opioid analgesic tolerance and previous work has shown that agonist-induced phosphorylation of the MOR C-tail contributes to this desensitisation. Moreover, we and others have shown that phosphorylation is important for β-arrestin recruitment to the receptor, and that ligands of different efficacies induce distinct patterns, or barcodes, of receptor phosphorylation. Within the MOR C-tail, the370TREHPSTANT379motif harbours Ser/Thr residues important for these regulatory functions.375Ser acts as a primary phosphorylation site of a ligand-dependent, hierarchical, and sequential process, whereby flanking370Thr,376Thr and379Thr residues can get subsequently phosphorylated. Here we used HEK293 GRK KO cells, in combination with phosphosite specific antibodies and site-directed mutagenesis of the MOR, to evaluate the contribution of the different GRK subfamilies to ligand-induced phosphorylation barcodes and β-arrestin2 recruitment. We show that both GRK subfamilies (GRK2/3 and GRK5/6) promote phosphorylation of Thr370and Ser375. However, only GRK2/3 induce phosphorylation of Thr376and Thr379, which is required to promote robust β-arrestin recruitment to the receptor. Moreover, while DAMGO and fentanyl can engage all kinases to promote Thr370and Ser375phosphorylation, under endogenous GRK expression conditions, morphine-induced phosphorylation of these residues is specifically mediated by GRK5/6. These data provide insight into the mechanisms of MOR regulation and suggest that the cellular complement of the different GRK subfamilies plays an important role in determining the tissue responses of distinct opioid agonists.
Searchlight-based trial-wise fMRI decoding in the presence of trial-by-trial correlations
Authors: Soch Joram
Published: December 2023

In multivariate pattern analysis (MVPA) for functional magnetic resonance imaging (fMRI) signals, trial-wise response amplitudes are sometimes estimated using a general linear model (GLM) with one onset regressor for each trial. When using rapid event-related designs with trials closely spaced in time, those estimates can be highly correlated due to the temporally smoothed shape of the hemodynamic response function. In previous work (Soch, J., Allefeld, C., & Haynes, J.-D. (2020). Inverse transformed encoding models – a solution to the problem of correlated trial-by-trial parameter estimates in fMRI decoding.NeuroImage, 209, 116449, 1-19.https://doi.org/10.1016/j.neuroimage.2019.116449), we have proposed inverse transformed encoding modelling (ITEM), a principled approach for trial-wise decoding from fMRI signals in the presence of trial-by-trial correlations. Here, we (i) perform simulation studies addressing its performance for multivariate signals and (ii) present searchlight-based ITEM analysis – which allows to predict a variable of interest from the vicinity of each voxel in the brain. We empirically validate the approach by confirminga prioriplausible hypotheses about the well-understood visual system.
Deciphering abdominal aortic diseases through T-cell clonal repertoire of perivascular adipose tissue
Authors: Piacentini Luca , Vavassori Chiara , Werba Pablo , Saccu Claudio , Spirito Rita , Colombo Gualtiero I.
Published: December 2023

Recent studies suggested that immune-mediated inflammation of perivascular adipose tissue (PVAT) of abdominal aortic aneurysms (AAA) contributes to disease development and progression. Whether the PVAT of AAA is characterized by a specific adaptive immune signature remains unknown. To investigate this hypothesis, we sequenced the T-cell receptor β-chain (TCRβ) in the PVAT of AAA patients and compared with patients with aortic occlusive disease (AOD), who share with the former anatomical site of the lesion, risk factors but differ in pathogenic mechanisms. Our results demonstrate that AAA patients have a lower repertoire diversity than those with AOD and significant differences in V/J gene segment usage. Furthermore, we identified a set of 7 public TCRβ clonotypes that distinguished AAA and AOD with very high accuracy. We also found that the TCRβ repertoire differentially characterizes small and large AAA (aortic diameter <55 mm and ≥55 mm, respectively). This work supports the hypothesis that T-cell-mediated immunity is fundamental in AAA pathogenesis and opens up new clinical perspectives.

