Miracle-dz/UniFAR-FTUs huggingface dataset:
Distinctive Therapeutic Effects of Non-Euphorigenic Cannabis Extracts in Osteoarthritis.

Introduction: Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. Objective: We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Methods and Results: Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Conclusions: Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.
Perceived Stress Levels and Associated Factors in Adult Patients with Primary Open-angle Glaucoma: A Prospective Survey Study

Purpose To investigate adult primary open-angle glaucoma (POAG) patients’ perceived stress levels and to examine the associations with their clinical characteristics. Methods Sixty-seven POAG patients, excluding those meeting the exclusion criteria (retinal or neurological disease diagnoses) comprised the study population. A validated questionnaire, namely Perceived Stress Scale-10 (PSS-10), was used to assess stress level. Additional data on glaucoma surgery history, medical benefit receipt, comorbidities, and daily antiglaucoma medication number were collected. The clinical characteristics of high (PSS-10 ≥15) and low stress (PSS-10 <15) patients and the risk factors associated with high stress level were subjected to a multivariable logistic regression analysis. Results The patients were 56.8 ± 12.6 years of age on average, and 29 (43.3%) were female. The mean PSS-10 level was 13.5 ± 5.3 (range, 1–27) for the entire patient group; 31 patients (46.3%) were in the high stress group. In the high stress group relative to the low stress group, best-corrected visual acuity in the better eye was lower (p = 0.044) and the visual field defects, in both eyes, were more severe (better eye, p = 0.005; worse eye, p = 0.026). A logistic regression analysis indicated that severe visual field defect in the better eye (odds ratio, 1.159; 95% confidence interval, 1.016–1.323; p = 0.028) and lower best-corrected visual acuity in the better eye (odds ratio, 4.707; 95% confidence interval, 0.580–6.189; p = 0.072) were both likely to associated with high stress level in patients with POAG. Conclusions These findings suggest an association between severe visual function loss and higher mental stress level in POAG patients. Stress level, therefore, might be an important consideration in POAG patient management.
Reduced sister chromatid cohesion acts as a tumor penetrance modifier

Sister chromatid cohesion (SCC) is an important process in chromosome segregation. ESCO2 is essential for establishment of SCC and is often deleted/altered in human cancers. We demonstrate that esco2 haploinsufficiency results in reduced SCC and accelerates the timing of tumor onset in both zebrafish and mouse p53 heterozygous null models, but not in p53 homozygous mutant or wild-type animals. These data indicate that esco2 haploinsufficiency accelerates tumor onset in a loss of heterozygosity (LOH) sensitive background. Analysis of The Cancer Genome Atlas (TCGA) confirmed ESCO2 deficient tumors have elevated number of LOH events throughout the genome. Further, we demonstrated heterozygous loss of sgo1, important in maintaining SCC, also results in reduced SCC and accelerated tumor formation in a p53 heterozygous background. Surprisingly, while we did observe elevated levels of chromosome missegregation and micronuclei formation in esco2 heterozygous mutant animals, this chromosomal instability did not contribute to the accelerated tumor onset in a p53 heterozygous background. Interestingly, SCC also plays a role in homologous recombination, and we did observe elevated levels of mitotic recombination derived p53 LOH in tumors from esco2 haploinsufficient animals; as well as elevated levels of mitotic recombination throughout the genome of human ESCO2 deficient tumors. Together these data suggest that reduced SCC contributes to accelerated tumor penetrance through elevated mitotic recombination.
Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice

Background Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25–30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. Methods In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. Results Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. Conclusions Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.
Search Strategies Improve With Practice, but Not With Time Pressure or Financial Incentives

