Miracle-dz/UniFAR-FTUs huggingface dataset:
New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

Sodium–glucose cotransporter‐2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known. Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.
Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule

This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects were trained to self-administer the opioid remifentanil (0.3 µg/kg/injection) under a progressive-ratio schedule of reinforcement. The reinforcing effects of fentanyl (0.1–10 µg/kg/injection) or alprazolam (1.0–100 µg/kg/injection) alone, or in combinations of fixed proportions (1:1, 1:3, and 3:1 fentanyl:alprazolam, with 1:1 based on the potencies of drugs alone) were evaluated in single-day test sessions (with double determinations). Dose-equivalence analysis was used to determine the extent to which fentanyl and alprazolam combinations differed from additivity. Fentanyl functioned as a positive reinforcer in all monkeys, while alprazolam was a reinforcer in 3 of 6 monkeys only. Therefore, drug combination data were grouped as “alprazolam-taking” and “non-alprazolam-taking” monkeys. For alprazolam-taking monkeys, we observed additive effects for the 3:1 and 1:3 combinations, and a significant supra-additive interaction for the 1:1 combination of fentanyl and alprazolam. For 2 of the 3 non-alprazolam-taking monkeys, the combination of fentanyl and alprazolam resulted in enhanced reinforcing effects relative to either drug alone. However, the one monkey showed primarily inhibitory, or suppressive effects, with the 3:1 dose combination resulting in a relatively modest rightward shift in the fentanyl dose-response function. In summary, our findings show that combining fentanyl and alprazolam generally result in proportion-dependent additive or supra-additive enhancements. These data raise the possibility that the prevalence of opioid-benzodiazepine polydrug abuse may reflect a unique enhancement of these drugs’ reinforcing effects, although individual differences may exist. SIGNIFICANCE STATEMENT Addressing the critical question of the degree to which benzodiazepines can modulate the abuse-related effects of opioids may provide improved pathways to treatment of this common form of polydrug addiction. In the present study, we show that combinations of the opioid fentanyl and the benzodiazepine alprazolam can be more reinforcing than either drug alone in a rhesus monkey model, suggesting that enhancement of reinforcement processes may underlie this prevalent form of polydrug use disorder.
Sometimes “we” can help: parents’ pronoun use buffers fear and anxiety transmission

ABSTRACT Background and objectives: Parents’ natural language when describing health-related threats reflects parents’ cognitions that may shape their transmission of anxiety and fear. Parents’ greater communal focus (i.e., higher we-talk) and less self-focus (i.e., lower I-talk) may buffer against intergenerational fear/anxiety transmission. The current study investigated whether the relation between parents’ and children’s anxiety and pandemic-related fear differed by parent we- and I-talk. Design and Methods: Parents of 114 children (2–19 years; M = 9.75, SD = 3.73) completed online measures assessing children’s and parents’ anxiety and COVID-19-related fears, and engaged in a written reflection on their early pandemic experiences. The proportion of parents’ we-talk and I-talk during the reflection was obtained using Linguistic Inquiry Word Count software. Results: Results of multilevel structural equation models were partially consistent with expectations: The protective effect of we-talk was only observed for parents with lower fear/anxiety. For parents with higher fear/anxiety, higher I-talk was associated with lower child fear/anxiety. At higher levels of parent we-talk and at lower levels of I-talk, there was an unexpectedly positive association between parents’ and children’s fear/anxiety. Conclusions: The concordance between parents’ and their children’s fear/anxiety differs depending on parents’ natural language when reflecting on the pandemic.
Hardy-type inequalities

Part 1 The one-dimensional Hardy inequality on (a,b): historical remarks various methods of deriving it necessary and sufficient conditions for various classes of smooth functions u (u(a) = 0, or u(b) = 0, or u(a) = u(b) = 0). Part 2 The n-dimensional Hardy inequality: the approach via the one-dimensional case (special coordinates, special weights) the approach via differential equations (general weights) the approach via weighted norm inequalities (weights from the Muckenhoupt class AP) general necessary and sufficient conditions (the Maz'ja approach via capacities). Part 3 Weighted norm inequalities (a short survey of some special results). Part 4 Imbedding theorems for weighted Sobolev spaces: the Hardy inequality as an imbedding of a weighted Sobolev space into a weighted Lebesgue space the one-dimensional case the n-dimensional case special weights.
Darter fishes exhibit variable intraspecific head shape allometry and modularity

