bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a model to predict the risk of early graft failure after adult-to-adult living donor liver transplantation: An ELTR study
Authors: Giglio Mariano Cesare , Dolce Pasquale , Yilmaz Sezai , Tokat Yaman , Acarli Koray , Kilic Murat , Zeytunlu Murat , Unek Tarkan , Karam Vincent , Adam René , Polak Wojciech Grzegorz , Fondevila Constantino , Nadalin Silvio , Troisi Roberto Ivan ,   for the European Liver and Intestine Transplant Association (ELITA)
Published: December 2023

Graft survival is a critical end point in adult-to-adult living donor liver transplantation (ALDLT), where graft procurement endangers the lives of healthy individuals. Therefore, ALDLT must be responsibly performed in the perspective of a positive harm-to-benefit ratio. This study aimed to develop a risk prediction model for early (3 months) graft failure (EGF) following ALDLT. Donor and recipient factors associated with EGF in ALDLT were studied using data from the European Liver Transplant Registry. An artificial neural network classification algorithm was trained on a set of 2073 ALDLTs, validated using cross-validation, tested on an independent random-split sample (n=518), and externally validated on United Network for Organ Sharing Standard Transplant Analysis and Research data. Model performance was assessed using the AUC, calibration plots, and decision curve analysis. Graft type, graft weight, level of hospitalization, and the severity of liver disease were associated with EGF. The model (http://ldlt.shinyapps.io/eltr_app) presented AUC values at cross-validation, in the independent test set, and at external validation of 0.69, 0.70, and 0.68, respectively. Model calibration was fair. The decision curve analysis indicated a positive net benefit of the model, with an estimated net reduction of 5–15 EGF per 100 ALDLTs. Estimated risks>40% and<5% had a specificity of 0.96 and sensitivity of 0.99 in predicting and excluding EGF, respectively. The model also stratified long-term graft survival (p<0.001), which ranged from 87% in the low-risk group to 60% in the high-risk group. In conclusion, based on a panel of donor and recipient variables, an artificial neural network can contribute to decision-making in ALDLT by predicting EGF risk.
Irritable bowel syndrome – less irritable, or better treatments?
Authors: Travers Paul , Lacy Brian E. , Cangemi David J.
Published: December 2023

Purpose of review

Irritable bowel syndrome (IBS) is a chronic, often bothersome disorder of gut-brain interaction (DGBI) characterized by abdominal pain associated with a change in stool frequency and/or caliber. Recent advancements have improved our understanding of the underlying pathophysiology, thus opening new avenues for therapeutic intervention. The purpose of this review is to summarize the current literature regarding treatment modalities for IBS.

Recent findings

Altering the gut microbiome via probiotic and antibiotic administration, avoiding dietary triggers, and modulating the gut-brain axis have all proven efficacious for the management of IBS symptoms. Several gut-specific pharmacotherapies are approved for the treatment of IBS, many of which primarily address either diarrhea or constipation, although many patients remain symptomatic despite appropriate use. Brain-gut behavioral therapies (BGBTs) are increasingly used to treat symptoms of IBS, particularly in those who do not respond to traditional therapies. Virtual reality represents an exciting new approach to treating DGBIs, like IBS, though data are limited.

As our understanding of IBS continues to evolve, so should our therapeutic approach. Individualizing the therapeutic approach is of utmost importance.
Heavy antiretroviral exposure and exhausted/limited antiretroviral options: predictors and clinical outcomes
Authors: Mocroft Amanda , Pelchen-Matthews Annegret , Hoy Jennifer , Llibre Josep M. , Neesgaard Bastian , Jaschinski Nadine , Domingo Pere , Rasmussen Line Dahlerup , Günthard Huldrych F. , Surial Bernard , Öllinger Angela , Knappik Michael , de Wit Stephane , Wit Ferdinand , Mussini Cristina , Vehreschild Joerg , Monforte Antonella D’Arminio , Sonnerborg Anders , Castagna Antonella , Anne Alain Volny , Vannappagari Vani , Cohen Cal , Greaves Wayne , Wasmuth Jan C. , Spagnuolo Vincenzo , Ryom Lene ,   for the RESPOND cohort collaboration∗
Published: December 2023

Objectives:

People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort.

Methods:

Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]).

Results:

Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59–1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5–15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19–1.46), development of CKD (1.84; 1.59–2.13), CVD (1.64; 1.38–1.94), AIDS (1.18; 1.07–1.30), and current CD4+ cell count of 350 cells/μl or less (vs. 351–500 cells/μl, 1.51; 1.32–1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015–2017; 0.52; 0.47–0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40–0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48–2.05).

Conclusion:

Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018–2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.
Outcomes of Robotic Versus Laparoscopic Pancreatoduodenectomy After Learning Curves of Surgeons
Authors: Zhang Xiu-Ping , Xu Shuai , Zhao Zhi-Ming , Yu Guang-Sheng , Han Bing , Chen Xiong , Ma Yun-Tao , Xu Zong-Zhen , Liu Zhao , Li En-Shan , Guo Xiang-Feng , Gao Yuan-Xing , Zhao Guo-Dong , Lau Wan Yee , Liu Jun , Liu Rong
Published: December 2023

Objective:

This study aimed to compare robotic pancreatoduodenectomy (RPD) with laparoscopic pancreatoduodenectomy (LPD) in operative and oncologic outcomes.