When searching for an object, do we minimize the number of eye movements we need to make? Under most circumstances, the cost of saccadic parsimony likely outweighs the bene ﬁ t, given the cost is exten-sive computation and the bene ﬁ t is a few hundred milliseconds of time saved. Previous research has measured the proportion of eye movements directed to locations where the target would have been visi- ble in the periphery as a way of quantifying the proportion of super ﬂ uous ﬁ xations. A surprisingly large range of individual differences has emerged from these studies, suggesting some people are highly ef ﬁ cient and others much less so. Our question in the current study is whether these individual differences can be explained by differences in motivation. In two experiments, we demonstrate that neither time pressure nor ﬁ nancial incentive led to improvements of visual search strategies; the majority of participants continued to make many super ﬂ uous ﬁ xations in both experiments. The wide range of individual differences in ef ﬁ ciency observed previously was replicated here. We observed small but consistent improvements in strategy over the course of the experiment (regardless of reward or time pressure) sug- gesting practice, not motivation, makes participants more ef ﬁ cient. In this study, neither time pressure nor ﬁ nancial incentive led to improvements in visual search strategies, ruling out motivation as the explanation for the large individual differences in search ef ﬁ ciency seen in previous studies. Small but consistent improvements in strategy over time suggest experience, rather than differences in motivation, could help explain why some participants are more ef ﬁ cient than others.
Orthogonalization of a Boolean Function

Orthogonalization is the process of transforming a conjunctive normal form of a Boolean function to orthogonal conjunctive normal form, i.e. to a normal form in which any two clauses contain a pair of complementary literals. Orthogonal disjunctive normal form is de¯ned similarly. The problem is of great relevance in several application, e
Whole‐exome sequencing of a patient with primary central nervous system T‐cell lymphoma: Clinicopathological features and genomic profiling

Primary central nervous system T‐cell lymphoma (T‐PCNSL) is a rare neoplasm, and its underlying genetic features are poorly understood. Herein, we present the case of a 64‐year‐old man with T‐PCNSL who presented with left‐side limb weakness. Brain magnetic resonance imaging revealed a right parietal space‐occupying lesion. Immunohistochemically, the tumor was positive for CD3, CD4, CD5, CD8, and CD56, and the Ki‐67 labeling index was approximately 20%. These pathological features are consistent with those of T‐cell lymphoma. Whole exome sequencing was performed, and we found a variant in the ACSS3 gene that could be related to disease pathogenesis. Our findings may help advance our understanding of the molecular pathogenesis of T‐PCNSL. Further molecular analysis of such cases could help to improve adjuvant molecular diagnostic methods and targeted therapies for T‐PCNSL.
Unravelling the role of macrophages in cardiovascular inflammation through imaging: a state-of-the-art review

Abstract Cardiovascular disease remains the leading cause of death and disability for patients across the world. Our understanding of atherosclerosis as a primary cholesterol issue has diversified, with a significant dysregulated inflammatory component that largely remains untreated and continues to drive persistent cardiovascular risk. Macrophages are central to atherosclerotic inflammation, and they exist along a functional spectrum between pro-inflammatory and anti-inflammatory extremes. Recent clinical trials have demonstrated a reduction in major cardiovascular events with some, but not all, anti-inflammatory therapies. The recent addition of colchicine to societal guidelines for the prevention of recurrent cardiovascular events in high-risk patients with chronic coronary syndromes highlights the real-world utility of this class of therapies. A highly targeted approach to modification of interleukin-1-dependent pathways shows promise with several novel agents in development, although excessive immunosuppression and resulting serious infection have proven a barrier to implementation into clinical practice. Current risk stratification tools to identify high-risk patients for secondary prevention are either inadequately robust or prohibitively expensive and invasive. A non-invasive and relatively inexpensive method to identify patients who will benefit most from novel anti-inflammatory therapies is required, a role likely to be fulfilled by functional imaging methods. This review article outlines our current understanding of the inflammatory biology of atherosclerosis, upcoming therapies and recent landmark clinical trials, imaging modalities (both invasive and non-invasive) and the current landscape surrounding functional imaging including through targeted nuclear and nanobody tracer development and their application.
Multisensory perception is not influenced by previous concussion history in retired rugby union players