Allometry, the relationship between anatomical proportions and body size, may either limit or facilitate the diversification of morphology. We examined the impact of allometry in darter fish morphology, which displays a variety of trophic morphologies. This study aimed to address (a) whether there was significant variation in darter head allometry, (b) if allometry contributed to head shape diversity in adults, and (c) if darters show head shape modularity associated with allometry. We used geometric morphometrics to quantify head shape across 10 different species and test for heterogeneity in allometric slopes. In addition, we quantified the degree of modularity between the preorbital and postorbital regions of the darter head, both before and after correction for body size. We found that different species have unique allometric slopes, particularly among the Simoperca subgenus, and that closely related darter species tend to show ontogenetic divergence, contributing to the diversity of head shapes observed in adults. We suggest that such a pattern may result from the similarity of juvenile diets due to gape limitation. We also found that several species show significant modularity in head shape but that modularity was evolutionarily labile and only sometimes impacted by head shape allometry. Overall, our work suggests that ontogenetic shape development may have been important to the evolution of head shape in darters, particularly in the evolution of foraging traits and microhabitat.
Survival of patients and risk factors for subependymoma: a population-based study

ABSTRACT Objective Given the paucity of data on the subependymoma, we aimed to evaluate its risk factors from the Surveillance, Epidemiology, and End Results (SEER) database. Methods We collected survival and clinical information on patients with subependymoma diagnosed between 1975 and 2016 from the SEER database and screened them according to inclusion and exclusion criteria. Then, univariate and multivariate Cox regression analyses were used to identify significant prognostic factors, and nomograms were constructed to visualize the results. The concordance index (C-index), receiver operating characteristic (ROC), and calibration curves were used to assess the predictive ability of the nomogram. We divided the patient scores into two groups according to the high- and low-risk groups and constructed a survival curve using Kaplan–Meier analysis. Results A total of 731 patients were initially enrolled, including 511 (69.9%) males and 220 (30.1%) females. After screening, a total of 581 patientswere further evaluated by statistical analysis. The 5- and 10-year survival estimates were 92.0% and 81.9%, respectively. Sex (male, p=0.018; HR=2.3547, 95% CI=1.158-4.788) and age (≥56 years, p<0.001; HR=5.640, 95% CI= 3.139-10.133) were identified as independent prognostic factors for overall survival. The nomogram contained 4 prognostic factors. The C-index was 0.741, and the ROC and calibration curves also indicated the good predictability of the nomogram. Conclusion In this large cohort, a significant association was noted between age/sex and outcome, which could serve an important role for patient education. Even though a significant association was not found between the extent of resection and outcome, the effect of surgery on prognosis should be further explored. Abbreviations: AUC: area under the curve; CI: confidence interval; C-index: concordance index; CNS: central nervous system; GTR: gross total resection; HR: hazard ratio; NOS: not specific; OS: overall survival; PTR: partial resection; ROC: receiver operating characteristic; SEER: Surveillance, Epidemiology, and End Results; STR: subtotal resection; WHO: World Health Organization
Prevalence and factors influencing the occurrence of spasticity in stroke patients: a retrospective study

ABSTRACT Background To describe the prevalence and clinical characteristics of stroke patients without spasticity, and simultaneously analyse the factors related to post-stroke non-spasticity. Methods In this retrospective study, information on patients hospitalized in the department of rehabilitation, Daping Hospital, over the past eight years was collected. Demographic information and clinical characteristics were statistically analysed. Results A total of 819 stroke patients with an average age of 61.66±13.72 years old were analysed, including 561 males (68.5%), and 258 females (31.5%). In this study, 201 (24.5%) patients developed spasticity, and 618 (75.5%) patients had no spasticity. Patients without spasticity were older than those with spasticity. Patients with ischemic stroke and mild functional impairment were also less likely to have spasticity. Post-stroke spasticity may be related to age [odd ratio (OR): 0.982; 95% CI:0.965 to 0.999; P = 0.042), hemorrhagic stroke (OR: 1.643; 95% CI: 1.029 to 2.626; P = 0.038), National Institute of Health Stroke Scale (NIHSS) Scores (OR: 1.132; 95% CI: 1.063 to 1.204; P = 0.000]. Conclusion Most stroke patients do not have spasticity, especially the elderly, patients with ischemic stroke, and those with mild functional impairment, suggesting that not all upper motor nerve injuries lead to increased muscle tension. For young individuals, patients with hemorrhagic stroke, and those with moderate to severe functional impairment, close follow-up is necessary to identify the occurrence of spasticity early on and then formulate corresponding rehabilitation strategies for prompt intervention.
Investigation of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of the HIV-1 Maturation Inhibitor GSK3640254 Using an Intravenous Microtracer Combined with EnteroTracker for Biliary Sampling

