Miracle-dz/UniFAR-FTUs huggingface dataset:
Q-Finder: An Algorithm for Credible Subgroup Discovery in Clinical Data Analysis — An Application to the International Diabetes Management Practice Study

Addressing the heterogeneity of both the outcome of a disease and the treatment response to an intervention is a mandatory pathway for regulatory approval of medicines. In randomized clinical trials (RCTs), confirmatory subgroup analyses focus on the assessment of drugs in predefined subgroups, while exploratory ones allow a posteriori the identification of subsets of patients who respond differently. Within the latter area, subgroup discovery (SD) data mining approach is widely used—particularly in precision medicine—to evaluate treatment effect across different groups of patients from various data sources (be it from clinical trials or real-world data). However, both the limited consideration by standard SD algorithms of recommended criteria to define credible subgroups and the lack of statistical power of the findings after correcting for multiple testing hinder the generation of hypothesis and their acceptance by healthcare authorities and practitioners. In this paper, we present the Q-Finder algorithm that aims to generate statistically credible subgroups to answer clinical questions, such as finding drivers of natural disease progression or treatment response. It combines an exhaustive search with a cascade of filters based on metrics assessing key credibility criteria, including relative risk reduction assessment, adjustment on confounding factors, individual feature’s contribution to the subgroup’s effect, interaction tests for assessing between-subgroup treatment effect interactions and tests adjustment (multiple testing). This allows Q-Finder to directly target and assess subgroups on recommended credibility criteria. The top-k credible subgroups are then selected, while accounting for subgroups’ diversity and, possibly, clinical relevance. Those subgroups are tested on independent data to assess their consistency across databases, while preserving statistical power by limiting the number of tests. To illustrate this algorithm, we applied it on the database of the International Diabetes Management Practice Study (IDMPS) to better understand the drivers of improved glycemic control and rate of episodes of hypoglycemia in type 2 diabetics patients. We compared Q-Finder with state-of-the-art approaches from both Subgroup Identification and Knowledge Discovery in Databases literature. The results demonstrate its ability to identify and support a short list of highly credible and diverse data-driven subgroups for both prognostic and predictive tasks.
Development of an Albumin-Based PSMA Probe With Prolonged Half-Life

Prostate-specific membrane antigen (PSMA) is an attractive target for the diagnosis and therapy of prostate cancer as it is specifically overexpressed in prostate cancer cells. Improving the circulation of radioligands in the blood is considered as an effective strategy that can improve tumor burden, which benefits detection of small lesions and improves the effect of PSMA radioligand therapy (PRLT). In this study, we introduced maleimidopropionic acid (MPA) to a PSMA-targeted tracer and developed Al18F-PSMA-CM, which targets human serum albumin (HSA) binding and PSMA. Al18F-PSMA-CM is evaluated in vitro and in vivo for stability, PSMA specificity, and biodistribution in 22Rv1 tumor-bearing mice. Al18F-PSMA-CM was prepared with a radiochemical purity of >99% and specific activity of 11.22–18.70 MBq/nmol. Al18F-PSMA-CM was stable in vitro and in vivo and prolonged circulation in blood with a binding ratio of 47 ± 3.2% and Kd value of 3.08 ± 0.45 nM to HSA. The uptake of Al18F-PSMA-CM in PSMA(+) 22Rv1 cells was increased in 2 h, and the uptake was blocked by a PSMA inhibitor, ZJ-43. The Kd value of Al18F-PSMA-CM to PSMA was 8.46 ± 0.24 nM. Al18F-PSMA-CM was accumulated in kidneys and 22Rv1 tumors [74.76 ± 15.42 and 6.16 ± 0.74 ID%/g at 2 h post injection (p.i.)], which were decreased by −80.0 and −84.3% when co-injected with ZJ-43. Al18F-PSMA-CM showed high PSMA specificity and accumulated in 22Rv1 tumors with increasing uptake in 4 h. MPA moiety showed the ability to prolong the half-life of tracers, and the MPA-conjugated tracer showed the potential to improve tumor uptake. MPA may be a choice to develop radiopharmaceuticals for PRLT of prostate cancer.
Frequency-Specific Regional Homogeneity Alterations in Tourette Syndrome