Background:

Previous studies comparing RPD with LPD have only been carried out in small, single-center studies with variable quality.

Methods:

Consecutive patients from nine centers in China who underwent RPD or LPD between 2015 and 2022 were included. A 1:1 propensity score matching (PSM) was used to minimize bias.

Results:

Of the 2255 patients, 1158 underwent RPD, and 1097 underwent LPD. After PSM, 1006 patients were enrolled in each group. The RPD group had significantly shorter operative time (270.0 vs 305.0 minutes, P<0.001), lower intraoperative blood transfusion rate (5.9% vs 12.0%, P<0.001), lower conversion rate (3.8% vs 6.7%, P=0.004), and higher vascular reconstruction rate (7.9% vs 5.6%, P=0.040) than the LPD group. There were no significant differences in estimated blood loss, postoperative length of stay, perioperative complications, and 90-day mortality. Patients who underwent vascular reconstruction had similar outcomes between the 2 groups, although they had significantly lower estimated blood loss (300.0 vs 360.0 mL; P=0.021) in the RPD group. Subgroup analysis on pancreatic ductal adenocarcinoma found no significant differences between the 2 groups in median recurrence-free survival (14.3 vs 15.3 mo, P=0.573) and overall survival (24.1 vs 23.7 mo, P=0.710).

Conclusions:

In experienced hands, both RPD and LPD are safe and feasible procedures with similar surgical outcomes. RPD had a perioperative advantage over LPD, especially in vascular reconstruction. For pancreatic ductal adenocarcinoma patients, RPD resulted in similar oncological and survival outcomes as LPD.
Rescue Allocation Modes in Eurotransplant Kidney Transplantation: Recipient Oriented Extended Allocation Versus Competitive Rescue Allocation—A Retrospective Multicenter Outcome Analysis
Authors: Assfalg Volker , Miller Gregor , Stocker Felix , Hüser Norbert , Hartmann Daniel , Heemann Uwe , Tieken Ineke , Zanen Wouter , Vogelaar Serge , Rosenkranz Alexander R. , Schneeberger Stefan , Függer Reinhold , Berlakovich Gabriela , Ysebaert Dirk R. , Jacobs-Tulleneers-Thevissen Daniel , Mikhalski Dimitri , van Laecke Steven , Kuypers Dirk , Mühlfeld Anja S. , Viebahn Richard , Pratschke Johann , Melchior Sebastian , Hauser Ingeborg A. , Jänigen Bernd , Weimer Rolf , Richter Nicolas , Foller Susan , Schulte Kevin , Kurschat Christine , Harth Ana , Moench Christian , Rademacher Sebastian , Nitschke Martin , Krämer Bernhard K. , Renders Lutz , Koliogiannis Dionysios , Pascher Andreas , Hoyer Joachim , Weinmann-Menke Julia , Schiffer Mario , Banas Bernhard , Hakenberg Oliver , Schwenger Vedat , Nadalin Silvio , Lopau Kai , Piros Laszlo , Nemes Balazs , Szakaly Peter , Bouts Antonia , Bemelman Frederike J. , Sanders Jan S. , de Vries Aiko P. J. , Christiaans Maarten H. L. , Hilbrands Luuk , van Zuilen Arjan D. , Arnol Miha , Stippel Dirk , Wahba Roger
Published: December 2023

Background.

Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries.

Methods.

The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods.

Results.

Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y.

Conclusions.

REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany.
Balloon Rises Above: REBOA at Zone 1 May Be Superior to Resuscitative Thoracotomy
Authors: Brenner Megan , Zakhary Bishoy , Coimbra Raul , Scalea Thomas , Moore Laura , Moore Ernest , Cannon Jeremy , Spalding Chance , Ibrahim Joseph , Dennis Bradley
Published: December 2023

BACKGROUND:

The use of Zone 1 REBOA for life-threatening trauma has increased dramatically.

STUDY DESIGN:

The Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery database was queried for blunt and penetrating trauma between 2013 and 2021. Outcomes were examined both for mechanisms of injury combined and separately and for combinations of abdominal injury with and without traumatic brain injury and chest injuries (Abbreviated Injury Scale [AIS] score >2).

RESULTS:

A total of 531 patients underwent REBOA (408 with blunt injury and 123 with penetrating injury) and 1,603 (595 with blunt injury and 1,008 with penetrating injury) underwent resuscitative thoracotomy (RT). Mean age was 38.5 ± 16 years and mean injury severity score was 34.5 ± 21; 57.7% had chest AIS score of more than 2, 21.8% had head AIS score of more than 2, and 37.3% had abdominal AIS score of more than 2. Admission Glasgow Coma Scale was 4.9 + 4, and systolic blood pressure at aortic occlusion (AO) was 22 + 40 mmHg. No differences in outcomes in REBOA or RT patients were identified between institutions (p > 0.5). After inverse probability weighting, Glasgow Coma Scale, age, injury severity score, systolic blood pressure at AO, CPR at AO, and blood product transfusion, REBOA was superior to RT in both blunt (odds ratio [OR] 4.7, 95% CI 1.9 to 11.7) and penetrating (OR 4.9, 95% CI 1.7 to 14) injuries, across all spectrums of injury (p < 0.01). Overall mortality was significantly higher for AO more than 90 minutes compared with less than 30 minutes in blunt (OR 4.6, 95% CI 1.5 to 15) and penetrating (OR 5.4, 95% CI 1.1 to 25) injuries. Duration of AO more than 60 minutes was significantly associated with mortality after penetrating abdominal injury (OR 5.1, 95% CI 1.1 to 22) and abdomen and head (OR 5.3, 95% CI 1.6 to 18).

