bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between miRNA-124, miRNA-544a, and TNF-α levels in acute spinal cord injury
Authors: Ma Xiaomin , Ma Tao , Chang Long , Chen Xiaolei , Xia Gen , Li Chen , Liu Huan 
Published: March 2022

Abstract
Study design
Retrospective.

Objectives
Acute spinal cord injury (ASCI) is caused by direct or indirect strikes from external forces on the spinal cord. Here, we investigated the correlation between the miR-124, miR-544a, and TNF-α levels in patients with ASCI, aiming to evaluate the potential usage of miR-124 and miR-544a in ASCI diagnosis.

Setting
University/hospital.

Methods
A total of 90 (58 male/32 female) ASIA patients and 15 (9 male/6 female) control patients (with acute limb trauma) were involved in the presented study. The ASIA patients were further subclustered based on the International Standards for the Neurological Classification of SCI (ISNCSCI) exam. 30 (18 male/12 female)cases were determined to have complete spinal cord injury (CSCI) and classified as ASIA grade A (Complete); 30 (20 male/10 female) cases were determined to have incomplete spinal cord injury (ISCI) and classified as ASIA grade B (sensory incomplete), C (motor incomplete), or D (motor incomplete); 30 (20 male/10 female) cases were determined to have normal neurological function (NNF) and classified as ASIA grade E (Normal). Plasma miR-124, miRNA-544a, and tumor necrosis factor-alpha (TNF-α) levels were measured from the blood samples collected 24 h, 48 h, and 72 h after trauma.

Results
The levels of miR-124 and miR-544a in the CSCI and ISCI groups were significantly higher than those of the NNF and the control group 24 h after injury (P < 0.05). The increased levels gradually declined from 24 h to 72 h after injury. The area under the receiver operating characteristic curve (ROC) of miR-124, miR-544a and TNF-α 24 h after trauma in patients with acute spinal cord injury were 0.948 [95% CI (0.890, 1.000)], 0.815 [95% CI (0.638, 0.994)] and 0.770 [95% CI (0.641, 0.879)], respectively.

Conclusion
The miRNA-124 and miRNA-544a levels increased significantly in ASCI patients compared with control patients 24 h after injury. These increased levels gradually reduced from 24 h to 72 h after injury. There is a strong positive correlation between miRNA-124, miRNA-544a, and acute spinal cord injury.

Sponsorship
The present study was supported by a University-level project of Ningxia Medical University (Project Number: XY2017147).
Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging
Authors: Strating Esther , Wassenaar Emma , Verhagen Mathijs , Rauwerdink Paulien , van Schelven Susanne , de Hingh Ignace , Rinkes Inne Borel , Boerma Djamila , Witkamp Arjen , Lacle Miangela , Fodde Riccardo , Volckmann Richard , Koster Jan , Stedingk Kris , Giesel Frederik , de Roos Remmert , Poot Alex , Bol Guus , Lam Marnix , Elias Sjoerd , Kranenburg Onno 
Published: March 2022

Abstract
Background
In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed.

Methods
To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3–5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer.

Results
Fibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake.

Conclusion
FAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.
Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma
Authors: Thieme Elana , Liu Tingting , Bruss Nur , Roleder Carly , Lam Vi , Wang Xiaoguang , Nechiporuk Tamilla , Shouse Geoffrey , Danilova Olga V. , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Kurtz Stephen E. , Danilov Alexey V. 
Published: March 2022

AbstractAberrant B-cell receptor (BCR) signaling is a key driver in lymphoid malignancies. Bruton tyrosine kinase (BTK) inhibitors that disrupt BCR signaling have received regulatory approvals in therapy of mantle cell lymphoma (MCL). However, responses are incomplete and patients who experience BTK inhibitor therapy failure have dire outcomes. CG-806 (luxeptinib) is a dual BTK/SYK inhibitor in clinical development in hematologic malignancies. Here we investigated the pre-clinical activity of CG-806 in MCL. In vitro treatment with CG-806 thwarted survival of MCL cell lines and patient-derived MCL cells in a dose-dependent manner. CG-806 blocked BTK and SYK activation and abrogated BCR signaling. Contrary to ibrutinib, CG-806 downmodulated the anti-apoptotic proteins Mcl-1 and Bcl-xL, abrogated survival of ibrutinib-resistant MCL cell lines, and partially reversed the pro-survival effects of stromal microenvironment-mimicking conditions in primary MCL cells. Dual BTK/SYK inhibition led to mitochondrial membrane depolarization accompanied by mitophagy and metabolic reprogramming toward glycolysis. In vivo studies of CG-806 demonstrated improved survival in one of the two tested aggressive MCL PDX models. While suppression of the anti-apoptotic Bcl-2 family proteins and NFκB signaling correlated with in vivo drug sensitivity, OxPhos and MYC transcriptional programs were upregulated in the resistant model following treatment with CG-806. BAX and NFKBIA were implicated in susceptibility to CG-806 in a whole-genome CRISPR-Cas9 library screen (in a diffuse large B-cell lymphoma cell line). A high-throughput in vitro functional drug screen demonstrated synergy between CG-806 and Bcl-2 inhibitors. In sum, dual BTK/SYK inhibitor CG-806 disrupts BCR signaling and induces metabolic reprogramming and apoptosis in MCL. The Bcl-2 network is a key mediator of sensitivity to CG-806 and combined targeting of Bcl-2 demonstrates synergy with CG-806 warranting continued exploration in lymphoid malignancies.
Regulation of the Tec family of non-receptor tyrosine kinases in cardiovascular disease
Authors: Yin Zeyu , Zou Yuanming , Wang Dong , Huang Xinyue , Xiong Shengjun , Cao Liu , Zhang Ying , Sun Yingxian , Zhang Naijin 
Published: March 2022

