bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroprotective Efficacy of the Glucocorticoid Receptor Modulator PT150 in the Rotenone Mouse Model of Parkinson’s Disease
Authors: Latham Amanda S. , Rocha Savannah M. , McDermott Casey P. , Reigan Philip , Slayden Richard A. , Tjalkens Ronald B. 
Published: April 2024

AbstractParkinson’s disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days, immediately followed by oral treatment with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.
Moving in pain - A preliminary study evaluating the immediate effects of experimental knee pain on locomotor biomechanics
Authors: Charlton Jesse M. , Chang Elyott , Hou Sabrina W. , Lo Ernest , McClure Emily , Plater Cole , Wong Samantha , Hunt Michael A. 
Published: April 2024

AbstractPain changes how we move, but it is often confounded by other factors due to disease or injury. Experimental pain offers an opportunity to isolate the independent affect of pain on movement. We used cutaneous electrical stimulation to induce experimental knee pain during locomotion to study the short-term motor adaptions to pain. While other models of experimental pain have been used in locomotion, they lack the ability to modulate pain in real-time. Twelve healthy adults completed the single data collection session where they experienced six pain intensity conditions (0.5, 1, 2, 3, 4, 5 out of 10) and two pain delivery modes (tonic and phasic). Electrodes were placed over the lateral infrapatellar fat pad and medial tibial condyle to deliver the 10 Hz pure sinusoid via a constant current electrical stimulator. Pain intensity was calibrated prior to each walking bout based on the target intensity and was recorded using an 11-point numerical rating scale. Knee joint angles and moments were recorded over the walking bouts and summarized in waveform and discrete outcomes to be compared with baseline walking. Knee joint angles changed during the swing phase of gait, with higher pain intensities resulting in greater knee flexion angles. Minimal changes in joint moments were observed but there was a consistent pattern of decreasing joint stiffness with increasing pain intensity. Habituation was limited across the 30-90 second walking bouts and the electrical current needed to deliver the target pain intensities showed a positive linear relationship. Experimental knee pain shows subtle biomechanical changes and favourable habituation patterns over short walking bouts. Further exploration of this model is needed in real-world walking conditions and over longer timeframes to quantify motor adaptations.
Atrial fibrillation and mortality in critically ill patients undergoing emergent fixed-wing air ambulance transport: a retrospective cohort study
Authors: Sundbom Marcus Fredriksson , Langelotz Hannah , Nyström Helena , A’roch Roman , Haney Michael 
Published: April 2024

AbstractObjectiveTo examine if atrial fibrillation at the time of emergency transport to tertiary care hospital by air ambulance is associated with increased mortality risk.DesignRetrospective cohort study. Logistic regression and Cox regression were used to assess associations of condition with outcome (mortality). Propensity score matching (1:1) was used to identify the comparison cases.SettingOne tertiary care centre in sparsely populated northern SwedenParticipantsCritical care cases undergoing emergent fixed-wing air transport in the northern healthcare region of Sweden was included. 2143 cases were included in the study between 2000-2016.Primary and secondary outcomes measuresThe primary outcome was mortality risk at 90-days post transport in cases with atrial fibrillation during the fixed-wing air ambulance transport. The secondary outcome measures were vasopressor and impaired oxygenation was associated with mortality at 90-days post transport.ResultsAtrial fibrillation showed a higher 90-day post transport mortality risk estimate in the multivariate analysis of all cases, hazard ratio (HR) 1.70 (95% CI 1.08-2.67, p=0.022). In a propensity matched analysis, no increased mortality risk for atrial fibrillation was observed at the same time interval with hazard ratio 1.22 (0.65-2.27, p=0.536). In the secondary analysis, vasopressor use was associated with atrial fibrillation at the time of transport whereas impaired oxygenation was not associated with an increased risk of atrial fibrillation.ConclusionNo increased mortality risk at 90 days was seen for cases with atrial fibrillation at time of transport in this cohort using a propensity score matched approach.Article summaryStrengths and limitationsExplores the scarcely studied topic of mortality risk and atrial fibrillation at time of transport with fixed-wing air ambulanceQuasi-experimental approach with propensity score matching to handle selection biasNo co-morbidity and disease severity data which risk confounding resultsA single transport system was studied which limits generalizability
Equitable deep learning for diabetic retinopathy detection using multi-dimensional retinal imaging with fair adaptive scaling: a retrospective study
Authors: Shi Min , Afzal Muhammad Muneeb , Huang Hao , Wen Congcong , Luo Yan , Khan Muhammad Osama , Tian Yu , Kim Leo , Elze Tobias , Fang Yi , Wang Mengyu 
Published: April 2024