CONCLUSIONS:

In-hospital survival is higher for patients undergoing REBOA than RT for all injury patterns. Complete AO by REBOA or RT should be limited to less than 30 minutes. Neither hospital and procedure volume nor trauma verification level impacts outcomes for REBOA or RT.
Unraveling the Molecular Complexity of Bicuspid Aortopathy: Lessons from Comparative Proteomics
Authors: Pozo-Vilumbrales Bárbara , Martín-Chaves Laura , López-Unzu Miguel A. , Soto-Navarrete María Teresa , Pavón-Morón Javier , Rodriguez-Capitán Jorge , Corujo Borja Fernández
Published: December 2023

Background

Molecular markers and pathways involved in the etiology and pathophysiology of bicuspid aortopathy are poorly understood. The aim here is to delve into the molecular and cellular mechanisms of the disease and identify potential predictive molecular markers using a well-established isogenic hamster model (T-strain) of bicuspid aortic valve (BAV) and thoracic aortic dilatation (TAD).

Methods

Comparative quantitative proteomics combined with western blot and morpho-molecular analyses in the ascending aorta of tricuspid aortic valve (TAV) and BAV animals from the T-strain, and TAV animals from a control strain. This strategy allows discriminating between genetic and hemodynamic factors in genetically homogeneous populations.

Results

The major molecular alteration in the aorta of genetically homogeneous BAV individuals is PI3K/AKT overactivation caused by changes in the EGF, ANGII and TGF-β pathways. PI3K/AKT affects downstream eNOS, MAP2K1/2, NF-κB, mTOR and WNT pathways. Most of these alterations are seen in independent patient studies with different clinical presentations, but not in TAV hamsters from T-strain that mainly exhibit WNT pathway downregulation.

Conclusions

We identify a combination of defective interconnected molecular pathways, directly linked to the central PI3K/AKT pathway, common to both BAV-associated TAD patients and hamsters. The defects indicate smooth muscle cell shift towards the synthetic phenotype induced by endothelial-to-mesenchymal transition, oxidative stress and inflammation. WNT signaling represent one genetic factor that may cause structural aortic abnormalities and aneurysm predisposition, whereas hemodynamics is the main trigger of molecular alterations, probably determining aortopathy progression. We identify twenty-seven novel potential biomarkers with a high predictive value.
Expression Patterns ofMalgenes and its Association with Differential Maltose and Maltotriose Transport rate of TwoSaccharomyces pastorianusYeasts
Authors: Hernández-Vásquez César I. , García-García Jorge H. , Pérez-Ortega Esmeralda R. , Martínez-Segundo Adriana G. , Damas-Buenrostro Luis C. , Pereyra-Alférez Benito
Published: December 2023

Microorganisms play a significant role in fermented food biotechnology by converting raw materials in human edible organoleptic and nutritive components, especially in the beer brewing industry. The lager-style beer is the dominant industrial beer type, and it is fermented bySaccharomyces pastorianus(Sp) whose members encompass two groups. Typically, strains belonging to group I are deficient in maltotriose consumption. The main variables linked to this phenotype are fermentation conditions, the presence of maltotriose transporters, copy number variation of maltose and maltotriose transporters, and differential genetic regulation. This study was aimed to determine that the differences the alpha-glycoside consumption phenotypes of two Sp strains, Sp820 and Sp790, are related with different phylogenetic distribution and gene expression of the transporters ScMalx1, SeMalx1, ScAGT1, SeAGT1,MTT1 andMPHx. Biochemical analyses of the transport rate confirmed that the Sp790 strain transported more maltose and maltotriose, 28% and 32% respectively, than Sp820 strain. In addition, detection of Sp790 transcripts indicated the presence of all theMalgenes analyzed since the first day of fermentation, whereas Sp820 only presented transcripts for the ScMalx1, ScAGT1, andMPHx genes. These results indicate that a multifactorial phenomenon related with phylogenetic distribution, polymorphisms in transmembrane domains and the difference in the genetic expression of maltose and maltotriose transporters are involved in the phenotypic diversity related with maltose and maltotriose consumption in two lager yeast.

