bluuebunny/crossref_metadata_2025_split huggingface dataset:
MST1/2 exerts a pivotal role in inducing neuroinflammation and Coxsackievirus-A10 replication by interacting with innate immunity
Authors: Hu Yajie , Zhong Minigmei , Lv Yaming , Zhao Wei , Qian Baojiang , Song Jie , Zhang Yunhui 
Published: April 2024

AbstractCoxsackievirus-A10 (CV-A10), responsible for the hand, foot and mouth disease (HFMD) pandemic, could cause serious central nervous system (CNS) complications. The underlying molecular basis of CV-A10 and host interactions inducing neuropathogenesis is still unclear. The Hippo signaling pathway, historically known for a dominator of organ development and homeostasis, has recently been implicated as an immune regulator. However, its role in host defense against CV-A10 has not been investigated. Herein, it was found that CV-A10 proliferated in HMC3 cells and promoted the release of inflammatory cytokines. Moreover, pattern recognition receptors (PRRs)-mediated pathways, including TLR3-TRIF-TRAF3-TBK1-NF-κB axis, RIG-I/MDA5-MAVS-TRAF3-TBK1-NF-κB axis and TLR7-MyD88-IRAK1/IRAK4-TRAF6-TAK1-NF-κB axis, were examined to be elevated under CV-A10 infection. Meanwhile, it was further uncovered that Hippo signaling pathway was inhibited in HMC3 cells with CV-A10 infection. Previous studies have been reported that there exist complex relations between innate immune and Hippo signaling pathway. Then, plasmids of knockdown and overexpression of MST1/2 were transfected into HMC3 cells. Our results showed that MST1/2 suppressed the levels of inflammatory cytokines via interacting with TBK1 and IRAK1, and also enhanced virus production via restricting IRF3 and IFN-β expressions. Overall, these data obviously pointed out that CV-A10 accelerated the formation of neuroinflammation by the effect of the Hippo pathway on the PRRs-mediated pathway, which delineates a negative immunoregulatory role for MST1/2 in CV-A10 infection and the potential for this pathway to be pharmacologically targeted to treat CV-A10.
Acute patients discharged without an established diagnosis: risk of mortality and readmission of nonspecific diagnoses compared to disease-specific diagnoses
Authors: Gregersen Rasmus , Villumsen Marie , Mottlau Katarina Høgh , Maule Cathrine Fox , Nygaard Hanne , Rasmussen Jens Henning , Christensen Mikkel Bring , Petersen Janne 
Published: April 2024

Abstract
Background
Nonspecific discharge diagnoses after acute hospital courses represent patients discharged without an established cause of their complaints. These patients should have a low risk of adverse outcomes as serious conditions should have been ruled out. We aimed to investigate the mortality and readmissions following nonspecific discharge diagnoses compared to disease-specific diagnoses and assessed different nonspecific subgroups.

Methods
Register-based cohort study including hospital courses beginning in emergency departments across 3 regions of Denmark during March 2019–February 2020. We identified nonspecific diagnoses from the R- and Z03-chapter in the ICD-10 classification and excluded injuries, among others—remaining diagnoses were considered disease-specific. Outcomes were 30-day mortality and readmission, the groups were compared by Cox regression hazard ratios (HR), unadjusted and adjusted for socioeconomics, comorbidity, administrative information and laboratory results. We stratified into short (3–<12 h) or lengthier (12–168 h) hospital courses.

Results
We included 192,185 hospital courses where nonspecific discharge diagnoses accounted for 50.7% of short and 25.9% of lengthier discharges. The cumulative risk of mortality for nonspecific vs. disease-specific discharge diagnoses was 0.6% (0.6–0.7%) vs. 0.8% (0.7–0.9%) after short and 1.6% (1.5–1.7%) vs. 2.6% (2.5–2.7%) after lengthier courses with adjusted HRs of 0.97 (0.83–1.13) and 0.94 (0.85–1.05), respectively. The cumulative risk of readmission for nonspecific vs. disease-specific discharge diagnoses was 7.3% (7.1–7.5%) vs. 8.4% (8.2–8.6%) after short and 11.1% (10.8–11.5%) vs. 13.7% (13.4–13.9%) after lengthier courses with adjusted HRs of 0.94 (0.90–0.98) and 0.95 (0.91–0.99), respectively. We identified 50 clinical subgroups of nonspecific diagnoses, of which Abdominal pain (n = 12,462; 17.1%) and Chest pain (n = 9,599; 13.1%) were the most frequent. The subgroups described differences in characteristics with mean age 41.9 to 80.8 years and mean length of stay 7.1 to 59.5 h, and outcomes with < 0.2–8.1% risk of 30-day mortality and 3.5–22.6% risk of 30-day readmission.