AbstractTyrosine phosphorylation by protein tyrosine kinases (PTKs) is a type of post-translational modification. Tec kinases, which are a subfamily of non-receptor PTKs, were originally discovered in the hematopoietic system and include five members: Tec, Btk, Itk/Emt/Tsk, Etk/Bmx, and Txk/Rlk. With the progression of modern research, certain members of the Tec family of kinases have been found to be expressed outside the hematopoietic system and are involved in the development and progression of a variety of diseases. The role of Tec family kinases in cardiovascular disease is receiving increasing attention. Tec kinases are involved in the occurrence and progression of ischemic heart disease, atherosclerosis, cardiac dysfunction associated with sepsis, atrial fibrillation, myocardial hypertrophy, coronary atherosclerotic heart disease, and myocardial infarction and post-myocardial. However, no reviews have comprehensively clarified the role of Tec kinases in the cardiovascular system. Therefore, this review summarizes research on the role of Tec kinases in cardiovascular disease, providing new insights into the prevention and treatment of cardiovascular disease.
Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase
Authors: Cheng Jiaxuan , Li Ningning , Huo Yunjing , Dang Shangyu , Tye Bik-Kwoon , Gao Ning , Zhai Yuanliang 
Published: March 2022

AbstractThe Dbf4-dependent kinase Cdc7 (DDK) regulates DNA replication initiation by phosphorylation of the MCM double hexamer (MCM-DH) to promote helicase activation. Here, we determine a series of cryo electron microscopy (cryo-EM) structures of yeast DDK bound to the MCM-DH. These structures, occupied by one or two DDKs, differ primarily in the conformations of the kinase core. The interactions of DDK with the MCM-DH are mediated exclusively by subunit Dbf4 straddling across the hexamer interface on the three N-terminal domains (NTDs) of subunits Mcm2, Mcm6, and Mcm4. This arrangement brings Cdc7 close to its only essential substrate, the N-terminal serine/threonine-rich domain (NSD) of Mcm4. Dbf4 further displaces the NSD from its binding site on Mcm4-NTD, facilitating an immediate targeting of this motif by Cdc7. Moreover, the active center of Cdc7 is occupied by a unique Dbf4 inhibitory loop, which is disengaged when the kinase core assumes wobbling conformations. This study elucidates the versatility of Dbf4 in regulating the ordered multisite phosphorylation of the MCM-DH by Cdc7 kinase during helicase activation.
Representations of molecules and materials for interpolation of quantum-mechanical simulations via machine learning
Authors: Langer Marcel F. , Goeßmann Alex , Rupp Matthias 
Published: March 2022

AbstractComputational study of molecules and materials from first principles is a cornerstone of physics, chemistry, and materials science, but limited by the cost of accurate and precise simulations. In settings involving many simulations, machine learning can reduce these costs, often by orders of magnitude, by interpolating between reference simulations. This requires representations that describe any molecule or material and support interpolation. We comprehensively review and discuss current representations and relations between them. For selected state-of-the-art representations, we compare energy predictions for organic molecules, binary alloys, and Al–Ga–In sesquioxides in numerical experiments controlled for data distribution, regression method, and hyper-parameter optimization.
Development and validation of a web-based prediction tool on minor physical anomalies for schizophrenia
Authors: Wang Xin-Yu , Lin Jin-Jia , Lu Ming-Kun , Jang Fong-Lin , Tseng Huai-Hsuan , Chen Po-See , Chen Po-Fan , Chang Wei-Hung , Huang Chih-Chun , Lu Ke-Ming , Tan Hung-Pin , Lin Sheng-Hsiang 
Published: March 2022