IMPORTANCE

Beer is the third most popular beverage around the world and has roughly 90% market share in the alcoholic beverage industry.Saccharomyces pastorianus(Sp) strains, which are widely used for lager beer production, have a phenotypic diversity involved in maltotriosa consumption. The fermentation of this sugar is fundamental for the flavor landscape produced during lager beer brewing. This phenotypic diversity encompasses lager yeast strain with remarkable ability to consume maltotriose; Sp group II, to poor capacity of consumption for some lager yeast belonging to Sp group I. Research in this field indicate that variables like conditions of fermentation, presence of maltotriose transporter specific genes, and differential gene regulation can cause this diversity. The significance of our study is to approximate and also contribute to the elucidation of mechanistic variables involved in such phenotypic variability that will allow the development of more controlled and efficient biotechnological processes around beer brewing industry.
Tirofiban in Acute Ischemic Stroke Patients Undergoing Endovascular Thrombectomy with Preceding intravenous Thrombolysis
Authors: Wu Yuefei , Zhu Tianrui , Yang Jianhong , Abuduaini Mayila , Liu Feifeng , Zhang Yue , Parsons Mark W. , Li Gang , Lin Longting
Published: December 2023

Background

The effectiveness of Tirofiban administration to acute ischemic stroke patients undergoing endovascular thrombectomy (EVT) after intravenous thrombolysis (IVT) remains unclear. This study examined the effect of intraarterial or intravenous tirofiban during endovascular thrombectomy following thrombolysis.

Methods

Patients with acute ischemic stroke who received EVT after thrombolysis were selected from the International Stroke Perfusion Imaging Registry, and divided into three groups according to tirofiban administration. Safety outcomes were symptomatic intracerebral hemorrhage (sICH) and parenchymal hematoma type-2 (PH2). Efficacy outcomes included successful recanalization, complete recanalization, functional independence, and death at 3-months. Univariate and multivariate regression estimates are listed as “estimate [95% confidence interval] p-value”.

Results

We analyzed a total of 682 patients who underwent EVT after IVT. Among them, 53 (7.77%) were treated with intraarterial tirofiban (IA-tirofiban group), 80 (11.73%) were treated with intravenous tirofiban (IV-tirofiban group), while 549 (80.50%) patients were not treated with tirofiban (non-tirofiban group). There were no significant differences between groups in the incidences of PH2 or sICH (P=0.413,P=0.256). There were significant differences in successful recanalization, functional independence, and death at 3-months (P=0.031,P<0.001,P=0.010). There was no difference between IA-tirofiban and non-tirofiban in terms of safety or efficacy outcomes. Compared with non-tirofiban, IV-tirofiban was not associated with PH2 (P=0.111; adjustedP=0.705) or sICH (P=0.263; adjustedP=0.168), but was associated with higher odds of successful recanalization (OR=8.94 [1.22–65.53],P=0.031; adjusted OR=8.24 [1.08–62.59], adjustedP=0.041), 3-month functional independence (OR=3.21 [1.88–5.50],P<0.001; adjusted OR=2.22 [1.21–4.12], adjustedP=0.011) and lower odds of 3-month death (OR=0.20 [0.17–0.27],P=0.007; adjusted OR=0.25 [0.07–0.92], adjustedP=0.039).

Conclusions

In acute ischemic stroke patients undergoing mechanical thrombectomy with preceding intravenous thrombolysis, both intraarterial and intravenous tirofiban could be safe. However, only intravenous tirofiban was associated with clinical benefit. Further randomized clinical trials are needed to confirm these findings.
Peripheral inflammation is associated with structural brain atrophy and cognitive decline linked to mild cognitive impairment and Alzheimer’s disease
Authors: Liang Nuanyi , Nho Kwangsik , Newman John W. , Arnold Matthias , Huynh Kevin , Meikle Peter J. , Borkowski Kamil , Kaddurah-Daouk Rima ,   Alzheimer’s Disease Metabolomics Consortium,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Mounting evidence points towards inflammation as an important factor in Alzheimer’s disease (AD) pathogenesis. In this study, we investigated the relationship between a key marker of inflammation – glycoprotein acetyls (GlycA) – in blood and cognitive and brain structural changes in over 1500 participants enrolled into the Alzheimer’s Disease Neuroimaging Initiative. We evaluated those associations cross-sectionally at baseline, followed by an evaluation of whether baseline GlycA can inform about future disease progression. Our results support the following findings: 1) GlycA is elevated in participants diagnosed with AD compared to cognitively normal participants; 2) GlycA level correlates negatively with regional brain volumes in females diagnosed with late mild cognitive impairment (LMCI) or AD; 3) baseline GlycA level is associated with executive function decline at 3-9 year follow-up in both male and female participants diagnosed with LMCI at baseline; and 4) baseline GlycA is associated with decline in entorhinal cortex volume at years 2, 4 and 6-8 of follow-up in both male and female participants diagnosed with LMCI at baseline. In conclusion, peripheral inflammation was found to be positively associated with AD diagnosis and future decline in cognition and regional brain volumes. However, we note that the cross-sectional relationship between peripheral inflammation and AD-related brain atrophy is specific to sex and diagnostic status. Our findings point to peripheral inflammation as a risk factor in AD development, which enables the identification of potential markers and therapeutic intervention for participants who are at risk.
Speech-induced suppression and vocal feedback sensitivity in human cortex
Authors: Ozker Muge , Yu Leyao , Dugan Patricia , Doyle Werner , Friedman Daniel , Devinsky Orrin , Flinker Adeen
Published: December 2023