Conclusions
In unadjusted analyses, nonspecific diagnoses had a lower risk of mortality and readmission than disease-specific diagnoses but had a similar risk after adjustments. We identified 509 clinical subgroups of nonspecific diagnoses with vastly different characteristics and prognosis.
Cell-specific extracellular vesicle-encapsulated exogenous GABA controls seizures in epilepsy
Authors: R Abhijna Ballal , K Shivakumar Reddy , Chandran Divya , Hegde Sumukha , Upadhya Raghavendra , SE Praveen Kumar , Shenoy Smita , Devi Vasudha , Upadhya Dinesh 
Published: April 2024

Abstract
Background
Epilepsy affects ∼60 million people worldwide. Most antiseizure medications in the market act on voltage-gated sodium or calcium channels, indirectly modulating neurotransmitter GABA or glutamate levels or multiple targets. Earlier studies made significant efforts to directly deliver GABA into the brain with varied success. Herein, we have hypothesized to directly deliver exogenous GABA to the brain with epilepsy through extracellular vesicles (EVs) from human GABA-producing cells and their progenitors as EVs largely mimic their parent cell composition.

Methods
Human neural stem cells (NSCs), medial ganglionic eminence (MGE) cells, and GABAergic interneurons (INs) were generated from induced pluripotent stem cells (iPSCs) and characterized. EVs were isolated from NSCs, MGE cells, and INs and characterized for size and distribution, morphological features, and molecular markers. Exogenous GABA was passively loaded to the isolated EVs as a zwitterion at physiological pH, and the encapsulated dose of GABA was quantified. Epilepsy was developed through status epilepticus induction in Fisher rats by administration of repeated low doses of kainic acid. The extent of the seizures was measured for 10 h/ day for 3–6 months by video recording and its evaluation for stage III, IV and V seizures as per Racine scale. EVs from INs, MGE cells, and NSCs encapsulated with exogenous GABA were sequentially tested in the 4th, 5th, and 6th months by intranasal administration in the rats with epilepsy for detailed seizure, behavioral and synapse analysis. In separate experiments, several controls including exogenic GABA alone and EVs from INs and MGE cells were evaluated for seizure-controlling ability.

Results
Exogenic GABA could enter the brain through EVs. Treatment with EVs from INs and MGE cells encapsulated with GABA significantly reduced total seizures, stage V seizures, and total time spent in seizure activity. EVs from NSCs encapsulated with GABA demonstrated limited seizure control. Exogenic GABA alone and EVs from INs and MGE cells individually failed to control seizures. Further, exogenic GABA with EVs from MGE cells improved depressive behavior while partially improving memory functions. Co-localization studies confirmed exogenous GABA with presynaptic vesicles in the hippocampus, indicating the interaction of exogenous GABA in the brain with epilepsy.

Conclusion
For the first time, the study demonstrated that exogenous GABA could be delivered to the brain through brain cell-derived EVs, which could regulate seizures in temporal lobe epilepsy. It is identified that the cellular origin of EVs plays a vital role in seizure control with exogenous GABA.
Transcriptomic profiling across human serotonin neuron differentiation via the FEV reporter system
Authors: Li Yingqi , Duan Jinjin , Li You , Zhang Meihui , Wu Jiaan , Wang Guanhao , Li Shuanqing , Hu Zhangsen , Qu Yi , Li Yunhe , Hu Xiran , Guo Fei , Cao Lining , Lu Jianfeng 
Published: April 2024

Abstract
Background
The detailed transcriptomic profiles during human serotonin neuron (SN) differentiation remain elusive. The establishment of a reporter system based on SN terminal selector holds promise to produce highly-purified cells with an early serotonergic fate and help elucidate the molecular events during human SN development process.

