Miracle-dz/UniFAR-FTUs huggingface dataset:
Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine

Striking stereoselective disposition of the antidepressant and smoking cessation aid bupropion (BUP) and its active metabolites observed clinically influence patients’ response to BUP therapy and its clinically important drug-drug interactions (DDI) with CYP2D6 substrates. However, understanding of the biochemical mechanisms responsible is incomplete. This study comprehensively examined hepatic and extrahepatic stereoselective metabolism of BUP in vitro. Racemic-, R-, and S-BUP were incubated separately with pooled cellular fractions of human liver [microsomes (HLMs), S9 fractions (HLS9s), and cytosols (HLCs)] and intestinal [microsomes (HIMs), S9 fractions (HIS9s), and cytosols (HICs)] and cofactors. Formations of diastereomers of 4-hydroxyBUP (OHBUP), threohydroBUP (THBUP), and erythrohydroBUP (EHBUP) were quantified using a novel chiral ultra-high performance liquid chromatography/tandem mass spectrometry method. Racemic BUP (but not R- or S-BUP) was found suitable to determine stereoselective metabolism of BUP; both enantiomers showed complete racemization. Compared with that of RR-THBUP, the in vitro intrinsic clearance (Clint) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions, and HLCs, respectively; Clint for the formation of SS-OHBUP and RS-EHBUP was also higher (2.7- to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, ≥ 95% of total reduction was accounted by the formation of RR-THBUP. Ours is the first to demonstrate marked stereoselective reduction of BUP in HLCs, HIMs, HIS9 fractions, and HICs, providing the first evidence for tissue- and cellular fraction-dependent stereoselective metabolism of BUP. These data may serve as the first critical step toward understanding factors dictating BUP’s stereoselective disposition, effects, and DDI risks. SIGNIFICANCE STATEMENT This work provides a deeper insight into bupropion (BUP) stereoselective oxidation and reduction to active metabolites in cellular fractions of human liver and intestine tissues. The results demonstrate tissue- and cellular fraction-dependent stereospecific metabolism of BUP. These data may improve prediction of BUP stereoselective disposition and understanding of BUP’s effects and CYP2D6-dependent drug-drug interaction in vivo.
Timing of invasive strategy in non-ST-elevation acute coronary syndrome: a meta-analysis of randomized controlled trials

Abstract Aims The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial. Recent randomized controlled trials (RCTs) and long-term follow-up data have yet to be included in a contemporary meta-analysis. Methods and results A systematic review of RCTs that compared an early IS vs. delayed IS for NSTE-ACS was conducted by searching MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. A meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. This study was registered with PROSPERO (CRD42021246131). Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality [RR: 0.90, 95% confidence interval (CI): 0.78–1.04], MI (RR: 0.86, 95% CI: 0.63–1.16), admission for HF (RR: 0.66, 95% CI: 0.43–1.03), repeat re-vascularization (RR: 1.04, 95% CI: 0.88–1.23), major bleeding (RR: 0.86, 95% CI: 0.68–1.09), or stroke (RR: 0.95, 95% CI: 0.59–1.54) were observed. Recurrent ischaemia (RR: 0.57, 95% CI: 0.40–0.81) and length of stay (median difference: −22 h, 95% CI: −36.7 to −7.5 h) were reduced with an early IS. Conclusion In all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, or increase major bleeding or stroke when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS.
Hyaluronic acid in the treatment of dry eye disease

