bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-β-lactamase against tebipenem
Authors: Ono Daisuke , Cmolik Anna , Bethel Christopher R. , Ishii Yoshikazu , Drusin Salvador I. , Moreno Diego M. , Vila Alejandro J. , Bonomo Robert A. , Mojica Maria F. 
Published: July 2024

ABSTRACT

Imipenemase (IMP) metallo-β-lactamases (MBLs) hydrolyze almost all available β-lactams including carbapenems and are not inhibited by any commercially available β-lactamase inhibitor. Tebipenem (TP) pivoxil is the first orally available carbapenem and possesses a unique bicyclic azetidine thiazole moiety located at the R2 position. TP has potent
in vitro
activity against
Enterobacterales
producing extended-spectrum and/or AmpC β-lactamases. Thus far, the activity of TP against IMP-producing strains is understudied. To address this knowledge gap, we explored the structure activity relationships of IMP MBLs by investigating whether IMP-6, IMP-10, IMP-25, and IMP-78 [MBLs with expanded hydrolytic activity against meropenem (MEM)] would demonstrate enhanced activity against TP. Most of the
Escherichia coli
DH10B strains expressing IMP-1 variants displayed a ≥twofold MIC difference between TP and MEM, while those expressing VIM or NDM variants demonstrated comparable MICs. Catalytic efficiency (
k
cat
/
K
M
) values for the TP hydrolysis by IMP-1, IMP-6, IMP-10, IMP-25, and IMP-78 were significantly lower than those obtained for MEM. Molecular dynamic simulations reveal that V67F and S262G substitutions (found in IMP-78) reposition active site loop 3, ASL-3, to better accommodate the bicyclic azetidine thiazole side chain, allowing microbiological/catalytic activity to approach that of comparison MBLs used in this study. These findings suggest that modifying the R2 side chain of carbapenems can significantly impact hydrolytic stability. Furthermore, changes in conformational dynamics due to single amino acid substitutions should be used to inform drug design of novel carbapenems.
Genetic engineering of
Salmonella
spp. for novel vaccine strategies and therapeutics
Authors: Bansal Garima , Ghanem Mostafa , Sears Khandra T. , Galen James E. , Tennant Sharon M. 
Published: July 2024

ABSTRACT

Salmonella enterica
is a diverse species that infects both humans and animals.
S. enterica
subspecies
enterica
consists of more than 1,500 serovars. Unlike typhoidal
Salmonella
serovars which are human host-restricted, non-typhoidal
Salmonella
(NTS) serovars are associated with foodborne illnesses worldwide and are transmitted via the food chain. Additionally, NTS serovars can cause disease in livestock animals causing significant economic losses.
Salmonella
is a well-studied model organism that is easy to manipulate and evaluate in animal models of infection. Advances in genetic engineering approaches in recent years have led to the development of
Salmonella
vaccines for both humans and animals. In this review, we focus on current progress of recombinant live-attenuated
Salmonella
vaccines, their use as a source of antigens for parenteral vaccines, their use as live-vector vaccines to deliver foreign antigens, and their use as therapeutic cancer vaccines in humans. We also describe development of live-attenuated
Salmonella
vaccines and live-vector vaccines for use in animals.
The Raf kinase inhibitors Dabrafenib and Regorafenib impair Zika virus replication via distinct mechanisms
Authors: Wilken Lucas , Rimmelzwaan Guus F. , Elbahesh Husni 
Published: July 2024

ABSTRACT

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that has been associated with congenital neurological defects in fetuses born to infected mothers. At present, no vaccine or antiviral therapy is available to combat this devastating disease. Repurposing drugs that target essential host factors exploited by viruses is an attractive therapeutic approach. Here, we screened a panel of clinically approved small-molecule kinase inhibitors for their antiviral effects against a clinical isolate of ZIKV and thoroughly characterized their mechanisms of action. We found that the Raf kinase inhibitors Dabrafenib and Regorafenib potently impair the replication of ZIKV, but not that of its close relative dengue virus. Time-of-addition experiments showed that both inhibitors target ZIKV infection at post-entry steps. We found that Dabrafenib, but not Regorafenib, interfered with ZIKV genome replication by impairing both negative- and positive-strand RNA synthesis. Regorafenib, on the other hand, altered steady-state viral protein levels, viral egress, and blocked NS1 secretion. We also observed Regorafenib-induced ER fragmentation in ZIKV-infected cells, which might contribute to its antiviral effects. Because these inhibitors target different steps of the ZIKV infection cycle, their use in combination therapy may amplify their antiviral effects which could be further explored for future therapeutic strategies against ZIKV and possibly other flaviviruses.