ABSTRACT Background To assess whether concussion history adversely affects multisensory integration, we compared susceptibility to the Sound-Induced Flash Illusion (SIFI) in retired professional rugby players compared to controls. Methods Retired professional rugby players ((N = 58) and retired international rowers (N = 26) completed a self-report concussion history questionnaire and the SIFI task. Susceptibility to the SIFI (i.e., perceiving two flashes in response to one flash paired with two beeps) was assessed at three stimulus onset asynchronies (70 ms, 150 ms or 230 ms). Logistic mixed-effects regression modeling was implemented to evaluate how athlete grouping, previous concussion history and total number of years playing sport, impacted the susceptibility to the SIFI task. The statistical significance of a fixed effect of interest was determined by a likelihood ratio test. Results Former rugby players had significantly more self-reported concussions than the rower group (p < 0.001). There was no impact of athlete grouping (i.e., retired professional rugby players and retired international rowers), years participation in elite sport or concussion history on performance in the SIFI. Conclusion A career in professional rugby, concussion history or number of years participating in professional rugby was not found to be predictive of performance on the SIFI task.
Gap junctions regulate the activity of AgRP neurons and diet-induced obesity in male mice.

Recent studies indicated an important role of connexins, gap junction proteins, in the regulation of metabolism. However, most of these studies focused on glial expression of connexins, whereas the actions of connexins in neurons are still poorly investigated. Thus, the present study had the objective to investigate the possible involvement of gap junctions, and in particular connexin 43 (CX43), for the central regulation of energy homeostasis. Initially, we demonstrated that hypothalamic CX43 expression was suppressed in fasted mice. Using whole-cell patch-clamp recordings, we showed that pharmacological blockade of gap junctions induced hyperpolarization and decreased the frequency of action potentials in 50 to 70% of agouti-related protein (AgRP)-expressing neurons, depending on the blocker used (carbenoxolone disodium, TAT-Gap19 or Gap 26). When recordings were performed with a biocytin-filled pipette, this intercellular tracer was detected in surrounding cells. Then, an AgRP-specific CX43 knockout (AgRPΔCX43) mouse was generated. AgRPΔCX43 mice exhibited no differences in body weight, adiposity, food intake, energy expenditure and glucose homeostasis. Metabolic responses to 24 hours fasting or during refeeding were also not altered in AgRPΔCX43 mice. However, AgRPΔCX43 male, but not female mice exhibited a partial protection against high-fat diet-induced obesity, even though no significant changes in energy intake or expenditure were detected. In summary, our findings indicate that gap junctions regulate the activity of AgRP neurons, and AgRP-specific CX43 ablation is sufficient to mildly prevent diet-induced obesity specifically in males.
Effects of lactate administration on hypertrophy and mTOR signaling activation in mouse skeletal muscle

Lactate is a metabolic product of glycolysis and has recently been shown to act as a signaling molecule that induces adaptations in oxidative metabolism. In this study, we investigated whether lactate administration enhanced muscle hypertrophy and protein synthesis responses during resistance exercise in animal models. We used male ICR mice (7–8 weeks old) were used for chronic (mechanical overload induced by synergist ablation: [OL]) and acute (high‐intensity muscle contraction by electrical stimulation: [ES]) resistance exercise models. The animals were intraperitoneally administrated a single dose of sodium lactate (1 g/kg of body weight) in the ES study, and once a day for 14 consecutive days in the OL study. Two weeks of mechanical overload increased plantaris muscle wet weight (main effect of OL: p < 0.05) and fiber cross‐sectional area (main effect of OL: p < 0.05), but those were not affected by lactate administration. Following the acute resistance exercise by ES, protein synthesis and phosphorylation of p70 S6 kinase and ribosomal protein S6, which are downstream molecules in the anabolic signaling cascade, were increased (main effect of ES: p < 0.05), but lactate administration had no effect. This study demonstrated that exogenous lactate administration has little effect on the muscle hypertrophic response during resistance exercise using acute ES and chronic OL models. Our results do not support the hypothesis that elevated blood lactate concentration induces protein synthesis responses in skeletal muscle.
Composite carotid intima-media thickness as a risk predictor of coronary heart disease in a selected population in Sri Lanka