Tourette syndrome (TS) is a developmental neuropsychiatric disorder with onset during childhood. Because of its complex spectrum of phenotypes, the underlying pathophysiology of TS is still unclear. Resting-state functional magnetic resonance imaging demonstrated aberrant spontaneous neural synchronization in conventional frequency band (0.01–0.08 Hz) in TS. No published studies have reported abnormalities of local synchronization across different frequency bands. We estimated the alterations of local synchronization across five bands ranging from 0 to 0.25 Hz. Seventy-nine children with TS and 63 age-, sex-, and handedness-matched healthy children were recruited. Frequency-specific regional homogeneity (ReHo) and independent component analysis were used to identify functional alterations between TS and healthy children. TS patients showed significantly increased ReHo in the left precentral gyrus and decreased ReHo in the right operculum. Abnormal ReHo alterations of the superior frontal gyrus, superior parietal gyrus, anterior cingulate gyrus, putamen, superior temporal gyrus, and operculum were observed in different frequency bands. TS patients showed increased connectivity of the right superior frontal gyrus within the left executive control network. In addition, a significantly negative correlation was found between Yale Global Tic Severity Scale (YGTSS) vocal score and ReHo values of the right operculum in the highest frequency bands (0.198–0.25 Hz), while a significant positive correlation was found between YGTSS motor score and altered connectivity of the right superior frontal gyrus. The present study revealed frequency-specific abnormal alterations of ReHo in the whole brain and altered connectivity within the executive control network of TS children. Its neural importance and clinical practicability require further investigation.
A Minimal Setup for Spontaneous Smile Quantification Applicable for Valence Detection

Tracking emotional responses as they unfold has been one of the hallmarks of applied neuroscience and related disciplines, but recent studies suggest that automatic tracking of facial expressions have low validation. In this study, we focused on the direct measurement of facial muscles involved in expressions such as smiling. We used single-channel surface electromyography (sEMG) to evaluate the muscular activity from the Zygomaticus Major face muscle while participants watched music videos. Participants were then tasked with rating each video with regard to their thoughts and responses to each of them, including their judgment of emotional tone (“Valence”), personal preference (“Liking”) and rating of whether the video displayed strength and impression (“Dominance”). Using a minimal recording setup, we employed three ways to characterize muscular activity associated with spontaneous smiles. The total time spent smiling (ZygoNum), the average duration of smiles (ZygoLen), and instances of high valence (ZygoTrace). Our results demonstrate that Valence was the emotional dimension that was most related to the Zygomaticus activity. Here, the ZygoNum had higher discriminatory power than ZygoLen for Valence quantification. An additional investigation using fractal properties of sEMG time series confirmed previous studies of the Facial Action Coding System (FACS) documenting a smoother contraction of facial muscles for enjoyment smiles. Further analysis using ZygoTrace responses over time to the video events discerned “high valence” stimuli with a 76% accuracy. Additional validation of this approach came against previous findings on valence detection using features derived from a single channel EEG setup. We discuss these results in light of both the recent replication problems of facial expression measures, and in relation to the need for methods to reliably assess emotional responses in more challenging conditions, such as Virtual Reality, in which facial expressions are often covered by the equipment used.
Generation of a Genetically Modified Chimeric Plasmodium falciparum Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Malaria Vaccine Development

Chimeric rodent malaria parasites with the endogenous circumsporozoite protein (csp) gene replaced with csp from the human parasites Plasmodium falciparum (Pf) and P. vivax (Pv) are used in preclinical evaluation of CSP vaccines. Chimeric rodent parasites expressing PfCSP have also been assessed as whole sporozoite (WSP) vaccines. Comparable chimeric P. falciparum parasites expressing CSP of P. vivax could be used both for clinical evaluation of vaccines targeting PvCSP in controlled human P. falciparum infections and in WSP vaccines targeting P. vivax and P. falciparum. We generated chimeric P. falciparum parasites expressing both PfCSP and PvCSP. These Pf-PvCSP parasites produced sporozoite comparable to wild type P. falciparum parasites and expressed PfCSP and PvCSP on the sporozoite surface. Pf-PvCSP sporozoites infected human hepatocytes and induced antibodies to the repeats of both PfCSP and PvCSP after immunization of mice. These results support the use of Pf-PvCSP sporozoites in studies optimizing vaccines targeting PvCSP.
Vitamin D Status and Survival in Stage II-III Colorectal Cancer