Across the animal kingdom, neural responses in the auditory cortex are suppressed during vocalization, and humans are no exception. A common hypothesis is that suppression increases sensitivity to auditory feedback, enabling the detection of vocalization errors. This hypothesis has been previously confirmed in non-human primates, however a direct link between auditory suppression and sensitivity in human speech monitoring remains elusive. To address this issue, we obtained intracranial electroencephalography (iEEG) recordings from 35 neurosurgical participants during speech production. We first characterized the detailed topography of auditory suppression, which varied across superior temporal gyrus (STG). Next, we performed a delayed auditory feedback (DAF) task to determine whether the suppressed sites were also sensitive to auditory feedback alterations. Indeed, overlapping sites showed enhanced responses to feedback, indicating sensitivity. Importantly, there was a strong correlation between the degree of auditory suppression and feedback sensitivity, suggesting suppression might be a key mechanism that underlies speech monitoring. Further, we found that when participants produced speech with simultaneous auditory feedback, posterior STG was selectively activated if participants were engaged in a DAF paradigm, suggesting that increased attentional load can modulate auditory feedback sensitivity.
Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification ofDYRK1A
Authors: Brierley CK , Yip BH , Orlando G , Goyal H , Wen S , Wen J , Levine MF , Jakobsdottir G M , Rodriguez-Meira A , Adamo A , Bashton M , Hamblin A , Clark SA , O’Sullivan J , Murphy L , Olijnik AA , Cotton A , Narina S , Pruett-Miller SM , Enshaei A , Harrison C , Drummond M , Knapper S , Tefferi A , Antony-Debré I , Thongjuea S , Wedge DC , Constantinescu S , Papaemmanuil E , Psaila B , Crispino JD , Mead AJ
Published: December 2023

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients (‘chr21amp’). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy.DYRK1A, a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate thatDYRK1Ais a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression.DYRK1Ais essential for BP-MPN cell proliferationin vitroandin vivo, and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.
Associations of Alzheimer’s disease with inpatient hospital costs and with quality-adjusted life years: Evidence from conventional and Mendelian randomization analyses in the UK Biobank
Authors: Dixon Padraig , Anderson Emma
Published: December 2023

BACKGROUND

Alzheimer’s disease and other dementias are progressive neurodegenerative disorders with profound impacts on cognitive function. There is a shortage of economic evidence relating to the impact Alzheimer’s disease on healthcare costs and quality-adjusted life-years (QALYs).

METHODS

We employed two study designs to model the association between Alzheimer’s disease and healthcare costs and QALYs. We first estimated conventional multivariable models of the association between Alzheimer’s disease and these core economic outcomes. However, these types of model may be confounded by diseases, processes, or traits that independently affect Alzheimer’s disease and either or both of healthcare costs and QALYs. We therefore also explored a complementary approach using germline genetic variation as instrumental variables in a Mendelian randomization analysis. We used single nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies of Alzheimer’s disease as instruments. We studied outcome data on inpatient hospital costs and QALYs in the UK Biobank cohort.

RESULTS

Data from up to 310,838 individuals were analyzed. N=55 cases of Alzheimer’s disease were reported at or before recruitment into UK Biobank. A further N=284 incident cases were identified over follow-up. Multivariable observational analysis of the prevalent cases suggested significant impacts on costs (£1,140 in cases, 95% Confidence Interval (CI): £825 to £1,456) and QALYs (−25%, 95% CI: -28% to -21%). Mendelian randomization estimates were very imprecise for costs (£3,082, 95% CI: -£7,183 to £13,348) and QALYs (−32%, 95% CI: -149% to 85%), likely due to the small proportion of variance (0.9%) explained in Alzheimer’s disease status by the most predictive set of SNPs.

IMPLICATIONS

Conventional multivariable models suggested important impacts of Alzheimer’s disease on inpatient hospital costs and QALYs, although this finding was based on very few cases which may have included instances of early-onset dementia. Mendelian randomization was very imprecise. Larger GWAS of clinical cases, improved understanding of the architecture of the disease, and the follow-up of cohorts until old age and death will help overcome these challenges.
A Day in the Life of Arabidopsis:24-Hour Time-lapse Single-nucleus Transcriptomics Reveal Cell-type specific Circadian Rhythms
Authors: Qin Yuwei , Liu Zhijian , Gao Shiqi , Long Yanping , Zhu Xinlong , Liu Bin , Gao Ya , Xie Qiguang , Nohales Maria A. , Xu Xiaodong , Zhai Jixian
Published: December 2023

Functional circadian clock is fundamental to the adaptation and survival of organisms. In land plants, the comprehensive profiling of circadian gene expression at the single-cell level is largely unknown partly due to the challenges in obtaining precisely-timed single cells from plant cells embedded within cell walls. To bridge this gap, we employed single-nucleus RNA sequencing (snRNA-seq) on twelve seedling samples collected at 2-hour intervals over a 24-hour day in Arabidopsis, yielding a total of over 130,000 nuclei. From this data, we found that three cell clusters in the shoot share a coherent rhythm, while more than 3,000 genes display cell-type specific rhythmic expression. Only 19 genes are oscillating in more than ten different cell types, and the majority of them are well-documented core oscillators, suggesting the snRNA-seq circadian data could be used to identify key circadian regulators in a broad range of plant systems. Our data provides the first comprehensive resource for plant circadian rhythms at the single-cell level (hosted athttps://zhailab.bio.sustech.edu.cn/sc_circadian).
Sex differences in the secular change in waist circumference relative to body mass index in the Americas and England from 1997 to 2020
Authors: Sánchez-Romero Luz M , Sagaceta-Mejía Janine , Mindell Jennifer S , Passi-Solar Álvaro , Bernabé-Ortiz Antonio , Tolentino-Mayo Lizbeth , Moody Alison , Scholes Shaun
Published: December 2023

Objective

To quantify changes over time in waist circumference (WC) relative to body mass index (BMI) by sex in the Americas (UnitedStates of America, Mexico, Chile, Peru) and England.