Different immune mechanisms may play a key role in the pathogenesis of distal aortic aneurysm and aortoiliac occlusive disease. The TCRβ repertoire of perivascular adipose tissue differs between the two pathologic conditions, suggesting the involvement of specific antigen-specific immune responses.
Statistical diversity distinguishes global states of consciousness
Authors: Starkey Joseph , Carhart-Harris Robin L. , Pigorini Andrea , Nobili Lino , Barrett Adam B.
Published: December 2023

Application of complexity measures to neurophysiological time series has seen increased use in recent years to identify neural correlates of global states of consciousness. Lempel-Ziv complexity is currently the de-facto complexity measure used in these investigations. However, by simply counting the number of patterns, this measure theoretically takes its maximum value for data that are completely random. Recently, a measure of ‘statistical complexity’ - which calculates the diversity of statistical interactions - has been devised which aims to account for and remove randomness seen in data. It was recently found that this measure decreases during anaesthesia in fruit flies. This paper investigates this statistical complexity measure on human neurophysiology data from different stages of sleep, and from individuals under the effects of three psychedelic substances: ketamine, lysergic acid diethylamide (LSD), and psilocybin. Results indicate that statistical complexity: (i) differentiates the different stages of sleep analogously to Lempel-Ziv complexity; (ii) increases relative to placebo for all three psychedelic substances. Thus, statistical complexity is a useful alternative measure for investigating the complexity of neural activity associated with different states of consciousness.
Predicting Phenotypic Traits Using a Massive RNA-seq Dataset
Authors: Hadish John Anthony , Honaas Loren A. , Ficklin Stephen Patrick
Published: December 2023

Transcriptomic data can be used to predict environmentally impacted phenotypic traits. This type of prediction is particularly useful for monitoring difficult-to-measure phenotypic traits and has become increasingly popular for monitoring high-value agricultural crops and in precision medicine. Despite this increase in popularity, little research has been done on how many samples are required for these models to be accurate, and which normalization should be used. Here we create a massive RNA-seq dataset from publicly availableArabidopsis thalianadata with corresponding measurements for age and tissue type. We use this dataset to determine how many samples are required for accurate model prediction and which normalization method is required. We find that Median Ratios Normalization significantly increases performance when predicting age. We also find that in the case of our dataset, only a few hundred samples are required to predict tissue types, and only a few thousand samples are necessary to accurately predict age. Researchers should consider these results when choosing the number of samples in a transcriptomic experiment and during data-processing.

Author Summary

Large datasets have become ubiquitous in both research and industry, with thousands and sometimes millions of samples being collected for a single project. In biology a prominent new technology is RNA-seq, which can be used to measure the expression level of thousands of genes for a single sample. These measurements are used for a variety of downstream applications, including predicting phenotypic traits (i.e. height, disease, etc.). A number of experiments have attempted to use RNA-seq data to make phenotype predictions with varying success. This is partially due to the small sample size of their experiments. RNA-seq datasets are currently relatively small--only a dozen to a few hundred samples--due to the cost per sample. This is expected to change as the cost of sequencing decreases. In this paper we create a massive conglomerate RNA-seq dataset from publicly availableArabidopsis thalianaRNA-seq data. We use this dataset to determine how many samples are required to accurately predict plant age and tissue type using machine learning models. We also explore the best way to normalize large datasets. Our results show the potential of massive RNA-seq datasets, and can be used to inform experimental design for phenotype prediction.
Bottom-up parameterization of enzyme rate constants: Reconciling inconsistent data
Authors: Zielinski Daniel C. , Matos Marta R.A. , de Bree James E. , Glass Kevin , Sonnenschein Nikolaus , Palsson Bernhard O.
Published: December 2023