SummaryBackgroundAs deep learning becomes increasingly accessible for automated detection of diabetic retinopathy (DR), questions persist regarding its performance equity among diverse identity groups. We aimed to explore the fairness of current deep learning models and further create a more equitable model designed to minimize disparities in performance across groups.MethodsThis study used one proprietary and two publicly available datasets, containing two-dimensional (2D) wide-angle color fundus images, scanning laser ophthalmoscopy (SLO) fundus images, and three-dimensional (3D) Optical Coherence Tomography (OCT) B-Scans, to assess deep learning models for DR detection. We developed a Fair Adaptive Scaling (FAS) module that dynamically adjusts the significance of samples during model training for DR detection, aiming to lessen performance disparities across varied identity groups. FAS was incorporated into both 2D and 3D deep learning models to facilitate the binary classification of DR and non-DR cases. The area under the receiver operating characteristic curve (AUC) was adopted to measure the model performance. Additionally, we devised an equity-scaled AUC metric, which evaluates model fairness by balancing overall AUC against disparities among groups.FindingsUsing in-house color fundus images on the racial attribute, the overall AUC and ES-AUC of EfficientNet, after integrating with FAS, improved from 0.88 and 0.83 to 0.90 and 0.84 (p < 0.05), with AUCs for Asians and Whites improving by 0.04 and 0.03, respectively (p < 0.01). Regarding gender, both the overall AUC and ES-AUC of EfficientNet improved by 0.01 (p < 0.05) after integrating with FAS. While using in-house SLO fundus images based on race, the overall AUC and ES-AUC of EfficientNet improved from 0.80 to 0.83 (p < 0.01), with AUCs for Asians, Blacks, and Whites improving by 0.02, 0.01 and 0.04, respectively (p < 0.05). On gender, FAS improved the overall AUC and ES-AUC of EfficientNet by 0.02, with both genders showing an improvement of 0.02 (p < 0.01). Using the 3D deep learning model DenseNet121 on in-house OCT-B-Scans based on race, FAS improved the overall AUC and ES-AUC from 0.875 and 0.81 to 0.884 and 0.82 respectively, where the AUCs for Asians and Blacks improved by 0.03 and 0.02 (p < 0.01). On gender, FAS improved the overall AUC and ES-AUC of DenseNet121 by 0.04 and 0.03, while the AUCs for Females and Males improved by 0.05 and 0.04 (p < 0.01), respectively.InterpretationExisting deep learning models indeed exhibit variable performance across diverse identity groups in DR detection. The FAS proves beneficial in enhancing model equity and boosting DR detection accuracy, particularly for underrepresented groups.
The grit personality trait, eating behavior, and obesity among Japanese adults
Authors: Kurita Noriaki , Maeshibu Takako , Aita Tetsuro , Wakita Takafumi , Kikuchi Hiroe 
Published: April 2024