GSK3640254 is a next-generation maturation inhibitor in development for HIV-1 treatment, with pharmacokinetics (PK) supporting once-daily oral dosing in human. This open-label, nonrandomized, two-period clinical mass balance and excretion study was used to investigate the excretion balance, PK, and metabolism of GSK3640254. Five healthy men received a single intravenous microtracer of 100 μg [14C]GSK3640254 with a concomitant oral nonradiolabeled 200-mg tablet followed by an oral 85-mg dose of [14C]GSK3640254 14 days later. Complementary methods, including intravenous microtracing and accelerator mass spectrometry, allowed characterization of several parameters, including fraction absorbed, fraction escaping gut metabolism, hepatic extraction ratio, and renal clearance. Intravenous PK of GSK3640254 was characterized by low plasma clearance (1.04 l/h), moderate terminal phase half-life (21.7 hours), and low volume of distribution at steady state (28.7 L). Orally dosed GSK3640254 was absorbed (fraction absorbed, 0.26), with a high fraction escaping gut metabolism (0.898) and a low hepatic extraction ratio (0.00544), all consistent with low in vitro intrinsic clearance in liver microsomes and hepatocytes. No major metabolites in human plasma required further qualification in animal studies. Both unchanged parent GSK3640254 and its oxidative and conjugative metabolites were excreted into bile, with GSK3640254 likely subject to further metabolism through enterohepatic recirculation. Renal elimination of GSK3640254 as the parent drug or its metabolites was negligible, with >94% of total recovery of oral dose and >99% of the recovered radioactivity in feces. Altogether, the data suggest that systemically available GSK3640254 was slowly eliminated almost entirely by hepatobiliary secretion, primarily as conjugative and oxidative metabolites. SIGNIFICANCE STATEMENT The combination of an intravenous 14C microtracer with duodenal bile sampling using EnteroTracker in a human absorption, distribution, metabolism, and excretion study enabled derivation of absorption and first-pass parameters, including fraction absorbed, proportion escaping first-pass extraction through the gut wall and liver, hepatic extraction, and other conventional clinical pharmacokinetic parameters. This approach identified hepatic metabolism and biliary excretion as a major elimination pathway for absorbed drug, which would be overlooked based solely on analyses of plasma, urine, and fecal matrices.
Immune Cell Deformability in Depressive Disorders: Longitudinal Associations Between Depression, Glucocorticoids and Cell Deformability

Background: Cell deformability of all major blood cell types is increased in depressive disorders (DD). Furthermore, impaired glucocorticoid secretion is causally related to DD. Nevertheless, there are no longitudinal studies examining changes in glucocorticoid output and depressive symptoms regarding cell deformability in DD. Aim: To investigate, whether changes in depressive symptoms or hair glucocorticoids predict cell deformability in DD. Methods: In 136 individuals, depressive symptoms (PHQ-9) and hair glucocorticoids (cortisol and cortisone) were measured at timepoint one (T1), while one year later (T2) depressive symptoms and hair glucocorticoids were remeasured and additionally cell deformability of peripheral blood cells was assessed and DD status was determined by clinical interview. Results: Depression severity at T1 predicted higher cell deformability in monocytes and lymphocytes over the entire sample. Subjects with continuously high depressive symptoms at T1 and T2 showed elevated monocyte deformability as compared to subjects with low depressive symptoms. Depression severity at T1 of subjects with a lifetime persistent depressive disorder (PDD) was associated with elevated monocyte, neutrophil, and granulo-monocyte deformability. Depression severity at T1 of subjects with a 12-month PDD was positively associated with monocyte deformability. Furthermore, increases in glucocorticoid concentrations from T1 to T2 tended to be associated with higher immune cell deformability, while strongest associations emerged for the increase in cortisone with elevated neutrophil and granulo-monocyte deformability in the 12-month PDD group. Conclusion: Continuously elevated depressive symptomatology as well as an increase in glucocorticoid levels over one year are associated with higher immune cell deformability, particularly in PDD. These findings suggest, that persistent depressive symptomatology associated with increased glucocorticoid secretion may lead to increased immune cell deformability thereby compromising immune cell function and likely contributing to the perpetuation of PDD.
Defect Physics, Delithiation Mechanism, and Electronic and Ionic Conduction in Layered Lithium Manganese Oxide Cathode Materials