Methods
A fifth Ewing variant (FEV)-EGFP reporter system was established by CRISPR/Cas9 technology to indicate SN since postmitotic stage. FACS was performed to purify SN from the heterogeneous cell populations. RNA-sequencing analysis was performed for cells at four key stages of differentiation (pluripotent stem cells, serotonergic neural progenitors, purified postmitotic SN and purifed mature SN) to explore the transcriptomic dynamics during SN differentiation.

Results
We found that human serotonergic fate specification may commence as early as day 21 of differentiation from human pluripotent stem cells. Furthermore, the transcriptional factors ZIC1, HOXA2 and MSX2 were identified as the hub genes responsible for orchestrating serotonergic fate determination.

Conclusions
For the first time, we exposed the developmental transcriptomic profiles of human SN via FEV reporter system, which will further our understanding for the development process of human SN.

Graphical Abstract
Biochemical, morphological and molecular assessments of n butanol fraction of Phoenix dactylifera L. following exposure to inorganic mercury on the liver of Wistar rats
Authors: Abubakar Musa Garba , Agbon AN , Musa SA , Hamman WO , Oladele SB 
Published: April 2024

Abstract
Background
Mercury chloride (HgCl2) damages tissues it comes in contact with in sufficient concentration. This study evaluated the protective effects of n-butanol fraction of Phoenix dactylifera (BFPD) on mercury-triggered liver toxicity in Wistar rats. 25 male rats were divided into 5 groups of 5 rats each. Group I was administered 2 ml/kg of distilled water; group II was administered 5 mg/kg of HgCl2; group III was administered 500 mg/kg of BFPD + 5 mg/kg of HgCl2; group IV was administered 1000 mg/kg of BFPD + 5 mg/kg of HgCl2, while group V was administered 100 mg/kg of silymarin + 5 mg/kg of HgCl2. orally for 2 weeks. The rats were euthanized and liver tissue blood samples were collected for histological, histochemical, stereological, immunohistochemical, molecular, and biochemical studies.

Results
The results revealed that HgCl2 induced oxidative stress in the rats evident by histoarchitectural distortions and altered levels of liver enzymes, proteins, and oxidative stress biomarkers when compared to the control. However, BFPD treatment restored these changes. Glutathione peroxidase levels decreased (p < 0.05) in the HgCl2−treated group when compared to the control and BFPD-treated groups. HgCl2 group revealed reduced reactivity with histochemical and immunohistochemical stains (Masson’s Trichrome and B cell Lymphoma 2) when compared to the control, with a significant decrease in quantified liver Bcl-2 stain intensity when compared to the silymarin-treated group. BFPD administration revealed normal staining intensity comparable to the control. HgCl2 administration revealed a remarked decrease in the number of hepatocytes when compared to the control, BFPD, and silymarin groups. BFPD preserved (p < 0.05) the stereological features when compared to the HgCl2-treated group. GPx activity in the liver decreased (p < 0.05) with HgCl2 administration when compared to the control and silymarin-treated groups. BFPD attenuated GPx gene activity to levels similar to the control indicating some level of amelioration against HgCl2-induced toxicity.

Conclusions
The ability of BFPD to mitigate HgCl2 triggered liver alterations could be attributed to the antioxidant property of its flavonoid content. Therefore, BFPD may be a potential candidate for treating and managing liver-induced mercury intoxication.
Anesthesia-Related Closed Claims in Free-Standing Ambulatory Surgery Centers
Authors: Pimentel Marc Philip T. , Chung Scott , Ross Jacqueline M. , Wright Daniel , Urman Richard D. 
Published: April 2024

BACKGROUND:
As higher acuity procedures continue to move from hospital-based operating rooms (HORs) to free-standing ambulatory surgery centers (ASCs), concerns for patient safety remain high. We conducted a contemporary, descriptive analysis of anesthesia-related liability closed claims to understand risks to patient safety in the free-standing ASC setting, compared to HORs.

METHODS:
Free-standing ASC and HOR closed claims between 2015 and 2022 from The Doctors Company that involved an anesthesia provider responsible for the claim were included. We compared the coded data of 212 free-standing ASC claims with 268 HOR claims in terms of severity of injury, major injuries, allegations, comorbidities, contributing factors, and financial value of the claim.