AbstractBackgroundDespite the stigma attributing obesity to a lack of willpower, research on the interrelationships among an individual’s willpower, eating behaviors, and obesity is lacking.ObjectiveThis study aimed to quantify the extent to which multidimensional eating behaviors mediated the association between obesity and grit, which share commonalities with self-control.MethodsThis cross-sectional study involved Japanese adults across a wide range of age groups. Grit was measured using an 8-item short grit scale. Multidimensional eating behaviors were measured using the Japanese version of the 21-item Three-Factor Eating Questionnaire-R21, comprising uncontrolled eating, emotional eating, and cognitive restraint. Obesity was defined as a body mass index ≥25.0 kg/m2, which is the World Health Organization’s cutoff specific to Asian populations in the Asia-Pacific region. A series of logistic regression models were created to analyze the association between grit and obesity with and without eating behaviors. Mediation analyses using the Karlson Holm Breen method were performed to determine whether eating behavior mediated this association.ResultsOf the 1641 adults, 26.8% were obese. A higher grit level was associated with a lower likelihood of obesity, less uncontrolled and emotional eating, and higher cognitive restraint. Uncontrolled and emotional eating fully mediated the association between grit and obesity, whereas cognitive restraint only partially mediated this association.ConclusionsThe inverse association between grit and obesity was mediated by multidimensional eating behaviors. Identifying impairments in eating behaviors, rather than focusing on an individual’s lack of willpower, may contribute to dispelling the aforementioned stigma and facilitating a dialogue for the prevention and management of obesity.
Identifying subtypes of youth suicidality based on psychopathology: alterations in genetic, neuroanatomical and environmental features
Authors: Wu Xinran , Palaniyappan Lena , van Velzen Laura , Yu Gechang , Fan Huanxin , Yu Liu , Becker Benjamin , Cheng Wei , Zhao Xingming , Feng Jianfeng , Sahakian Barbara J. , Robbins Trevor W. , Schumann Gunter , Schmaal Lianne , Zhang Jie 
Published: April 2024

SummaryOne of the most complex human behaviours that defies singular explanatory models is suicidal behaviour, especially in the youth. A promising approach to make progress with this conundrum is to parse distinct subtypes of this behaviour. Utilizing 1,624 children with suicidal thoughts and behaviors (STBs) and 3,224 healthy controls from the ABCD Study, we clustered children with STB based on thirty-four cognitive and psychopathological measures which capture suicide-related risk-moderating traits. Environmental and genetic risk factors, as well as neuroanatomical characteristics of each subtype, were then compared with controls. We identified five distinct STB subtypes, each revealing unique neuroanatomy, environmental/genetic risks, and persistence patterns. Subtype 1 (Depressive, 9.6%) exhibited the most severe depressive symptoms. Subtype 2 (Externalizing, 20.1%) displayed anatomical and functional alterations in frontoparietal network and increased genetic risk for ADHD. Subtype 3 (Cognitive Deficit, 20.4%) demonstrated lower cognitive performance and widespread white-matter deficits. Subtype 4 (Mild Psychotic, 22.2%) presented higher prodromal psychotic symptoms, often unnoticed by parents. Subtype 5 (High Functioning, 27.6%) showed larger total brain volume, better cognition, and higher socio-economic status, contrasting subtypes 1-4. Only Subtypes 1 and 2 demonstrate persistent STB features at the 2-year follow-up. Our results suggested that youth suicidal behaviour may result from several distinct bio-behavioral pathways that are identifiable through co-occurring psychopathology, and provide insights into the underlying neural mechanisms and corresponding intervention strategies.
Tunable Universal OR-gated CAR T cells for AML
Authors: Siddiqui Menna Y. , Chen Jingyao , Loffredo Madeline , Lee Seunghee , Deng Han , Li Yongshuai , Leemans Nelia , Lu Tim , Garrison Brian S. , Ayala Marcela Guzmán , Frankel Nicholas W. , Wong Wilson W. 
Published: April 2024