AbstractIn support of the neurodevelopmental model of schizophrenia, minor physical anomalies (MPAs) have been suggested as biomarkers and potential pathophysiological significance for schizophrenia. However, an integrated, clinically useful tool that used qualitative and quantitative MPAs to visualize and predict schizophrenia risk while characterizing the degree of importance of MPA items was lacking. We recruited a training set and a validation set, including 463 schizophrenia patients and 281 healthy controls to conduct logistic regression and the least absolute shrinkage and selection operator (Lasso) regression to select the best parameters of MPAs and constructed nomograms. Two nomograms were built to show the weights of these predictors. In the logistic regression model, 11 out of a total of 68 parameters were identified as the best MPA items for distinguishing between patients with schizophrenia and controls, including hair whorls, epicanthus, adherent ear lobes, high palate, furrowed tongue, hyperconvex fingernails, a large gap between first and second toes, skull height, nasal width, mouth width, and palate width. The Lasso regression model included the same variables of the logistic regression model, except for nasal width, and further included two items (interpupillary distance and soft ears) to assess the risk of schizophrenia. The results of the validation dataset verified the efficacy of the nomograms with the area under the curve 0.84 and 0.85 in the logistic regression model and lasso regression model, respectively. This study provides an easy-to-use tool based on validated risk models of schizophrenia and reflects a divergence in development between schizophrenia patients and healthy controls (https://www.szprediction.net/).
Investigating repetitive transcranial magnetic stimulation on cannabis use and cognition in people with schizophrenia
Authors: Bidzinski Karolina Kozak , Lowe Darby J. E. , Sanches Marcos , Sorkhou Maryam , Boileau Isabelle , Kiang Michael , Blumberger Daniel M. , Remington Gary , Ma Clement , Castle David J. , Rabin Rachel A. , George Tony P. 
Published: March 2022

AbstractCannabis use disorder (CUD) occurs at high rates in schizophrenia, which negatively impacts its clinical prognosis. These patients have greater difficulty quitting cannabis which may reflect putative deficits in the dorsolateral prefrontal cortex (DLPFC), a potential target for treatment development. We examined the effects of active versus sham high-frequency (20-Hz) repetitive transcranial magnetic stimulation (rTMS) on cannabis use in outpatients with schizophrenia and CUD. Secondary outcomes included cannabis craving/withdrawal, psychiatric symptoms, cognition and tobacco use. Twenty-four outpatients with schizophrenia and CUD were enrolled in a preliminary double-blind, sham-controlled randomized trial. Nineteen participants were randomized to receive active (n = 9) or sham (n = 10) rTMS (20-Hz) applied bilaterally to the DLPFC 5x/week for 4 weeks. Cannabis use was monitored twice weekly. A cognitive battery was administered pre- and post-treatment. rTMS was safe and well-tolerated with high treatment retention (~90%). Contrast estimates suggested greater reduction in self-reported cannabis use (measured in grams/day) in the active versus sham group (Estimate = 0.33,p = 0.21; Cohen’sd = 0.72), suggesting a clinically relevant effect of rTMS. A trend toward greater reduction in craving (Estimate = 3.92,p = 0.06), and significant reductions in PANSS positive (Estimate = 2.42,p = 0.02) and total (Estimate = 5.03,p = 0.02) symptom scores were found in the active versus sham group. Active rTMS also improved attention (Estimate = 6.58,p < 0.05), and suppressed increased tobacco use that was associated with cannabis reductions (Treatment x Time:p = 0.01). Our preliminary findings suggest that rTMS to the DLPFC is safe and potentially efficacious for treating CUD in schizophrenia.
Reduced erythrocyte membrane polyunsaturated fatty acid levels indicate diminished treatment response in patients with multi- versus first-episode schizophrenia
Authors: Li Nana , Yang Ping , Tang Mimi , Liu Yong , Guo Wenbin , Lang Bing , Wang Jianjian , Wu Haishan , Tang Hui , Yu Yan , Wu Xiangxin , Zeng Cuirong , Cao Ting , Cai Hualin 
Published: March 2022

AbstractAntipsychotic effects seem to decrease in relapsed schizophrenia patients and the underlying mechanisms remain to be elucidated. Based on the essential role of polyunsaturated fatty acids in brain function and the treatment of schizophrenia, we hypothesize that disordered fatty acid metabolism may contribute to treatment resistance in multi-episode patients. We analyzed the erythrocyte membrane fatty acids in 327 schizophrenia patients under various episodes (numbers of patients: first-episode drug naïve 89; 2–3 episodes 110; 4–6 episodes 80; over 6 episodes 48) and 159 age- and gender-matched healthy controls. Membrane fatty acid levels and PANSS scales were assessed at baseline of antipsychotic-free period and one-month of follow-up after treatment. Totally, both saturated and unsaturated fatty acids were reduced at baseline when compared to healthy controls. Subgroup analyses among different episodes indicated that in response to atypical antipsychotic treatment, the membrane fatty acids were only increased in patients within 3 episodes, and this therapeutic effects on omega-3 index were merely present in the first episode. Results of fatty acid ratios suggested that dysregulations of enzymes such as D6 desaturase, D5 desaturase, and elongases for polyunsaturated fatty acids in patients with multi-episode schizophrenia could account for the differences. Additionally, certain fatty acid level/ratio changes were positively correlated with symptom improvement. The alterations of C22:5n3 and omega-3 index, gender, and the number of episodes were significant risk factors correlated with treatment responsiveness. Using targeted metabolomic approach, we revealed the potential mechanisms underlying abnormal fatty acid metabolism responsible for reduced treatment response in patients with multi-episode schizophrenia.
Machine learning and phone data can improve targeting of humanitarian aid
Authors: Aiken Emily , Bellue Suzanne , Karlan Dean , Udry Chris , Blumenstock Joshua E. 
Published: March 2022