Vitamin D status has been shown to be positively correlated with the morbidity and prognosis of colorectal cancer (CRC) patients. However, the prognostic effect of vitamin D status on patients with stage II and III CRC, especially Asian patients, remains unclear. A total of 728 patients (523 in the primary cohort and 205 in the validation cohort) who were diagnosed with stage II-III CRC between January 2011 and December 2015 were enrolled. Their serum 25-hydroxyvitamin D3 [25(OH)D] levels were tested. Kaplan-Meier curves and Cox regression analyses were carried out. Subgroup analyses were conducted according to tumor location. In the primary cohort, the serum 25(OH)D level was positively correlated with the overall survival (OS) of all CRC patients (p= 0.016) and stage III patients (p= 0.009), while no correlation was found between 25(OH)D level and the prognosis of patients with stage II CRC. Moreover, 25(OH)D level was an independent prognostic factor for the OS of all patients with CRC [HR 0.541, 95% CI 0.334–0.875, p=0.012] and those with stage III CRC (HR 0.563, 95% CI 0.319–0.993, p=0.047). Subgroup analysis indicated that only in the left-sided subgroup, stage III CRC patients with high 25(OH)D levels had better OS than those with low 25(OH)D levels (HR 0.474, 95% CI 0.230–0.978, p=0.043). In the validation cohort, serum 25(OH)D levels were verified to have prognostic value for patients with stage III CRC (HR 0.220, 95% CI 0.080–0.602, p=0.003), and low 25(OH)D levels indicated worse OS for left-sided stage III CRC patients (HR 0.233, 95% CI 0.075–0.727, p=.012). In conclusion, vitamin D status is positively correlated with the survival of CRC patients, especially those with left-sided stage III CRC.
Experimental Manipulations to Test Theory-Driven Mechanisms of Cognitive Behavior Therapy

Despite decades of randomized-controlled trials demonstrating the efficacy of cognitive-behavior therapy (CBT), the mechanisms by which CBT achieves its effects remain unclear. Here, we describe how one adaptive intervention, the sequential multiple assignment randomized trial (SMART), can be used to randomize patients at multiple decision points in treatment to draw stronger causal claims about mechanisms unfolding in the course of CBT. We illustrate this design using preliminary data and case examples from an ongoing SMART in which we are testing the role of aversive reactions to negative emotions as a hypothesized mechanism of change in the Unified Protocol. Finally, we address common concerns with SMARTs and highlight how mechanistic research serves to personalize and optimize the delivery of CBT.
Biomedical Evaluation of Lansium parasiticum Extract-Protected Silver Nanoparticles Against Haemonchus contortus, a Parasitic Worm

Here we show the novel anti-helminthic potential of Lansium parasiticum aqueous extract-protected silver nanoparticles (LAgNPs) against albendazole-resistant gastrointestinal parasite Haemonchus contortus. LAgNPs showed LD50 values of 65.6 ± 32.8 nM (12 h), 139.6 ± 39.9 nM (12 h), and 64.3 ± 8.5 nM (24 h) against adult male, female, and L3 larvae, respectively. LAgNPs was also quite effective in inhibiting egg hatching, with an IC50 value of 144.4 ± 3.1 nM at 48 h of exposure. Exposure to LAgNPs generated oxidative stress and mediated physical damage in the worms' tissue. A sharp increase in reactive oxygen species and nitric oxide synthase levels was prominent due to LAgNPs' exposure. In response to oxidative stress, a sharp increase of stress-responsive enzymes' activity, like catalase, superoxide dismutase, and glutathione peroxidase activity, along with the concentration of glutathione, was observed in worm tissue, which indicated a LAgNP-responsive alteration of metabolism. The results give rise to the opportunity for the development of alternative treatment for drug-resistant parasitic worms.
Potential Simultaneous Inhibitors of Angiotensin-Converting Enzyme 2 and Transmembrane Protease, Serine 2