Abstract/SummaryAcute myeloid leukemia (AML) is a hematopoietic malignancy characterized by antigen heterogeneity and poor prognosis. A potential therapeutic approach to address this heterogeneity is targeting multiple surface antigens to prevent antigen escape and relapse. Chimeric antigen receptor (CAR) T cells are an adoptive cell therapy that have demonstrated remarkable clinical success in the treatment of B cell malignancies, and many efforts are underway to adapt them to myeloid malignancies. To tackle the heterogeneity of AML, logically targeting multiple antigens through an “A OR B” gated CAR circuit would be desirable. Here we combined FLT3 antigen targeting with the well characterized CD33 myeloid marker as a combinatorial OR gate approach using our split, universal, programmable (SUPRA) CAR platform. The split platform affords tunability over activation levels and multiplexed targeting that cannot be achieved through a tandem bispecific approach. We systematically characterized the specificity and sensitivity of different SUPRA CAR adapters against each target individually and in combination against a panel of target cell lines. Our results demonstrate that this CAR system can effectively target two antigens with equivalent efficacy to conventional CARs while reducing the engineering burden associated with designing CAR T cells against multiple antigens. Furthermore, we can characterize an effective dose range where off-target cytotoxicity against hematopoietic stem and progenitor cells is minimized. With the recent clinical advances in universal CAR designs, our SUPRA OR gate has the potential to provide an effective and safer solution to treating AML.
SHP-1 interacts with NFκB1 to inhibit its phosphorylation and nuclear translocation to suppress excessive bacterial inflammation
Authors: Wang Ningning , Tan Suxu , Wang Muyuan , Liu Hongning , Han Sen , Wu Zhendong , Ma Jie , Chen Songlin , Sha Zhenxia 
Published: April 2024

AbstractThe protein tyrosine phosphatase SHP-1 is a key negative regulator in cancer by dephosphorylating multiple target molecules. Specially in the NFκB signaling, where NFκB1/Rela dimer translocate to the nucleus and activate target gene transcription, SHP-1 inhibits the phosphorylation of Rela, while its regulation on NFκB1 has been unknown, especially in pathogen-induced inflammation. Chinese tongue sole, a representative flatfish, has been widely used as a genomics and disease model. Using the teleost and cellular model, we revealed for the first time that SHP-1 inhibits NFκB1 phosphorylation and nuclear translocation by interacting with NFκB1, thereby suppressing NFκB signaling to inhibit bacterial inflammation. In addition, we showed that SHP-1 decreased mortality and alleviated histopathological deterioration, manifested in the inhibition of immune-related pathways and secretion of pro- inflammatory cytokines. Using cellular model, SHP-1 overexpression reduced macrophages M1 polarization, phagocytosis, and oxidative stress, while silencing SHP- 1 exhibited opposite effects. Our findings systematically dissect the functions of SHP- 1 and provide mechanistic insights into the control of inflammation-related diseases.TeaserSHP-1 help maintain the cellular and individual homeostasis by inhibiting the excessive inflammation and immunity via regulating the NFκB signaling.
Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin release factor and estrogen regulation
Authors: Olson Kendra , Ingebretson Anna E. , Vogiatzoglou Eleftheria , Mermelstein Paul G. , Lemos Julia C. 
Published: April 2024

AbstractCholinergic interneurons (ChIs) act as master regulators of striatal output, finely tuning neurotransmission to control motivated behaviors. ChIs are a cellular target of many peptide and hormonal neuromodulators, including corticotropin releasing factor, opioids, insulin and leptin, which can influence an animal’s behavior by signaling stress, pleasure, pain and nutritional status. However, little is known about how sex hormones via estrogen receptors influence the function of these other neuromodulators. Here, we performed in situ hybridization on mouse striatal tissue to characterize the effect of sex and sex hormones on choline acetyltransferase (Chat), estrogen receptor alpha (Esr1), and corticotropin releasing factor type 1 receptor (Crhr1) expression. Although we did not detect sex differences in ChAT protein levels in the striatum, we found that female mice have moreChatmRNA-expressing neurons than males. At the population level, we observed a sexually dimorphic distribution ofEsr1- andCrhr1-expressing ChIs in the ventral striatum that demonstrates an antagonistic correlational relationship, which is abolished by ovariectomy. Only in the NAc did we find a significant population of ChIs that co-expressCrhr1andEsr1. At the cellular level,Crhr1andEsr1transcript levels were negatively correlated only during estrus, indicating that changes in sex hormones levels can modulate the interaction betweenCrhr1andEsr1mRNA levels. Together, these data provide evidence for the unique expression and interaction ofEsr1andCrhr1in ventral striatal ChIs, warranting further investigation into how these transcriptomic patterns might underlie important functions for ChIs at the intersection of stress and reproductive behaviors.
Challenging the impact of consortium diversity on bioaugmentation efficiency and native bacterial community structure in a freshly PAH-contaminated soil
Authors: Nieto E.E. , Festa S. , Colman D. , Morelli I. S. , Coppotelli B. M. 
Published: April 2024