Kinetic models of enzymes have a long history of use for studying complex metabolic systems and designing production strains. Given the availability of enzyme kinetic data from historical experiments and machine learning estimation tools, a straightforward modeling approach is to assemble kinetic data enzyme by enzyme until a desired scale is reached. However, this type of ‘bottom up’ parameterization of kinetic models has been difficult due to a number of issues including gaps in kinetic parameters, the complexity of enzyme mechanisms, inconsistencies between parameters obtained from different sources, andin vitro-in vivodifferences. Here, we present a computational workflow for the robust estimation of kinetic parameters for detailed mass action enzyme models while taking into account parameter uncertainty. The resulting software package, termed MASSef (the Mass Action Stoichiometry Simulation Enzyme Fitting package), can handle standard ‘macroscopic’ kinetic parameters, including Km, kcat, Ki, Keq, and nh, as well as diverse reaction mechanisms defined in terms of mass action reactions and ‘microscopic’ rate constants. We provide three enzyme case studies demonstrating that this approach can identify and reconcile inconsistent data either withinin vitroexperiments or betweenin vitroandin vivoenzyme function. The code and case studies are provided in the MASSef package built on top of the MASS Toolbox in Mathematica. This work builds on the legacy of knowledge on kinetic behavior of enzymes by enabling robust parameterization of enzyme kinetic models at scale utilizing the abundance of historical literature data and machine learning parameter estimates.

Author Summary

Detailed kinetic models of metabolism offer the promise of enabling new predictions of metabolic behavior and prospective design of metabolic function. However, parameterizing such models remains a substantial challenge. Historically, the kinetics of many enzymes have been measured usingin vitroassays, but integrating this data into consistent large-scale models and filling gaps in available data has been a primary difficulty. Here, we provide an algorithmic approach to parameterize enzyme kinetic models using diverse enzyme kinetic data. The approach reconciles inconsistent data and addresses the issue of gaps in available data implicitly through sampling alternative parameter sets. We provide a number of case studies demonstrating the approach on different enzymes. This work empowers the use of the large amount of historical and machine learning-estimated enzyme data and will aid in the construction of biochemically-accurate models of metabolism.
Development of resident and migratory three-spined stickleback,Gasterosteus aculeatus
Authors: Barnes Megan , Chakrabarti Lisa , MacColl Andrew
Published: December 2023

The three-spined stickleback (Gasterosteus aculeatus)is a teleost fish and a model organism in evolutionary ecology, useful for both laboratory and natural experiments. It is especially valued for the substantial intraspecific variation in morphology, behaviour and genetics. Classic work of Swarup (1958) [1] has described the development in the laboratory of embryos from a single freshwater population, but this was carried out at higher temperature than many stickleback would encounter in the wild and variation between populations was not addressed. Here we describe the development of embryos from two sympatric, saltwater ecotypes of stickleback from North Uist, Scotland raised at 14°C, the approximate temperature of North Uist lochs in the breeding season. The two ecotypes were (a) a large, migratory form in which the adults are completely plated with bony armour and (b) a smaller, low-plated form that is resident year-round in saltwater lagoons. By monitoring embryos every 24-hours post fertilisation, important characteristics of development were observed and photographed to provide a reference for North Uist ecotypes at this temperature. Hatching success was greater than 85% and did not differ between resident and migratory stickleback, but migratory eggs hatched significantly earlier than the resident ecotype. Our work provides a framework that can now be used to compare stickleback populations that may also grow in distinct environmental conditions, to help understand the breadth of normal developmental features and to characterise abnormal development.
Silver nanoparticle biosynthesis utilizingOcimum kilimandscharicumleaf extract and assessment of its antibacterial activity against certain chosen bacteria
Authors: Ouandaogo Horyomba Siaka , Diallo Souleymane , Odari Eddy , Kinyu Johnson
Published: December 2023