IMPORTANCE

There is an urgent need to develop effective therapeutics against re-emerging arboviruses associated with neurological disorders like Zika virus (ZIKV). We identified two FDA-approved kinase inhibitors, Dabrafenib and Regorafenib, as potent inhibitors of contemporary ZIKV strains at distinct stages of infection despite overlapping host targets. Both inhibitors reduced viral titers by ~1 to 2 log
10
(~10-fold to 100-fold) with minimal cytotoxicity. Furthermore, we show that Dabrafenib inhibits ZIKV RNA replication whereas Regorafenib inhibits ZIKV translation and egress. Regorafenib has the added benefit of limiting NS1 secretion, which contributes to the pathogenesis and disease progression of several flaviviruses. Because these inhibitors affect distinct post-entry steps of ZIKV infection, their therapeutic potential may be amplified by combination therapy and likely does not require prophylactic administration. This study provides further insight into ZIKV-host interactions and has implications for the development of novel antivirals against ZIKV and possibly other flaviviruses.
Effect of combined rapid access point-of-care intestinal ultrasound clinic on the management of inflammatory bowel disease
Authors: Grunshaw Nigel , Harrison Wendi , Owen Hayley , Smith Philip J 
Published: July 2024

BackgroundIntestinal ultrasound (IUS), although less widely practiced in the UK, offers several advantages in inflammatory bowel disease (IBD), particularly with regard to the accessibility of the test and immediate availability of reports.AimsTo assess the use of point-of-care IUS in influencing management change in IBD.MethodsA retrospective service evaluation review of 3 years of a rapid access IUS clinic performed in combination with IBD nurses in a District General Hospital setting.ResultsA total of 227 examinations were performed on 168 patients. All scans were performed by a consultant radiologist. 162 examinations (79%) were scanned and reported within 2 weeks of referral. 101/227 (44%) had evidence of significant active/obstructing disease, and in patients with known IBD, this rises to 101/185 (55%). Overall, 59.5% (135) of ultrasound examinations resulted in management changes.ConclusionWider adoption of IUS in a point-of-care setting has the potential to significantly guide patient management in IBD.
Temperature and firearm violence in four US cities: testing competing hypotheses
Authors: Bushover Brady , Mehranbod Christina A , Roberts Leah E , Gobaud Ariana N , Fish Carolyn , Gao Xiang , Zadey Siddhesh , Morrison Christopher N 
Published: July 2024

IntroductionFirearm violence is a major public health issue in the USA. There is growing evidence that firearm violence is associated with higher ambient temperatures. The aim of this study was to test competing hypotheses that could explain associations between temperature and firearm violence: temperature-aggression theory and routine activities theory.MethodsWe examined associations between elevated daily temperatures and shooting incidents in four US cities: Chicago, Illinois; Cincinnati, Ohio; New York, New York and Philadelphia, Pennsylvania. Temperature was operationalised using two different measures: daily maximum temperature and deviations of the daily maximum temperature from 30-year averages. Generalised linear autoregressive moving average models related temperature to shooting incidence while controlling for seasonal effects.ResultsAs maximum daily temperature deviates from the expected, there was an association with increased shooting incidents in all four cities (eg, New York: b=0.014, 95% CI=0.011 to 0.017). An interaction term created by multiplying daily maximum temperature by the daily difference of maximum temperature from a 30-year average was also found to have a positive association in all four cities (eg, New York: b=0.020, 95% CI=0.016 to 0.025).DiscussionThese findings accord with previous studies demonstrating a positive relationship between temperature and firearm violence and further support temperature-aggression theory as the primary causal mechanism.
Association between timing of operative interventions and mortality in emergency general surgery
Authors: Silver David S , Lu Liling , Beiriger Jamison , Reitz Katherine M , Khamzina Yekaterina , Neal Matthew D , Peitzman Andrew B , Brown Joshua B 
Published: July 2024