AbstractThe COVID-19 pandemic has devastated many low- and middle-income countries, causing widespread food insecurity and a sharp decline in living standards1. In response to this crisis, governments and humanitarian organizations worldwide have distributed social assistance to more than 1.5 billion people2. Targeting is a central challenge in administering these programmes: it remains a difficult task to rapidly identify those with the greatest need given available data3,4. Here we show that data from mobile phone networks can improve the targeting of humanitarian assistance. Our approach uses traditional survey data to train machine-learning algorithms to recognize patterns of poverty in mobile phone data; the trained algorithms can then prioritize aid to the poorest mobile subscribers. We evaluate this approach by studying a flagship emergency cash transfer program in Togo, which used these algorithms to disburse millions of US dollars worth of COVID-19 relief aid. Our analysis compares outcomes—including exclusion errors, total social welfare and measures of fairness—under different targeting regimes. Relative to the geographic targeting options considered by the Government of Togo, the machine-learning approach reduces errors of exclusion by 4–21%. Relative to methods requiring a comprehensive social registry (a hypothetical exercise; no such registry exists in Togo), the machine-learning approach increases exclusion errors by 9–35%. These results highlight the potential for new data sources to complement traditional methods for targeting humanitarian assistance, particularly in crisis settings in which traditional data are missing or out of date.
Reproducible brain-wide association studies require thousands of individuals
Authors: Marek Scott , Tervo-Clemmens Brenden , Calabro Finnegan J. , Montez David F. , Kay Benjamin P. , Hatoum Alexander S. , Donohue Meghan Rose , Foran William , Miller Ryland L. , Hendrickson Timothy J. , Malone Stephen M. , Kandala Sridhar , Feczko Eric , Miranda-Dominguez Oscar , Graham Alice M. , Earl Eric A. , Perrone Anders J. , Cordova Michaela , Doyle Olivia , Moore Lucille A. , Conan Gregory M. , Uriarte Johnny , Snider Kathy , Lynch Benjamin J. , Wilgenbusch James C. , Pengo Thomas , Tam Angela , Chen Jianzhong , Newbold Dillan J. , Zheng Annie , Seider Nicole A. , Van Andrew N. , Metoki Athanasia , Chauvin Roselyne J. , Laumann Timothy O. , Greene Deanna J. , Petersen Steven E. , Garavan Hugh , Thompson Wesley K. , Nichols Thomas E. , Yeo B. T. Thomas , Barch Deanna M. , Luna Beatriz , Fair Damien A. , Dosenbach Nico U. F. 
Published: March 2022

AbstractMagnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.
Activation mechanism of the class D fungal GPCR dimer Ste2
Authors: Velazhahan Vaithish , Ma Ning , Vaidehi Nagarajan , Tate Christopher G. 
Published: March 2022

AbstractThe fungal class D1 G-protein-coupled receptor (GPCR) Ste2 has a different arrangement of transmembrane helices compared with mammalian GPCRs and a distinct mode of coupling to the heterotrimeric G protein Gpa1–Ste2–Ste181. In addition, Ste2 lacks conserved sequence motifs such as DRY, PIF and NPXXY, which are associated with the activation of class A GPCRs2. This suggested that the activation mechanism of Ste2 may also differ. Here we determined structures of Saccharomyces cerevisiae Ste2 in the absence of G protein in two different conformations bound to the native agonist α-factor, bound to an antagonist and without ligand. These structures revealed that Ste2 is indeed activated differently from other GPCRs. In the inactive state, the cytoplasmic end of transmembrane helix H7 is unstructured and packs between helices H1–H6, blocking the G protein coupling site. Agonist binding results in the outward movement of the extracellular ends of H6 and H7 by 6 Å. On the intracellular surface, the G protein coupling site is formed by a 20 Å outward movement of the unstructured region in H7 that unblocks the site, and a 12 Å inward movement of H6. This is a distinct mechanism in GPCRs, in which the movement of H6 and H7 upon agonist binding facilitates G protein coupling.