RESULTS:
Free-standing ASC claims accounted for almost half of all anesthesia-related cases (44%, 212 of 480). Claims with high severity of injury were less frequent in free-standing ASCs (22%) compared to HORs (34%; P = .004). The most common types of injuries in both free-standing ASCs and HORs were dental injury (17% vs 17%) and nerve damage (14% vs 11%). No difference in frequency was noted for types of injuries between claims from free-standing ASCs versus HORs––except that burns appeared more frequently in free-standing ASC claims than in HORs (6% vs 2%; P = .015). Claims with alleged improper management of anesthesia occurred less frequently among free-standing ASC claims than HOR claims (17% vs 29%; P = .01), as well as positioning-related injury (3% vs 8%; P = .025). No difference was seen in frequency of claims regarding alleged improper performance of anesthesia procedures between free-standing ASCs and HORs (25% vs 19%; P = .072). Technical performance of procedures (ie, intubation and nerve block) was the most common contributing factor among free-standing ASC (74%) and HOR (74%) claims. Free-standing ASC claims also had a higher frequency of communication issues between provider and patient/family versus HOR claims (20% vs 10%; P = .004). Most claims were not associated with major comorbidities; however, cardiovascular disease was less prevalent in free-standing ASC claims versus HOR claims (3% vs 11%; P = .002). The mean ± standard deviation total of expenses and payments was lower among free-standing ASC claims ($167,000 ± $295,000) than HOR claims ($332,000 ± $775,000; P = .002).

CONCLUSIONS:
This analysis of medical malpractice claims may indicate higher-than-expected patient and procedural complexity in free-standing ASCs, presenting patient safety concerns and opportunities for improvement. Ambulatory anesthesia practices should consider improving safety culture and communication with families while ensuring that providers have up-to-date training and resources to safely perform routine anesthesia procedures.
“Shrewd and Sagacious” Middlemen: Black Go-Betweens in the Florida Borderlands, 1817–1836
Authors: Mair Edward 
Published: April 2024

Abstract
This article argues that Black Maroons were able to maintain a semiformal space of freedom in Territorial Florida through their work as go-betweens. Scholarship understands the utility of the Maroons to the Florida Indians, but this text posits that Black go-betweens, through their work as guides and interpreters, were also of vital importance to settlers. As Florida was Indigenous space prior to 1835, go-betweens became essential to settler ambitions in Florida, from officials of the Territorial Government to planters. The go-betweens’ ease of interaction with Indigenous and settler society shows that in spite of their status as fugitives from slavery, they could force the two dominant slaveholding societies in Florida to accept their claims of freedom. Furthermore, rather than simply falling prey to bribery, go-betweens used treaty proceedings between the Florida Indians and Territorial Government to have the interests of their own communities heard.
John Norton Reconsidered: Influence, Blood, and Belonging in the British Empire and Haudenosaunee Confederacy, 1786–1823
Authors: Ince Nathan 
Published: April 2024

Abstract
John Norton (fl. 1770–1823) has long fascinated historians. After having been taken in by the prominent Mohawk leader Thayendanegea Joseph Brant as a young man, Norton claimed to imperial outsiders that he occupied a position of great influence among the Haudenosaunee. Norton bolstered this assertion with the improbable story that his own father had been Cherokee. While many historians have accepted Norton’s claims, there is good reason to reconsider this view. Existing records, including Six Nations council minutes, suggest that not only did Norton misrepresent his ancestry, he greatly exaggerated his standing among the Grand River communities. Rather than an authentic representative of the Haudenosaunee Confederacy, it appears much more likely that Norton mobilized his claims of Cherokee blood and Six Nations belonging in order to gain remarkable influence in the British Atlantic World. Recognizing the power of these claims, his opponents eventually succeeded in undermining Norton’s self-presentation, eventually resulting in his political marginalization and ultimately in his exile from the Grand River under pain of death.
Biomechanical analysis of little penguins’ underwater locomotion from the free-ranging dive data
Authors: Masud Mahadi Hasan , Dabnichki Peter 
Published: April 2024