Background Segment-specific variations of carotid intima-media thickness (CIMT) have not been assessed in South Asian populations. The purpose of this study was to determine if segment-specific CIMTs or a composite-CIMT score is a better risk predictor of coronary heart disease in South Asian populations. Methods A comparative prospective study was conducted from November 2019 to October 2020 in a hospital in Colombo, Sri Lanka. Based on pre-defined inclusion and exclusion criteria, cases (having a diagnosis of Coronary Heart Disease (CHD), n = 338) and controls (non-CHD group, n = 356) were recruited. Ultrasound examination of the common carotid (CCA), the carotid bulb (CB) and the internal carotid segments (ICA) of the carotid vessels was conducted by a radiologist, and CIMTs were measured. A composite-CIMT score defined as the average value of all six segments of the left and right sides was derived. Results 694 participants were enrolled (male n = 399, 57.5%). The mean (±SD) age of the study sample was 60.2 (±9.86) years. There were variations in segment-specific values between the left and right vessels. The mean composite-CIMT value of the CHD group was significantly higher than that of the non-CHD group. A composite-CIMT score of 0.758 had a sensitivity of 98.4% and a specificity of 64.6% in distinguishing CHD from non-CHD groups (Area under the curve (AUC): 0.926). Conclusions Carotid artery segment-specific CIMT variations were present in this population. The composite CIMT score is better than segment-specific CIMTs in predicting CHD and may be used to predict CHD in this population.
High-level visual search in children with autism

Visual search has been classified as easy feature search, with rapid target detection and little set size dependence, versus slower difficult search with focused attention, with set size–dependent speed. Reverse hierarchy theory attributes these classes to rapid high cortical-level vision at a glance versus low-level vision with scrutiny, attributing easy search to high-level representations. Accordingly, faces “pop out” of heterogeneous object photographs. Individuals with autism have difficulties recognizing faces, and we now asked if this disability disturbs their search for faces. We compare search times and set size slopes for children with autism spectrum disorders (ASDs) and those with neurotypical development (NT) when searching for faces. Human face targets were found rapidly, with shallow set size slopes. The between-group difference between slopes (18.8 vs. 11.3 ms/item) is significant, suggesting that faces may not “pop out” as easily, but in our view does not warrant classifying ASD face search as categorically different from that of NT children. We also tested search for different target categories, dog and lion faces, and nonface basic categories, cars and houses. The ASD group was generally a bit slower than the NT group, and their slopes were somewhat steeper. Nevertheless, the overall dependencies on target category were similar: human face search fastest, nonface categories slowest, and dog and lion faces in between. We conclude that autism may spare vision at a glance, including face detection, despite its reported effects on face recognition, which may require vision with scrutiny. This dichotomy is consistent with the two perceptual modes suggested by reverse hierarchy theory.
Structure and Dynamics of Parallel b -Sheets, Hydrophobic Core, and Loops in Alzheimer’s A b Fibrils

We explore the relative contributions of different structural elements to the stability of A b ﬁbrils by molecular-dynamics simulations performed over a broad range of temperatures (298 K to 398 K). Our ﬁbril structures are based on solid-state nuclear magnetic resonance experiments of A b (1–40) peptides, with sheets of parallel b -strands connected by loops and stabilized by interior salt bridges. We consider models with different interpeptide interfaces, and different staggering of the N- and C-terminal b -strands along the ﬁbril axis. Multiple 10–20 ns molecular-dynamics simulations show that ﬁbril segments with 12 peptides are stable at ambient temperature. The different models converge toward an interdigitated side-chain packing, and present water channels solvating the interior D23/K28 salt bridges. At elevated temperatures, we observe the early phases of ﬁbril dissociation as a loss of order in the hydrophilic loops connecting the two b -strands, and in the solvent-exposed N-terminal b -sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal b -sheets on top of each other. The interior C-terminal b -sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of A b ﬁbrils.
A Pedagogical Introduction to the AGT Conjecture

The AGT conjecture is a natural identification between certain information-rich objects in 4d N = 2 supersymmetric gauge theories and Liouville conformal field theory. Though relatively easy to state, it rests upon a host of concepts and computational techniques developed over the span of 25 years, many of which were only recently uncovered. This thesis consists of two parts. The first half is written for the seasoned researcher who wishes to review the essential concepts, understand the statement of the conjecture, and observe how a proof of a simple but non-trivial subcase is performed. The second half is written for the curious student: it consists of a number of appendices dedicated to explaining in greater detail the topological objects appearing the history and statement of the conjecture, to proving many groupand representation-theoretic statements whose conclusions are frequently used in the literature but whose proofs appear rarely, and to introducing a rarely-studied but critically important matter representation: the trifundamental.