Using plants in the biological production of silver nanoparticles (AgNPs) is becoming increasingly important as a practical and environmentally benign method. In the current work, silver nanoparticles were made utilizing the significantOcimum kilimandscharicum, and their potential to combat certain bacteria was discussed. Both aqueous and methanol plant extracts were used for reducing silver nitrate at different time intervals (30 to 150 minutes) and pH (2 to 11). The UV-visible absorption spectrum recorded for both methanol and aqueous extracts revealed successful synthesis of AgNPs. The antimicrobial activity of the AgNPs was evaluated againstEscherichia coliATCC 25922,Salmonella choleraesuiusATCC 10708, andStaphylococcus aureusATCC 25923. 50mg/ml was the concentration of the extracts tested. The best zone of inhibition was recorded for the methanol and aqueous-mediated AgNPs, ranging from 12±1 to 16±1mm. The methanol and aqueous extract silver nanoparticles had the same Minimum Inhibitory Concentration (6.25±0.00 mg/ml), whereas the Minimum Bactericidal Concentrations were 12.5±0.00 and 25±0.00 mg/ml, respectively. The highest inhibition zone of 16±1 mm was observed againstSalmonella choleraesuiuswith 50±0.00 mg/ml aqueous silver nanoparticles. The results show that the silver nanoparticles made withOcimum kilimandscharicumhave potent antibacterial action against those microorganisms.
Whole-genome sequencing of half-a-million UK Biobank participants
Authors: Li Shuwei , Carss Keren J , Halldorsson Bjarni V , Cortes Adrian ,   UK Biobank Whole-Genome Sequencing Consortium
Published: December 2023

Summary Paragraph

Whole-genome sequencing (WGS) provides a comprehensive view of the genome, enabling detection of coding and non-coding genetic variation, and surveying complex regions which are difficult to genotype. Here, we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping1and whole-exome sequencing (WES) efforts2,3. This advance deepens our understanding of how genetics influences disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations with health-related phenotypes and identified novel genetic and clinical insights. While most genome-wide significant associations with disease traits were primarily observed in Europeans, we also identified strong or novel signals in individuals of African and Asian ancestries. Deeper capture of exonic variation in both coding and UTR sequences, strengthened and surfaced novel insights relative to WES analyses. This landmark dataset, representing the largest collection of WGS and available to the UK Biobank research community, will enable advances into our understanding of the human genome, and facilitate the discovery of new diagnostics, therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.

Abstract Figure

Graphic summary.

Framework of the WGS UKB study. This figure captures the flow of this manuscript. We start with the collection of patient samples by UK Biobank and followed by the strategy taken to perform WGS. We continue with quality control performed on GraphTyper and DRAGEN datasets, followed by variant calling of SNPs, in/dels, and structural variants (SV). Thereafter we defined the phenotypes (binary and quantitative) associated with SV, SNPs and at the gene level (rare variant analysis) and conclude with the definition of five ancestry groups and collective association effect as a cross-ancestry meta-analysis.
Haloperidol inhibits inflammasome activation via LAMTOR1 and reduces the risk of arthritides
Authors: Ambati Vidya L. , Yerramothu Praveen , Konduri Ranjith , Nguyen Joseph , Gelfand Bradley D. , Taylor E. Will , Werner Brian C. , Wang Shao-bin
Published: December 2023

Gout is the most prevalent form of inflammatory arthritis in the world. Although multiple treatments exist, many patients are poorly responsive. Here we report, using a health insurance database analysis, that use of the anti-psychotic haloperidol is associated with a reduced risk of incident gout. Haloperidol inhibits ASC speck formation, caspase-1 activation, and release of IL-1β and IL-6, suggesting that it inhibits NLRP3 inflammasome activation and downstream cytokine responses. We also identified LAMTOR1 as a novel binding partner for haloperidol and demonstrate that haloperidol inhibits the aggregation of LAMTOR1 and NLRP3. Since NLRP3 inflammasome activation has been implicated in gout, these data provide a foundation for exploring haloperidol as a potential therapy.