Outbreak of coronavirus disease 2019 occurred in Wuhan and has rapidly spread to almost all parts of world. GB-1, the herbal formula from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, is used for the prophylaxis of SARS-CoV-2 in Taiwan. In this study, we investigated that the effect of GB-1 and the index compounds of GB-1 on the ACE2 and TMPRSS2 expression through in vitro and in vivo study. In our result, GB-1 can inhibit ACE2 and TMPRSS2 protein expression in HepG2 cells, 293T cells, and Caco-2 cells without cytotoxicity. For the mouse model, GB-1 treatment could decrease ACE2 and TMPRSS2 expression levels of the lung and kidney tissue without adverse effects, including nephrotoxicity and hepatotoxicity. In the compositions of GB-1, 0.5–1 mg/ml of Glycyrrhiza uralensis Fisch. ex DC. extract could not inhibit ACE2 mRNA and protein expression in HepG2 cells. In addition, theaflavin-3-gallate could inhibit protein expression of ACE2 and TMPRSS2 without significant cytotoxicity. Our results suggest that GB-1 and theaflavin-3-gallate could act as potential candidates for prophylaxis or treatment of SARS-CoV-2 infection through inhibiting protein expression of ACE2 and TMPRSS2 for the further study.
Mir-124 Attenuates STAT3-Mediated TH17 Differentiation in Colitis-Driven Colon Cancer

Background Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the miR-124 acts as a safeguard to inhibit the pro-inflammatory production and reparative regeneration. Methods The expression levels of miR-124 and IL-17, IFN-γ were detected by qRT-PCR. TH17 or TH1 cells were detected by flow cytometer, respectively. The binding of STAT3 to the promoter region of IL-17 gene was analyzed by Chip assay. miR-124 binding to the 3′UTR of STAT3 gene was detected by reported plasmid construction and luciferase assay. Furthermore, DSS-induced colitis mice model and T cell transfer model were used to confirm the function of miR-124 in vivo. The related gene expression was analyzed by ELISA and western blot experiments. Results The results indicated that miR-124 decrease promotes colon tumorigenesis after Citrobacter rodentium infection and AOM/DSS induced colon cancer murine model. In molecular mechanism, miR-124 targets STAT3 to inhibit TH17 cell polarization and keep TH17 polarization in colonic microenvironment. Conclusions Our study strengthened the important role of miR-124 in the regulation of adaptive immune responses and blocking the development of colitis-related cancer.
Enteric Viruses Associated with Mid-growth Turkey Enteritis

SUMMARY. Since August 2014, the University of Minnesota Veterinary Diagnostic Laboratory has received cases of turkey enteritis that are clinically different from previously described cases of poult enteritis syndrome and light turkey syndrome. The birds develop dark green and extremely foul-smelling diarrhea starting at 8–10 wk of age, which may last up to 15–16 wk of age. The affected turkey flocks show poor uniformity, and feed conversion and market weights are reduced. Multiple-age farms are affected more often than the single-age farms. Morbidity varies from flock to flock and in some cases reaches 100%. At necropsy, undigested feed with increased mucus is observed in the intestines along with prominent mucosal congestion and/or hemorrhage. Microscopically, lymphocytic infiltrates expand the villi in duodenum and jejunum to form lymphoid follicles, which are often accompanied by heterophils. Next generation sequencing (Illumina Miseq) on a pool of feces from affected birds identified genetic sequences of viruses belonging to Astroviridae, Reoviridae, Picornaviridae, Picobirnaviridae, and Adenoviridae. On testing pools of fecal samples from apparently healthy (16 pools) and affected birds (30 pools), there was a higher viral load in the feces of affected birds. Picobirnavirus was detected only in the affected birds; 20 of 30 pools (66.7%) were positive. These results indicate that a high viral load of turkey picobirnavirus alone, or in association with novel picornaviruses, may be a cause of this new type of turkey enteritis.
Correction