BackgroundEmergency general surgery (EGS) often demands timely interventions, yet data for triage and timing are limited. This study explores the relationship between hospital arrival-to-operation time and mortality in EGS patients.Study designWe performed a retrospective cohort study using an EGS registry at four hospitals, enrolling adults who underwent operative intervention for a primary American Association for the Surgery of Trauma-defined EGS diagnosis between 2021 and 2023. We excluded patients undergoing surgery more than 72 hours after admission as non-urgent and defined our exposure of interest as the time from the initial vital sign capture to the skin incision timestamp. We assessed the association between operative timing quintiles and in-hospital mortality using a mixed-effect hierarchical multivariable model, adjusting for patient demographics, comorbidities, organ dysfunction, and clustering at the hospital level.ResultsA total of 1199 patients were included. The median time to operating room (OR) was 8.2 hours (IQR 4.9–20.5 hours). Prolonged time to OR increased the relative likelihood of in-hospital mortality. Patients undergoing an operation between 6.7 and 10.7 hours after first vitals had the highest odds of in-hospital mortality compared with operative times <4.2 hours (reference quintile) (adjusted OR (aOR) 68.994; 95% CI 4.608 to 1032.980, p=0.002). A similar trend was observed among patients with operative times between 24.4 and 70.9 hours (aOR 69.682; 95% CI 2.968 to 1636.038, p=0.008).ConclusionOur findings suggest that prompt operative intervention is associated with lower in-hospital mortality rates among EGS patients. Further work to identify the most time-sensitive populations is warranted. These results may begin to inform benchmarking for triaging interventions in the EGS population to help reduce mortality rates.Level of evidenceIV.
4D Weyl anomaly and diversity of the interior structure of quantum black hole
Authors: Ho Pei-Ming , Kawai Hikaru , Liao Henry , Yokokura Yuki 
Published: July 2024

AbstractWe study the interior metric of 4D spherically symmetric static black holes by using the semi-classical Einstein equation and find a consistent class of geometries with large curvatures. We approximate the matter fields by conformal fields and consider the contribution of the 4D Weyl anomaly, giving a state-independent constraint. Combining this with an equation of state yields an equation that determines the interior geometry completely. We explore the solution space of the equation in a non-perturbative manner for $$\hbar $$
ħ
. First, we find four types of asymptotic behaviors and examine the general features of the solutions. Then, by imposing physical conditions, we obtain approximately a general class of interior geometries: various combinations of dilute and dense structures without a horizon or singularity. This represents the diversity of the interior structure. Finally, we show that the number of possible patterns of such interior geometries corresponds to the Bekenstein–Hawking entropy.
Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures
Authors: Mahmood Umair , Blake Andrew , Rathee Sanjay , Samuel Leslie , Murray Graeme , Sebag-Montefiore David , Gollins Simon , West Nicholas P. , Begum Rubina , Bach Simon P. , Richman Susan D. , Quirke Phil , Redmond Keara L. , Salto-Tellez Manuel , Koelzer Viktor H. , Leedham Simon J. , Tomlinson Ian , Dunne Philip D. , Buffa Francesca M. ,   S:CORT consortium, Maughan Tim S. , Domingo Enric 
Published: July 2024

Abstract

Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826). Exploratory analyses were done with transcriptomic signatures for the endpoint of pathologic complete response (pCR), considering treatment regimen or CMS subtype. Relevant findings were tested for overall survival and recurrence-free survival. Immune and stromal signatures were strongly associated with pCR and lack of pCR, respectively, in RT and capecitabine (Cap)/5-fluorouracil (5FU)–treated patients (N = 387), in which the radiosensitivity signature (RSS) showed the strongest association. Upon addition of oxaliplatin (Ox; N = 123), stromal signatures switched direction and showed higher chances to achieve pCR than without Ox (p for interaction 0.02). Among Cap/5FU patients, most signatures performed similarly across CMS subtypes, except cytotoxic lymphocytes that were associated with pCR in CMS1 and CMS4 cases compared with other CMS subtypes (p for interaction 0.04). The only variables associated with survival were pCR and RSS. Although the frequency of pCR across different chemoradiation regimens is relatively similar, our data suggest that response rates may differ depending on the biological landscape of rectal cancer. Response to neoadjuvant RT in stroma-rich tumors may potentially be improved by the addition of Ox. RSS in preoperative biopsies provides predictive information for response specifically to neoadjuvant RT with 5FU.