Methods

Data from adults aged 25-64 years between 1997 and 2020 was analysed; US data was stratified by racial-ethnic groups. Sex-specific BMI and WC means, and obesity and abdominal obesity prevalence, were compared between the first and last surveys. Using data from all survey years, secular changes across the BMI and WC distributions were estimated applying quantile regression models. BMI was added as a predictor of WC to estimate secular changes in WC relative to BMI. Interaction terms were included in all models to evaluate differences by sex.

Results

BMI and WC (except Peru) showed larger secular increases at the upper-tails of the distributions in both sexes. Increases at the 50thand 75thWC centiles relative to BMI were more pronounced in women than in men, with larger increases in US non-Hispanic whites and in England. In men, increases in WC independently of BMI were most evident in Mexico.

Conclusions

Disease risk associated with visceral fat, is potentially underestimated by national surveillance efforts that quantifysecularchanges only in BMI.
PINK1 and BNIP3 mitophagy inducers have an antagonistic effect on Rbf1-induced apoptosis inDrosophila
Authors: Fages Mélanie , Ruby Vincent , Brusson Mégane , Arnold-Rincheval Aurore , Wintz Christine , Bouleau Sylvina , Guénal Isabelle
Published: December 2023

The structure and function of the mitochondrial network are finely regulated. Among the proteins involved in these regulations, mitochondrial dynamics actors have been reported to regulate the apoptotic process. We show here in theDrosophilamodel that the mitophagy inducers, PINK1 (PTEN- induced putative kinase 1) and BNIP3 (Bcl-2 Interacting Protein 3), modulate mitochondrial apoptosis differently. If close links between the fission-inducing protein DRP1 and Bcl-2 family proteins, regulators of apoptosis, are demonstrated, the connection between mitophagy and apoptosis is still poorly understood. InDrosophila, we have shown that Rbf1, a homolog of the oncosuppressive protein pRb, induces cell death in proliferating larval tissues through a mechanism involving the interaction of Drp1 with Debcl, a pro-apoptotic protein of the Bcl-2 family. This interaction is necessary to induce mitochondrial fission, ROS production, and apoptosis.

To better understand the interactions between the proteins involved in mitochondrial homeostasis and the apoptotic process, we focused on the role of two known players in mitophagy, the proteins PINK1 and BNIP3, during mitochondrial apoptosis induced by Rbf1 and Debcl in a proliferatingDrosophilalarval tissue. We show that Rbf1- or Debcl-induced apoptosis is accompanied by mitophagy. Interestingly, PINK1 and BNIP3 have distinct effects in regulating cell death. PINK1 promotesrbf1- ordebcl-induced apoptosis, whereas BNIP3 protects against Rbf1-induced apoptosis but reduces Debcl- induced tissue loss without inhibiting Debcl-induced cell death. Furthermore, our results indicate that BNIP3 is required to induce basal mitophagy while PINK1 is responsible for mitophagy induced byrbf1overexpression. These results highlight the critical role of mitophagy regulators in controlling homeostasis and cell fate.
Molecular Determinants and Signaling Effects of PKA RIα Phase Separation
Authors: Hardy Julia C. , Pool Emily H. , Bruystens Jessica G.H. , Zhou Xin , Li Qingrong , Zhou Daojia R. , Palay Max , Tan Gerald , Chen Lisa , Choi Jaclyn L.C. , Lee Ha Neul , Strack Stefan , Wang Dong , Taylor Susan S. , Mehta Sohum , Zhang Jin
Published: December 2023

Spatiotemporal regulation of intracellular signaling molecules, such as the 3’,5’-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures the specific execution of various cellular functions. Liquid-liquid phase separation (LLPS) of the ubiquitously expressed PKA regulatory subunit RIα was recently identified as a major driver of cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces combined with the cAMP-induced release of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence are required to drive RIα condensate formation in cytosol, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in the formation of a non-canonical R:C complex, which serves to maintain low basal PKA activity in the cytosol by enabling the recruitment of active PKA-C to RIα condensates. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.
Interaction with IP6K1 supports pyrophosphorylation of substrate proteins by the inositol pyrophosphate 5-IP7
Authors: Hamid Aisha , Ladke Jayashree S. , Shah Akruti , Pal Monisita , Ganguli Shubhra , Singh Arpita , Bhandari Rashna
Published: December 2023