MEDICAL SCIENCES Correction for “The myokine irisin increases cortical bone mass,” by Graziana Colaianni, Concetta Cuscito, Teresa Mongelli, Paolo Pignataro, Cinzia Buccoliero, Peng Liu, Ping Lu, Loris Sartini, Mariasevera Di Comite, Giorgio Mori, Adriana Di Benedetto, Giacomina Brunetti, Tony Yuen, Li Sun, Janne E. Reseland, Silvia Colucci, Maria I. New, Mone Zaidi, Saverio Cinti, and Maria Grano, which appeared in issue 39, September 29, 2015, of Proc Natl Acad Sci USA (112:12157–12162; first published September 15, 2015; 10.1073/pnas.1516622112). The authors note that their conflict of interest statement was omitted during publication. The authors declare that G.C. , C.C. , G.M. , G.B. , S. Colucci, S. Cinti, and M.G. are named inventors of a pending patent application related to the work described.
Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer’s disease pathogenesis

Chi3l1/YKL-40 is regulated by BMAL1 in astrocytes and influences AD pathogenesis in both mouse models and humans. Targeting astrocytes in AD Astrocytes and microglia play a dual role in Alzheimer’s disease (AD), increasing neuroinflammation and limiting plaque growth through phagocytic activity. The astrocytic protein YKL-40 is increased in the cerebrospinal fluid (CSF) of patients with AD; however, its role in AD pathophysiology is unclear. Here, Lananna et al. used mouse model and in vitro systems to show that Chi3l1, the gene coding for YKL-40, plays a detrimental role in AD. Its deletion reduced amyloid plaque formation and promoted Aβ phagocytosis. A polymorphism in CHI3L1 resulting in reduced protein expression was associated with slower AD progression in patients. The results suggest that YKL-40 could be targeted for reducing AD progression in patients. Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer’s disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene Chi3l1, is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of Chi3l1/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human CHI3L1 gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline, Chi3l1 deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD, Chi3l1 deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that Chi3l1 may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly, Chi3l1 knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of Chi3l1 is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal Chi3l1 expression, whereas deletion of the negative clock regulators PER1/PER2 increased Chi3l1 expression. Basal Chi3l1 mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of Chi3l1 was gated by the clock. Our findings reveal Chi3l1/YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory Chi3l1 induction.
Comparison of ZnO nanostructures grown using pulsed laser deposition, metal organic chemical vapor deposition, and physical vapor transport

This article compares the forms and properties of ZnO nanostructures grown on Si(111) and c-plane sapphire (c-Al(2)O(3)) substrates using three different growth processes: metal organic chemical vapor deposition (MOCVD), pulsed laser deposition (PLD), and physical vapor transport (PVT). A very wide range of ZnO nanostructures was observed, including nanorods, nanoneedles, nanocombs, and some novel structures resembelling "bevelled" nanowires. PVT gave the widest family of nanostructures. PLD gave dense regular arrays of nanorods with a preferred orientation perpendicular to the substrate plane on both Si and c-Al(2)O(3) substrates, without the use of a catalyst. X-ray diffraction (XRD) studies confirmed that nanostructures grown by PLD were better crystallized and more highly oriented than those grown by PVT and MOCVD. Samples grown on Si showed relatively poor XRD response but lower wavelength emission and narrower linewidths in PL studies.
A study of the formation of single- and double-walled carbon nanotubes by a CVD method.

The reduction in H2/CH4 atmosphere of aluminum-iron oxides produces metal particles small enough to catalyze the formation of single-walled carbon nanotubes. Several experiments have been made using the same temperature profile and changing only the maximum temperature (800-1070 °C). Characterizations of the catalyst materials are performed using notably 57Fe Mo¨ssbauer spectroscopy. Electron microscopy and a macroscopical method are used to characterize the nanotubes. The nature of the iron species (Fe3+, R-Fe, c-Fe-C, Fe3C) is correlated to their location in the material. The nature of the particles responsible for the high-temperature formation of the nanotubes is probably an Fe-C alloy which is, however, found as Fe3C by postreaction analysis. Increasing the reduction temperature increases the reduction yield and thus favors the formation of surface-metal particles, thus producing more nanotubes. The obtained carbon nanotubes are mostly single-walled and double-walled with an average diameter close to 2.5 nm. Several formation mechanisms are thought to be active. In particular, it is shown that the second wall can grow inside the first one but that subsequent ones are formed outside. It is also possible that under given experimental conditions, the smallest (<2 nm) catalyst particles preferentially produce double-walled rather than single-walled carbon nanotubes.