Significance:
Rectal cancers with stromal features may respond better to RT and 5FU/Cap with the addition of Ox. Within patients not treated with Ox, high levels of cytotoxic lymphocytes associate with response only in immune and stromal tumors. Our analyses provide biological insights about the outcome by different radiotherapy regimens in rectal cancer.
Grading of Aortic Valve Calcification Severity and Risk Stratification in Aortic Stenosis
Authors: Tastet Lionel , Ali Mulham , Pibarot Philippe , Capoulade Romain , Øvrehus Kristian Altern , Arsenault Marie , Haujir Amal , Bédard Élisabeth , Diederichsen Axel Cosmus Pyndt , Dahl Jordi S. , Clavel Marie‐Annick 
Published: July 2024

Background
Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value.

Methods and Results

This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler‐echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all‐cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex‐specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0–1.5 cm
2
and mean gradient 20–39 mm Hg) from mild AS (aortic valve area >1.5 cm
2
and mean gradient <20 mm Hg) were AVC ≥360 arbitrary units in women and ≥1037 arbitrary units in men. Based on the guidelines' thresholds for severe AS and the new thresholds in our study for moderate AS, 312 (34%) patients had mild, 253 (28%) moderate, and 350 (38%) severe AVC. During a mean follow‐up of 5.6±3.9 years, 183 (27%) deaths occurred. In Cox multivariable models, AVC remained associated with an increased risk of death (adjusted hazard ratio per grade increase, 1.94 [95% CI, 1.53–2.56];
P
<0.001).

Conclusions
A novel grading classification of anatomic AS severity based on sex‐specific thresholds of AVC provides significant prognostic value for predicting mortality. These findings support the complementarity of computed tomography‐calcium scoring to Doppler‐echocardiography to corroborate AS severity and enhance risk stratification in patients with AS.
Inositol 1,4,5‐Trisphosphate Receptors Regulate Vascular Smooth Muscle Cell Proliferation and Neointima Formation in Mice
Authors: Huang Fang , Zhang Fei , Huang Lei , Zhu Xiangbin , Huang Can , Li Na , Da Qingen , Huang Yu , Yang Huihua , Wang Hong , Zhao Lingyun , Lin Qingsong , Chen Zee , Xu Junjie , Liu Jie , Ren Mingming , Wang Yan , Han Zhen , Ouyang Kunfu 
Published: July 2024

Background

Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca
2+
has been recognized as a key player. However, the physiological role of Ca
2+
release via inositol 1,4,5‐trisphosphate receptors (IP
3
Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined.

Methods and Results

Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP
3
Rs in regulating VSMC proliferation. Expression of all 3 IP
3
R subtypes was increased in cultured VSMCs upon platelet‐derived growth factor‐BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP
3
R subtypes abolished endoplasmic reticulum Ca
2+
release in cultured VSMCs, significantly reduced cell proliferation induced by platelet‐derived growth factor‐BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle–specific deletion of all IP
3
R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase‐9 expression in injured vessels. Mechanistically, IP
3
R‐mediated Ca
2+
release may activate cAMP response element–binding protein, a key player in controlling VSMC proliferation, via Ca
2+
/calmodulin‐dependent protein kinase II and Akt. Loss of IP
3
Rs suppressed cAMP response element–binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca
2+
permeable ionophore, ionomycin, can reverse cAMP response element–binding protein phosphorylation in IP
3
R triple knockout VSMCs.