Dry eye disease (DED) is a highly prevalent and debilitating condition affecting several hundred million people worldwide. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan commonly used in the treatment of DED. This review aims to critically evaluate the literature on the safety and efficacy of artificial tears containing HA used in DED treatment. Literature searches were conducted in PubMed, including MEDLINE, and in Embase via Ovid with the search term: “(hyaluronic acid OR hyaluronan OR hyaluronate) AND (dry eye OR sicca)”. A total of 53 clinical trials are included in this review, including eight placebo‐controlled trials. Hyaluronic acid concentrations ranged from 0.1% to 0.4%. Studies lasted up to 3 months. A broad spectrum of DED types and severities was represented in the reviewed literature. No major complications or adverse events were reported. Artificial tears containing 0.1% to 0.4% HA were effective at improving both signs and symptoms of DED. Two major gaps in the literature have been identified: 1. no study investigated the ideal drop frequency for HA‐containing eyedrops, and 2. insufficient evidence was presented to recommend any specific HA formulation over another. Future investigations assessing the optimal drop frequency for different concentrations and molecular weights of HA, different drop formulations, including tonicity, and accounting for DED severity and aetiology are essential for an evidence‐based, individualized approach to DED treatment.
Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson’s disease

Abstract Purpose Parkinson’s disease (PD) is associated with the destruction of dopaminergic neurons in the substantia nigra (SN). Hydroxychloroquine (HCQ) has the capability to cross the blood–brain barrier and promote a neuroprotective potential. This study evaluated the effects of HCQ on the 6-hydroxydopamine (6-OHDA)-induced PD model in rats. Methods Wistar rats were randomly divided into sham, PD, PD + levodopa and PD + HCQ groups. The PD model was induced by a stereotactic administration of 6-OHDA into the left SN pars compacta (SNpc) and confirmed by rotation and the Murprogo’s tests. HCQ (100 mg/kg, p.o.) and levodopa (12 mg/kg, p.o.) were administered once a day for 21 days. Three weeks after surgery, the behavioral tests were performed. Brain lipid peroxidation index (MDA), glutathione peroxidase activity (GPx), total antioxidant capacity (TAC) levels and α-synuclein protein expression in the SN were also measured. Results The behavioral tests demonstrated that induction of PD increased the muscle rigidity and the number of rotations, which were reversed by HCQ treatment. Also, induction of PD was associated with an increase in α-synuclein protein levels and MDA and decreased TAC levels and GPx activity. However, HCQ decreased α-synuclein and MDA levels while increased TAC levels and GPx activity. In addition, histopathological data showed that HCQ protects dopaminergic neurons against 6-OHDA-induced toxicity. Conclusion According to the results, HCQ has a beneficial effect in improving PD-related pathophysiology, in part, by mitigating oxidative stress and protecting the dopaminergic neurons in the SN.
Meniscus Root Tears: A Clinical Review

Abstract Meniscus root tears are important to recognize early given their potentially devastating consequences on joint health. This injury results in the lost ability of the meniscus to transfer axial loads into hoop stress; therefore, it is functionally equivalent to a complete meniscectomy. This causes rapid progression of osteoarthritis and increased need to total knee arthroplasty in a previously healthy joint. Despite these consequences, root tears have only been discussed in the orthopedic literature in the last 10 to 15 years and have not been routinely integrated into nonoperative sports medicine education. It is important for all nonoperative sports medicine providers to properly diagnose and triage this injury early in its course to maximize joint preservation efforts. The goal of this manuscript is to review the anatomy, presentation, natural history, imaging, and treatment options for meniscal root tears.
Free to choose: Mutualist motives for partner choice, proportional division, punishment, and help

Mutualism–the disposition to cooperate in ways that benefit both actor and recipient–has been proposed as a key construct in the evolution of cooperation, with distinct adaptations for 1) partner choice, 2) division, 3) punishment, and 4) helping. However, no psychological validation of this 4-fold psychological structure exists, and no measure of the trait is available. To fill this need, in two pre-registered studies (total N = 902), we: (A) Develop and administer items assessing each of the four mutualist adaptations; (B) Show good fit to the predicted four factor model; (C) Demonstrate reliability and stability across time; (D) Evidence discriminant validity from existing constructs, including compassion and utilitarianism; (E) Establish external validity by predicting proportional choices in catch division, opposition to partner coercion, and reduced support for redistribution; and (F) Replicate each of these findings. Jointly, these results support the validity of mutualism, including a motive to maintain the freedom to choose, and provide reliable scales for use in integrating, further developing, and applying mutualism.
Erratic spatiotemporal vegetation growth anomalies drive population outbreaks in a trans-Saharan insect migrant