AbstractPolycyclic aromatic hydrocarbons (PAHs) are priority pollutants. We studied the effect of bioaugmentation with three allochthonous bacterial consortia with increasing diversity, SC AMBk, SC1 and SC4, in the structure and functionality of an acutely PAH-contaminated soil microbiome. The PAH supplementation increased the resource availability and the inocula were able to: efficiently degrade the PAHs supplemented after 15 days of incubation, become temporary established, and modify the number of total interactions with soil residents.SphingobiumandBurkholderia,both member of inoculants, were the major contributors to KO linked to degradation and to differentially abundant genera in inoculated microcosms, indicating their competitiveness in the soil. Bioaugmentation efficiency relayed on them, while further degradation, could be carried out by native microorganism. This is the one of the first works which applied three inocula, designed from naturally occurring bacteria and study their effect on the soil native community through the ANCOM-BC. We revealed that when a resource that can be use by the inoculant is added to the soil, it is not necessary a high-diversity inoculant to interact with native community and establish itself. This result has implications in the design of microbiome engineering for bioremediation processes
Detection ofSalmonellaTyphi andblaCTX-MGenes in Drinking Water, Wastewater, and Environmental Biofilms in Sindh Province, Pakistan
Authors: Tajammul Ayesha , Benson L. Scott , Ahmed Jamil , VanDerslice James , Tanner Windy 
Published: April 2024

AbstractTyphoid fever poses a significant public health risk, particularly in low- and middle-income countries where access to clean water and improved sanitation may be limited. In Pakistan, this risk is especially serious given the emergence of an extensively drug-resistant (XDR)SalmonellaTyphi strain, a strain attributed toS. Typhi acquisition of theblaCTX-M-15gene. The now-dominant XDRS. Typhi strain, non-XDRS. Typhi, andblaCTX-Mgenes are readily disseminated via drinking water and wastewater in Pakistan and may also be present in biofilms associated with these environmental sources. This study investigates the presence ofS. Typhi andblaCTX-Mgenes within these environmental compartments. Drinking water (n=35) or wastewater samples (n=35) and samples of their associated biofilms were collected from Karachi and Hyderabad, Pakistan. Samples were tested by PCR forS. Typhi andblaCTX-Mgroup 1 genes as a proxy forblaCTX-M-15. Heterotrophic plate counts (HPC) were conducted to assess microbial load.S. Typhi was detected by PCR in one bulk wastewater sample and one drinking water biofilm.BlaCTX-Mgroup 1 genes were detected in all sample types and were detected more frequently in bulk wastewater (n=13/35) than in drinking water (n=2/35) and more frequently overall in biofilm samples (n=22/70) versus bulk water (n=15/70). Detection ofblaCTX-Min biofilm was not significantly associated with detection in the associated bulk water sample. This study marks the first detection ofS. Typhi in drinking water biofilms and the first report ofblaCTX-Mgenes in environmental biofilms in Pakistan. Environmental biofilms, particularly in drinking water systems, may serve as reservoirs for human exposure toS. Typhi and drug resistance genes. This study underscores the importance of expanding surveillance strategies to include biofilm sampling, providing valuable insights into pathogen dissemination in water systems, and informing targeted public health interventions to prevent waterborne diseases.