Inositol pyrophosphates (PP-IPs) are a sub-family of water soluble inositol phosphates that possess one or more diphosphate groups. PP-IPs can transfer their β-phosphate group to a phosphorylated Ser residue to generate pyrophosphorylated Ser. This unique post-translational modification occurs on Ser residues that lie in acidic stretches within an intrinsically disordered protein sequence. Serine pyrophosphorylation is dependent on the presence of Mg2+ions, but does not require an enzyme for catalysis. The mechanisms by which cells can regulate this enzyme-independent modification are still unknown. Here, we show that IP6K1, an enzyme responsible for the synthesis of the PP-IP 5-IP7, interacts with several proteins that undergo 5-IP7 mediated pyrophosphorylation, and with CK2, a protein kinase that phosphorylates Ser residues prior to pyrophosphorylation. We characterized the interaction of IP6K1 with AP3B1, the β subunit of the AP3 adaptor protein complex, which is a known pyrophosphorylation substrate. We observe the formation of a protein complex between IP6K1, AP3B1, and the catalytic α-subunit of CK2, and show that disrupting IP6K1 binding to AP3B1 lowers its in vivo pyrophosphorylation. We propose that assembly of a substrate-CK2-IP6K complex would allow for coordinated pre-phosphorylation and pyrophosphorylation of the target serine residue, and provide a mechanism to regulate this enzyme-independent modification.
Functional connectivity, tissue microstructure and T2 at 11.1 Tesla distinguishes neuroadaptive differences in two traumatic brain injury models in rats: A Translational Outcomes Project in NeuroTrauma (TOP-NT) UG3 phase study
Authors: Kommireddy Rohan S. , Mehra Shray , Pompilus Marjory , Arja Rawad Daniel , Zhu Tian , Yang Zhihui , Fu Yueqiang , Zhu Jiepei , Kobeissy Firas , Wang Kevin K.W. , Febo Marcelo
Published: December 2023

Traumatic brain injuries (TBIs), particularly contusive types, are associated with disruptions in neuronal communication due to focal and diffuse axonal injury, as well as alterations in the neuronal chemical environment. These changes can negatively impact neuronal networks beyond the primary injury site. In this Translational Outcomes Project in NeuroTrauma (TOP-NT) UG3 phase study, we sought to use multimodal neuroimaging biomarker approach to assess functional connectivity and brain tissue microstructure, along with T2 relaxometry, in two experimental rat models of TBI: controlled cortical impact (CCI) and lateral fluid percussive injury (LFPI). Rats underwent imaging using an 11.1 Tesla scanner at 2 and 30 days post-injury. Naïve controls were scanned once to establish baseline comparisons for both TBI groups. Imaging modalities included functional magnetic resonance imaging (fMRI), diffusion-weighted imaging (DWI), and multi-echo T2 imaging. fMRI data were analyzed to evaluate functional connectivity across lateral and medial regions of interest (ROIs) in the cortical mantle, hippocampus, and dorsal striatum. DWI scans were used to generate maps of fractional anisotropy (FA) and mean, axial, and radial diffusivities (MD, AD, RD), focusing on cortical and white matter (WM) regions near the injury epicenter. Our findings revealed significantly increased contralateral intra-cortical connectivity at 2 days post-injury in both CCI and LFPI models, localized to similar cortical areas. This increased connectivity persisted at day 30 in the CCI model but not in LFPI. Changes in WM and cortical FA and diffusivities were observed in both models, with WM alterations predominating in CCI and cortical changes being more pronounced in LFPI. These results highlight the utility of multimodal MR imaging for characterizing distinct injury mechanisms in contusive and skull-penetrating TBI models.
Complement-mediated killing of bacteria by mechanical destabilization of the cell envelope
Authors: Benn Georgina , Bortolini Christian , Roberts David M. , Pyne Alice L. B. , Holden Séamus , Hoogenboom Bart W.
Published: December 2023

Complement proteins eliminate Gram-negative bacteria in serum via the formation of membrane attack complex (MAC) pores in the outer membrane. However, it remains unclear how outer membrane poration leads to inner membrane permeation and cell lysis. Using atomic force microscopy (AFM) on livingEscherichia coli(E. coli), we probed MAC-induced changes in the cell envelope and correlated these with subsequent cell death. Initially, bacteria survived despite the formation of hundreds of MACs randomly distributed over the cell surface. This was followed by larger-scale disruption of the outer membrane, including propagating defects and fractures, and by an overall swelling and stiffening of the bacterial surface, which precede inner membrane permeation. We conclude that bacterial cell lysis is only an indirect effect of MAC formation; outer membrane poration leads to mechanical destabilization of the cell envelope, reducing its ability to contain the turgor pressure, causing inner membrane permeation and cell death. This represents a previously unknown route to bacterial cell death that could be exploited by novel antibiotic treatments.
Torques within and outside the human spindle balance twist at anaphase
Authors: Neahring Lila , He Yifei , Cho Nathan H. , Liu Gaoxiang , Fernandes Jonathan , Rux Caleb J. , Nakos Konstantinos , Subramanian Radhika , Upadhyayula Srigokul , Yildiz Ahmet , Dumont Sophie
Published: December 2023