m) for a quadrant of Hu et al. ’ s eastern kernel. LAI values for two nested areas are plotted for speci ﬁ c days during both seasons, showing a contrasting signal between herbaceous and woody growth, reinforcing the evidence that Hu et al.'s vegetation growth detection is probably mostly driven by woody plants across their kernels.
Occupational COPD—The most under‐recognized occupational lung disease?

Chronic obstructive pulmonary disease (COPD) is caused by exposure to noxious particles and gases. Smoking is the main risk factor, but other factors are also associated with COPD. Occupational exposure to vapours, gases, dusts and fumes contributes to the development and progression of COPD, accounting for a population attributable fraction of 14%. Workplace pollutants, in particular inorganic dust, can initiate airway damage and inflammation, which are the hallmarks of COPD pathogenesis. Occupational COPD is still underdiagnosed, mainly due to the challenges of assessing the occupational component of the disease in clinical settings, especially if other risk factors are present. There is a need for specific education and training for clinicians, and research with a focus on evaluating the role of occupational exposure in causing COPD. Early diagnosis and identification of occupational causes is very important to prevent further decline in lung function and to reduce the health and socio‐economic burden of COPD. Establishing details of the occupational history by general practitioners or respiratory physicians could help to define the occupational burden of COPD for individual patients, providing the first useful interventions (smoking cessation, best therapeutic management, etc.). Once patients are diagnosed with occupational COPD, there is a wide international variation in access to specialist occupational medicine and public health services, along with limitations in workplace and income support. Therefore, a strong collaboration between primary care physicians, respiratory physicians and occupational medicine specialists is desirable to help manage COPD patients' health and social issues.
Corona was scary, lockdown was worse: A mixed-methods study of community perceptions on COVID-19 from urban informal settlements of Mumbai

The COVID-19 pandemic has magnified the multiple vulnerabilities of people living in urban informal settlements globally. To bring community voices from such settlements to the center of COVID-19 response strategies, we undertook a study in the urban informal settlements of Dharavi, Mumbai, from September 2020-April 2021. In this study, we have examined the awareness, attitudes, reported practices, and some broader experiences of the community in Dharavi with respect to COVID-19. We have used a mixed-methods approach, that included a cross-sectional survey of 468 people, and in-depth interviews and focus group discussions with 49 people living in this area. Data was collected via a mix of phone and face-to-face interviews. We have presented here the descriptive statistics from the survey and the key themes that emerged from our qualitative data. People reported high levels of knowledge about COVID-19, with television (90%), family and friends (56%), and social media (47%) being the main sources of information. The knowledge people had, however, was not free of misconceptions and fear; people were scared of being forcefully quarantined and dying alone during the early days of COVID-19. These fears had negative repercussions in the form of patient-related stigma and hesitancy in seeking healthcare. A year into the pandemic, however, people reported a shift in attitudes from ‘extreme fear to low fear’ (67% reported perceiving low/no COVID risk in October 2020), contributing to a general laxity in following COVID-appropriate behaviors. Currently, the community is immensely concerned about the revival of livelihoods, that have been adversely impacted due to the lockdown in 2020 as well as the continued ‘othering’ of Dharavi for being a COVID hotspot. These findings suggest that urban informal settlements like Dharavi need community-level messaging that counters misinformation and denial of the outbreak; local reinforcement of COVID-appropriate behaviours; and long-term social protection measures.
Experimental Support for the Possibility of Retrograde Genesis of Intraductal Carcinoma of the Prostate