Conclusions

Our results demonstrated an essential role of IP
3
R‐mediated Ca
2+
release from endoplasmic reticulum in regulating cAMP response element–binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.
Pediatric T-cell lymphoblastic lymphomas but not leukemias harbor TRB::NOTCH1 fusions with unfavorable outcome
Authors: te Vrugt Marcel , Wessolowski Janna , Randau Gerrit , Alfert Amelie , Mueller Stephanie , Scholten Kenneth , Sopalla Claudia , Lanvers-Kaminsky Claudia , Hotfilder Marc , Lamp Finn , Damm-Welk Christine , Luedersen Jette , Escherich Gabriele , zur Stadt Udo , Behrmann Lena , Woessmann Wilhelm , Oschlies Ilske , Marzi Matteo , Zimmermann Martin , Burkhardt Birgit 
Published: July 2024

Abstract
T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL) have common and distinguishing clinical and molecular features. Molecular prognostic factors are needed for T-LBL. We assessed the prevalence and prognostic impact of the T-cell receptor β (TRB)::NOTCH1 fusion in 192 pediatric patients with T-LBL and 167 pediatric patients with T-ALL, using novel multiplex polymerase chain reaction and genomic capture high-throughput sequencing techniques. The fusion was detected in 12 patients with T-LBL (6.3%) but in none of the patients with T-ALL (P = .0006, Fisher exact test). In T-LBL, the TRB::NOTCH1 fusion was associated with a significantly higher incidence of relapse (67% vs 17% in gene fusion-negative patients, P &lt; .001, Fisher exact test). The breakpoint in TRB was most frequently located in J2-7 (n = 6). In NOTCH1, the breakpoints varied between exon 24 and 27. Consequently, a truncated NOTCH1 with its dimerization, regulation, and signal transduction domains gets controlled by strong TRB enhancer elements. This study reveals a novel recurrent genetic variant with significant prognostic relevance in T-LBL, which was absent in T-ALL. The TRB::NOTCH1 fusion in T-LBL suggests a possible unique pathogenic mechanism divergent from T-ALL. Further studies will validate the role of the TRB::NOTCH1 fusion as prognostic marker in T-LBL and elucidate its pathogenic mechanisms.
Blood biodistribution and vector shedding of valoctocogene roxaparvovec in people with severe hemophilia A
Authors: Agarwal Suresh , Sandza Krystal , Obrochta Moss Kristin , Vora Monica , Bowen Alisa , Bunch Brenna , Holcomb Jennifer , Robinson Tara M. , Jayaram Kala , Russell Chris B. , Zoog Stephen , Vettermann Christian , Henshaw Joshua 
Published: July 2024

Abstract
Following systemically administered adeno-associated virus gene therapy, vector particles are widely distributed, raising concerns about horizontal or germline vector transmission. Characterization of biodistribution and kinetics of vector DNA in body fluids can address these concerns and provide insights into vector behavior in accessible samples. We investigated biodistribution and vector shedding profile of valoctocogene roxaparvovec in men with severe hemophilia A enrolled in the phase 3 GENEr8-1 trial. Participants (n = 134) received a single 6 × 1013 vector genome (vg)/kg infusion and were assessed over 3 years. Vector DNA was measured using 4 different assays. Total vector DNA was evaluated in blood, saliva, stool, semen, and urine by quantitative polymerase chain reaction (qPCR). Encapsidated vector DNA was measured in plasma and semen with immunocapture-based qPCR. Contiguity of vgs and assembly of inverted terminal repeat fusions were measured in whole blood and peripheral blood mononuclear cells (PBMCs) using multicolor digital PCR. Median peak vector DNA levels observed 1 to 8 days after dosing were highest in blood, followed by saliva, semen, stool, and urine. Concentrations declined steadily. Encapsidated vector DNA cleared faster than total vector DNA, achieving clearance by ≤12 weeks in plasma and semen. Predominant vector genome forms transitioned from noncontiguous to full-length over time in whole blood and PBMCs, indicating formation of stable circularized episomes within nucleated cells. The replication-incompetent nature of valoctocogene roxaparvovec, coupled with steady clearance of total and encapsidated vector DNA from shedding matrices, indicates transmission risk is low. This trial was registered at www.ClinicalTrials.gov as #NCT03370913.