At each cell division, nanometer-scale motors and microtubules give rise to the micron-scale spindle. Many mitotic motors step helically around microtubules in vitro, and most are predicted to twist the spindle in a left-handed direction. However, the human spindle exhibits only slight global twist, raising the question of how these molecular torques are balanced. Here, using lattice light sheet microscopy, we find that anaphase spindles in the epithelial cell line MCF10A have a high baseline twist, and we identify factors that both increase and decrease this twist. The midzone motors KIF4A and MKLP1 are redundantly required for left-handed twist at anaphase, and we show that KIF4A generates left-handed torque in vitro. The actin cytoskeleton also contributes to left-handed twist, but dynein and its cortical recruitment factor LGN counteract it. Together, our work demonstrates that force generators regulate twist in opposite directions from both within and outside the spindle, preventing strong spindle twist during chromosome segregation.
Direct disassembly of α-syn preformed fibrils into native α-syn monomers by an all-D-peptide
Authors: Sevenich Marc , Gering Ian , Vollmer Madita , Saisan Selma Aghabashlou , Tusche Markus , Kupreichyk Tatsiana , Pauly Thomas , Stoldt Matthias , Hoyer Wolfgang , Willuweit Antje , Kutzsche Janine , Lakomek Nils-Alexander , Nagel-Steger Luitgard , Gremer Lothar , Tamgüney Gültekin , Mohrlüder Jeannine , Willbold Dieter
Published: December 2023

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide. One of its central features is the neurodegeneration that starts in the substantia nigra and progressively tends to involve other brain regions. α-Synuclein (α-syn) and its aggregation during pathogenesis have been drawn into the center of attention, where especially soluble oligomeric and fibrillar structures are thought to play a key role in cell-to-cell transmission and induction of toxic effects. Here, we report the development of all-D-enantiomeric peptide ligands that bind monomeric α-syn with high affinity, thereby stabilizing the physiological intrinsically disordered structure and preventing initiation of aggregation, and more important, disassembling already existing aggregates. This “anti prionic” mode of action (MoA) has the advantage over other MoAs that it eliminates the particles responsible for disease propagation directly and independently of the immune system, thereby restoring the physiological monomer. Based on mirror image phage display on the D-enantiomeric full-length α-syn target, we identified SVD-1 and SVD-1a by next generation sequencing, Thioflavin-T screens and rational design. The compounds were analyzed with regard to their anti-aggregation potential and both compounds showed aggregation delaying as well as seed capacity reducing effects inde novoand seeded environments, respectively. High affinity towards the monomeric α-syn, in the low nano- to picomolar KDrange was identified by surface plasmon resonance (SPR). SVD-1a reduced toxic effects as well as intracellular seeding capacity of α-syn pre-fromed fibrils (PFF) in cell culture. SVD-1a disassembled α-syn PFF into monomers as identified by atomic force microscopy (AFM), time dependent dynamic light scattering (DLS) and size exclusion chromatography (SEC) analysis. The present work provides promising results on the development of lead compounds with this anti-prionic mode of action for treatment of Parkinson’s disease and other synucleinopathies.
Feeling inspired and nostalgic: associations between media context-induced positive emotions and behavioral change among vaccine-hesitant individuals in the late stages of the COVID-19 pandemic
Authors: Duong Hue Trong , Yachin Mor , Massey Zachary B.
Published: December 2023

Purpose

Campaigns to promote the COVID-19 vaccination messages to vaccine-hesitant consumers in the late stages of the pandemic are often met with resistance. This study aims to explore a way to leverage positive emotions induced from entertainment media consumption to promote vaccination messages to this audience group.

Design/methodology/approach

An online experiment was conducted with vaccine-hesitant consumers (N = 409). Participants viewed personally relevant entertainment music videos or mundane videos and vaccinated messages embedded in user-generated comments.

Findings

Data revealed that feelings of inspiration and nostalgia induced from entertainment media consumption increased vaccination intentions via increased risk perceptions and reduced anti-vaccination attitudes.

Practical implications

Social marketers should consider leveraging the combined effect of entertainment media-induced positive emotions and user-generated comments to motivate behavioral change among vaccine-hesitant individuals in the late stages of the COVID-19 pandemic.

Originality/value

The present study adds to social marketing literature by showing mechanisms that positive emotions induced from entertainment social media consumption might lead to health behavioral change.
The fiscal effects of armed conflicts in Africa
Authors: Ezeoha Abel , Igwe Anthony , Okoyeuzu Chinwe , Uche Chibuike
Published: December 2023

This study examines the impact of armed conflicts on the fiscal capacity of African governments. It made use of a data set covering 1997–2021 for 50 countries, as well as the system dynamic generalized method of moment estimation technique. The results show that, in the short run, conflicts undermine tax revenue, mount pressure on military expenditure, and force governments to rely more on mineral resource rents for their fiscal needs. As conflicts persist, this fiscal feature changes to a pattern that reflects a decline in mineral resource earnings and an increase in tax revenue. The impact on public health expenditure also changes from an increasing to a decreasing pattern, whereas the positive impact on military expenditure and external borrowing persists over time. The findings suggest that African countries in conflict can address their fiscal challenges by observing these patterns and putting in place policies that protect public resources (e.g., the adoption of digital financial technology protocols to facilitate remote revenue collection and strategic protection of mineral resource‐endowed zones from insurgents' control). Overall, enhancing government effectiveness and strengthening the institutions of governance is important to facilitate a quick return to normalcy in the event of conflict and to prevent future conflicts.