Background. Historically, intraductal carcinoma of the prostate (IDC-P) was postulated to be a retrograde spread of high-grade invasive prostate cancer. There is evidence that IDC-P can primarily originate in the prostatic ducts. The retrograde genesis has never been experimentally or clinically confirmed before. Methods. Biopsy proven intermediate or high-risk prostate cancer was orthotopically grafted in the prostate of severe combined immunodeficiency gamma mice. Cancer growth was monitored by serum PSA levels. The animals were sacrificed and grafted areas were histological examined. Results. Twenty-one of 23 mice survived and demonstrated rising serum PSA. In 10 of 21 animals, human prostate cancer was identified orthotopically. Except for one case where the human biopsy showed a Grade Group 2 prostate cancer and mouse graft was Grade Group 5, other 9 specimens showed comparable grades. One of the specimens demonstrated a cribriform invasive prostate cancer and adjacent IDC-P. Conclusion. These experimental data offer some evidence that invasive prostate cancer can demonstrate a retrograde spread in the prostatic ducts as IDC-P. Its ability to primarily arise in the ducts has been demonstrated in other studies. However, the issue which remains unresolved is in its most common presentation of IDC-P intermixed with high-grade invasive cancer if it is the former or the latter which came first. Possibly resolving this dilemma will shed some light on the existing controversies if IDC-P should or should not be graded when invasive cancer is present.
Lower COVID‐19 Incidence in Low‐Continentality West‐Coast Areas of Europe

In March 2020, the first known cases of COVID‐19 occurred in Europe. Subsequently, the pandemic developed a seasonal pattern. The incidence of COVID‐19 comprises spatial heterogeneity and seasonal variations, with lower and/or shorter peaks resulting in lower total incidence and higher and/or longer peaks resulting higher total incidence. The reason behind this phenomena is still unclear. Unraveling factors that explain why certain places have higher versus lower total COVID‐19 incidence can help health decision makers understand and plan for future waves of the pandemic. We test whether differences in the total incidence of COVID‐19 within five European countries (Norway, Sweden, Germany, Italy, and Spain), correlate with two environmental factors: the Köppen‐Geiger climate zones and the Continentality Index, while statistically controlling for crowding. Our results show that during the first 16 months of the pandemic (March 2020 to July 2021), climate zones with larger annual differences in temperature and annually distributed precipitation show a higher total incidence than climate zones with smaller differences in temperature and dry seasons. This coincides with lower continentality values. Total incidence increases with continentality, up to a Continentality Index value of 19, where a peak is reached in the semicontinental zone. Low continentality (high oceanic influence) appears to be a strong suppressing factor for COVID‐19 spread. The incidence in our study area is lowest at open low continentality west coast areas.
Energy saving screen materials : measurement method of radiation exchange, air permeability and humidity transport and a calculation method for energy saving

The objectives of the project were the quantifi cation of the greenhouse screen properties (emissivity and transmissivity for thermal infrared radiation, air permeability and humidity transport) and the determination of the total energy saving under defi ned conditions in order to be able to compare the performance of different screens (and suppliers) with each other. This helps growers to understand more about screen properties and allows them to make an informed choice of investment. The results show that impermeable screens and screens with low emissivity and low transmissivity for thermal infrared radiation give highest energy saving. Permeable screens give highest transport for humidity and lowest air humidity during screen usage without the need for additional mechanical dehumidifi cation.
Finite element algorithms for elastoplasticy and consolidation