ABSTRACT
Penguins are proficient swimmers, and their survival depends on their ability to catch prey. The diving behaviour of these fascinating birds should then minimize the associated energy cost. For the first time, the energy cost of penguin dives is computed from the free-ranging dive data, on the basis of an existing biomechanical model. Time-resolved acceleration and depth data collected for 300 dives of little penguins (Eudyptula minor) are specifically employed to compute the bird dive angles and swimming speeds, which are needed for the energy estimate. We find that the numerically obtained energy cost by using the free-ranging dive data is not far from the minimum cost predicted by the model. The outcome, therefore, supports the physical soundness of the chosen model; however, it also suggests that, for closer agreement, one should consider previously neglected effects, such as those due to water currents and those associated with motion unsteadiness. Additionally, from the free-ranging dive data, we calculate hydrodynamic forces and non-dimensional indicators of propulsion performance – Strouhal and Reynolds numbers. The obtained values further confirm that little penguins employ efficient propulsion mechanisms, in agreement with previous investigations.
Vector analysis of corneal astigmatism in cataractous eyes based on IOLMaster 700 biometry
Authors: Langenbucher Achim , Wendelstein Jascha , Cayless Alan , Hoffmann Peter , Szentmáry Nóra 
Published: April 2024

Purpose
The purpose of this study was to investigate the effect of the corneal back surface by comparing the keratometric astigmatism (K, derived from the corneal front surface) of a modern optical biometer against astigmatism of Total Keratometry (TK, derived from both corneal surfaces) in a large population with cataractous eyes. The results were then used to define linear prediction models to map K to TK.

Methods
From a large dataset containing bilateral biometric measurements (IOLMaster 700) in 9736 patients prior to cataract surgery, the total corneal astigmatism was decomposed into vectors for K, corneal back surface (BS), and TK. A multivariate prediction model (MV), simplified model with separation of vector components (SM) and a constant model (CM) were defined to map K to TK vector components.

Results
The K centroid (X/Y) showed some astigmatism with-the-rule (0.1981/-0.0211 dioptre (dpt)) whereas the TK centroid was located around zero (-0.0071/-0.0381 dpt against-the-rule) and the BS centroid showed systematic astigmatism against-the-rule (-0.2367/-0.0145 dpt). The respective TK–K centroid was located at -0.2052/-0.0302 dpt. The MV model showed the same performance (i.e. mean absolute residuum) as the SM did (0.1098 and 0.1099 dpt respectively) while the CM performed only slightly worse (0.1121 dpt mean absolute residuum).

Conclusion
In cases where tomographic data are unavailable statistical models could be used to consider the overall contribution of the back surface to the total corneal astigmatism. Since the performance of the CM is sufficiently close to that of MV and SM we recommend using the CM which can be directly considered e.g. as surgically induced astigmatism.
Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy
Authors: Ojo Oluwafemi Adeleke , Ogunlakin Akingbolabo Daniel , Akintayo Christopher Oloruntoba , Olukiran Olaoluwa Sesan , Adetunji Juliana Bunmi , Ajayi-Odoko Omolola Adenike , Ogwa Theophilus Oghenenyoreme , Molehin Olorunfemi Raphael , Ojo Omolara Olajumoke , Mothana Ramzi A. , Alanzi Abdullah R. 
Published: April 2024

Background and objective
Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway.

Methods
Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined.

Results
We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine).

Conclusion
Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.
Late-Onset Gastric Band Erosion Following Heavy Nonsteroidal Anti-inflammatory Drug Use
Authors: Makovich Zachary , Patel Brijesh 
Published: April 2024

ABSTRACT
Laparoscopic adjustable gastric band (LAGB) surgery is now an uncommon bariatric procedure; however, complications may still be encountered. A 64-year-old man with a history of LAGB placement 13 years prior presented with 2 months of epigastric pain. He endorsed chronic heavy nonsteroidal anti-inflammatory drug use. Computed tomography showed inflammation around the LAGB tubing with near-complete, circumferential erosion of the LAGB into the fundus. Upper endoscopy confirmed erosion of the LAGB along with port tubing into the gastroesophageal junction and fundus. The patient was referred to a foregut surgeon who performed robotic band removal.