Layered LiMnO$_2$ and Li$_2$MnO$_3$ are of great interest for lithium-ion battery cathodes because of their high theoretical capacities. The practical application of these materials is, however, limited due to poor electrochemical performance. We herein report a comprehensive first-principles study of defect physics in LiMnO$_2$ and Li$_2$MnO$_3$ using hybrid-density functional calculations. We find that manganese antisites have low formation energies in LiMnO$_2$ and may act as nucleation sites for the formation of impurity phases. The antisites can also occur with high concentrations in Li$_2$MnO$_3$; however, unlike in LiMnO$_2$, they can be eliminated by tuning the experimental conditions during preparation. Other intrinsic point defects may also occur and have an impact on the materials' properties and functioning. An analysis of the formation of lithium vacancies indicates that lithium extraction from LiMnO$_2$ is associated with oxidation at the manganese site, resulting in the formation of manganese small hole polarons; whereas in Li$_2$MnO$_3$ the intrinsic delithiation mechanism involves oxidation at the oxygen site, leading to the formation of bound oxygen hole polarons $\eta_{\rm O}^{+}$. The layered oxides are found to have no or negligible bandlike carriers and they cannot be doped n- or p-type. The electronic conduction proceeds through hopping of hole and/or electron polarons; the ionic conduction occurs through lithium monovacancy and/or divacancy migration mechanisms. Since $\eta_{\rm O}^{+}$ is not stable in the absence of negatively charged lithium vacancies in bulk Li$_2$MnO$_3$, the electronic conduction near the start of delithiation is likely to be poor. We suggest that the electronic conduction associated with $\eta_{\rm O}^{+}$ and, hence, the electrochemical performance of Li$_2$MnO$_3$ can be improved through nanostructuring and/or ion substitution.
Self-Regulated Learning and Working Memory Determine Problem-Solving Accuracy in Math

Abstract This study aims to understand the role of self-regulated learning (SRL) and its different processes in the relationship between working memory (WM) and problem-solving accuracy in math in primary school children. A sample of 269 primary school children (M age = 8.84, SD = 0.81, 58% boys) participated in this study. Tasks were used as intervention resources to assess children’s WM (i.e., reading and computation span tasks), SRL (i.e., a digital game), and performance (i.e., the performance in the game, as well as a traditional math problem). Through structural equation modeling, results revealed that WM predicted children’s SRL and their problem-solving accuracy in math, such that those with higher capability for temporary storage attained better accuracy. Accordingly, children’s SRL explained the relationship between WM capacity and problem-solving accuracy in math; such that the indirect effect of WM capacity through SRL was lower on problem-solving accuracy in math. Results indicated that the planning phase was a greater indicator of students’ SRL in problem-solving accuracy in math. These results highlight the importance of SRL competencies in explaining children’s performance in problem-solving in math.
How does an allowance for a non-working younger partner affect the retirement behaviour of couples?

Abstract We examine the effect of the partner allowance (PA) in the Dutch pension system on the retirement decisions of couples using administrative data. PA was paid to people who receive the public old-age pension with a partner younger than the state pension age (SPA) and with a low own income. PA worked as a financial incentive to retire earlier, especially for the younger partners. As of 1 April 2015, new old-age pensioners are no longer entitled to this allowance. We estimate the effect of this reform on the retirement behaviour of each spouse. To account for the fact that at the same time, another reform essentially put an end to generous early retirement arrangements, we compare singles and couples. We conclude that PA substantially increased female younger partners' probabilities to exit from part-time employment into retirement close to the older partner's SPA. On the other hand, there is no evidence that male younger partners (either full-time or part-time workers) responded to the PA reform. In addition, PA increased male older partners’ probabilities to retire in the years before reaching their SPA.
Development and initial validation of productive vocabulary tests for isiZulu, Siswati and English in South Africa

Multilingualism in education is encouraged in South Africa, and children are expected to become bilingual and biliterate during the early primary grades. Much focus has been placed on measuring literacy in children’s first language, often the medium of instruction (MOI), and English, the language typically used as MOI from fourth grade. However, vocabulary development in African contexts is underexplored, owing to the cost of existing English standardized tests, and the comparatively fewer linguistically and contextually appropriate vocabulary assessments in African languages. To address this gap, we document the development of corpus-informed contextually appropriate tests of productive vocabulary in isiZulu, Siswati, and English, which were used for a project evaluation. The initial validation phase included 412 children. Both tests were reliable and were concurrently validated with reading comprehension tests in each language, and oral language skills in English. This study contributes to our understanding of the factors that affect the variation in vocabulary knowledge in an African context, including age, grade repetition, and vocabulary in the other language. Only English vocabulary was affected by the remote rural location of the school. We recommend some modifications to the tests before they are validated further in other populations.
THE STAR FORMATION HISTORY OF ISOLATED DWARF UGC 4879

Recent observations of UGC 4879 with the Advanced Camera for Surveys on the Hubble Space Telescope confirm that it is a nearby isolated dwarf irregular galaxy. We measure a distance of 1.36 ± 0.03 Mpc using the tip of the red giant branch method. This distance puts UGC 4879 beyond the radius of first turnaround of the Local Group and ∼700 kpc from its nearest neighbor Leo A. This isolation makes this galaxy an ideal laboratory for studying pristine star formation uncomplicated by interactions with other galaxies. We present the star formation history of UGC 4879 derived from simulated color–magnitude diagrams.