Finite element analysis of nonlinear problems invariably uses piecewise linearisation to generate approximate solutions. In geomechanics, this linearisation may appear as: ̄ Discrete strain increments for the integration of nonlinear constitutive laws. ̄ Discrete load increments in nonlinear analyses. ̄ Discrete time steps in the analysis of consolidation. The size and distribution of these increments (or steps) has a direct bearing on the accuracy of the resulting solution. This Thesis describes several new algorithms for controlling the error caused by the use of discrete increments in nonlinear finite element analysis. The new schemes are unified by the fact that they all treat the governing relations as a system of ordinary differential equations. These equations are solved by adaptive integration with respect to real or pseudo time, and automatically adjust the size of each step by computing a local error measure. By holding this local error below a specified threshold, the schemes aim to constrain the global linearisation error to lie near a known tolerance. Adaptive substepping schemes for controlling the linearisation error in the solution of elastoplastic constitutive laws were first formulated by Sloan (1987). These methods are explicit and automatically subincrement the imposed strain increment at each stress point. Several important improvements to thesemethods aredeveloped in this Thesis. The performance of the enhanced explicit schemes is compared to several implicit schemes for a variety of boundary value problems. These examples illustrate that adaptive explicit methods are very competitive with implicit methods, and have the advantage of being simpler to implement for complex constitutive laws. The remainder of the Thesis is concerned with the development of new adaptive integration schemes for the solution of elastoplastic and coupled consolidation
Effect of chelated source of additional zinc and selenium on performance, yolk fatty acid composition, and oxidative stability in laying hens fed with oxidised oil

ABSTRACT 1. The following study determined whether the effects of the combined addition of zinc amino acid complex (ZA) and selenomethionine (SM) was superior to their single addition in controlling the oxidative stress induced by dietary oxidised fat in laying hens. 2. Two hundred and forty 32-week-old laying hens were divided into the following dietary treatments (each consisting of six replicates of eight birds): 1) a fresh soy oil (FSO) diet; 2) an oxidised soy oil (OSO) diet; 3) an OSO diet plus 20 mg zinc as ZA/kg (OSO+ZA); 4) an OSO diet plus 0.2 mg selenium as SM/kg (OSO+SM); and 5) an OSO diet plus ZA and SM (OSO+ZA+SM). 3. After 10 weeks of feeding hens, feed intake, egg production, and egg mass in the OSO+ZA+SM group were similar to the FSO group but better (P < 0.05) than those in the OSO group. Shell thickness and shell breaking strength were significantly improved by the OSO+ZA and OSO+ZA+SM treatments. 4. Increases in the yolk concentrations of palmitic acid and total saturated fatty acids (SFA), and decreases in yolk linoleic acid, n-6 polyunsaturated fatty acids (PUFA), total PUFA, and PUFA/SFA ratio were induced by dietary oxidised fat which were normalised (P < 0.05) by OSO+SM and OSO+ZA+SM. 5. An increase (P < 0.05) in malondialdehyde and a decrease in 2,2-diphenyl-picrylhydrazyl radical scavenging activity in the yolk, induced by dietary oxidised fat, was significantly improved by all dietary supplementations, but only birds fed the OSO+ZA+SM diet exhibited similar values to those fed FSO. 6. In conclusion, the simultaneous inclusion of organic zinc plus selenium in the oxidised fat diets was beneficial for improving egg-laying performance, yolk fatty acid profile, and oxidative stability, but not for internal egg quality, compared with either zinc or selenium alone in laying hens.
Histochemical analysis and storage behaviour of Ginger (Zingiber officinale Roscoe) under Zero-Energy Cool Chamber (ZECC)

In Kerala, a coastal land in India, Ginger is cultivated as a rainfed annual. The current study on morphological characters of seed rhizomes stored in Zero Energy Cool Chambers recorded a weight loss of 28% at three months after storage. The number of sprouting buds was maximum (12.25) in the seed rhizomes stored for three months. The dimensions of the bud measured at the varied periods of storage interval showed variation. The length of the bud increased from 0. 847μm to 2.19 μm and the breadth reduced from 1.19 μm to 0. 703μm in three months of storage. The current study provides the anatomical morphology of ginger seed rhizomes. Histochemical studies of seed rhizome for three months storage showed that the number of cork layers varied from 5–15, size of starch grain decreased on storage from 40 μm to 20 μm and the oil globules found inside the parenchymatous cells increased from 20 μm to 40 μm. These results will be helpful to understand the bud development of ginger seed rhizome during storage.