Miracle-dz/UniFAR-FTUs huggingface dataset:
Frontalis Suspension Using Autologous Fascia Lata in Children Under 3 Years Old

Purpose: To analyze functional results and complications of the use of autologous fascia lata in frontalis suspension in children under 3 years old and to confirm its technical viability. Methods: A retrospective review of 8 patients (12 eyes) who underwent frontalis suspension using autologous fascia lata sling. Results: Twelve eyes of 8 patients were analyzed, with an average age of 1.8 ± 0.6 years. Preoperatively, the mean margin-to-reflex distance 1 was −0.17 ± 0.577 mm. Postoperatively the mean margin-to-reflex distance 1 was 2.66 ± 0.492 mm without any graft donor site or corneal complications. No recurrence was recorded in the follow-up period (mean follow-up period 28.5 ± 32.33 months). Conclusions: Autologous fascia lata is an eligible material in frontalis suspension in children under 3 years old, despite the traditional oculoplastic dogma that advises against. Autologous fascial lata can be safely harvested and used for frontalis suspension in children under 3 years old. Supplemental Digital Content is available in the text.
Comparing three screen-based sedentary behaviours’ effect upon adolescents’ participation in physical activity: The ESSENS study

Background Literature focusing on the association between sedentary behaviours and physical activity has provided equivocal results and has been dominated by TV viewing as the indicator of sedentary behaviour. There is a need for more studies exploring the association between contemporary screen activities and physical activity among youth. Methods A cross-sectional study including 742 adolescents was conducted in 2016. Data were collected at school through an online questionnaire. Regression analyses were used to explore the association between different screen-based sedentary behaviours and participation in physical activity. Results The results showed that those with lower (vs higher) time spent on TV/movie streaming and electronic game playing both on weekdays and weekend days had significantly higher odds of participating in physical activity. There were no significant associations between socializing/surfing online both on weekdays and weekend days and physical activity in adjusted models. Conclusions TV/movie streaming and electronic game playing during both weekdays and weekend days were significantly inversely related with participating in physical activity. Initiatives aimed at reducing screen-based sedentary activities might result in favourable effects on physical activity levels among adolescents.
Screening and identification of bacterial strains for removal of COD from pulp and paper mill effluent

Present study was conducted to characterize the physico-chemical parameters of pulp and paper mill effluent. Out of these 15 bacterial isolates 2 were selected (1 each from treated; Alcaligenes faecalis (strain-1) and untreated effluent; Bacillus cereus (strain-2)) on the basis for their COD removal capacity of their respective effluent. Physico-chemical analysis confirmed the levels of various pollutants in pulp and paper mill effluent and further shown that treatment of effluent using Alcaligenes faecalis (strain-1) and Bacillus cereus (strain-2). This study revealed that the highest COD reduction (63.2%) was obtained with bacterial strain -2 (Bacillus cereus) at 35 C after 10 days of incubation period day at pH 6. At various optimized conditions such as pH, temperature, nutrient sources etc., bacterial strain Bacillus cereus (strain-2) was found to be more efficient than the other studied bacterial strain Alcaligenes faecalis (strain-1) in terms of COD removal from pulp and paper mill effluent.
Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. Surprisingly, C-terminal domain mutations were associated with decreased wheelchair use and increased forced vital capacity. Dp116 and Dp71 mutations were also linked with decreased wheelchair use, while Dp140 mutations significantly predicted cardiomyopathy. Finally, we found that 12.3% and 7% of DMD patients in the registry could be treated with FDA-approved exon 51- and 53-skipping therapies, respectively.
Epigenetic Modifications, and Alterations in Cell Cycle and Apoptosis Pathway in A549 Lung Carcinoma Cell Line upon Exposure to Perfluoroalkyl Substances

Per- and polyfluoroalkyl substances (PFAS) are a group of human-made compounds with strong C-F bonds, and have been used in various manufacturing industries for decades. PFAS have been reported to deleterious effect on human health, which has led to studies identifying the possible toxicity and toxicity routes of these compounds. We report that these compounds have the potential to cause epigenetic modifications, and to induce dysregulation in the cell proliferation cycle as well as apoptosis in A549 lung cancer cells when exposed to 10-, 200- and 400 μM concentrations of each compound. Our studies show that exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) may cause hypomethylation in the epigenome, but changes in the epigenetic makeup are not evident upon exposure to GenX. We establish that exposure to lower doses of these compounds causes the cells’ balance to shift to cell proliferation, whereas exposure to higher concentrations shifts the balance more towards apoptosis. Furthermore, the apoptosis pathway upon exposure to GenX, PFOA, and PFOS has also been identified. Our findings suggest that exposure to any of these compounds may have profound effects in patients with pre-existing lung conditions or could trigger lung cancinogenesis.
Joint Hypermobility Does Not Increase the Risk of Developing Hip Pain, Cartilage Defects, or Retirement in Professional Ballet Dancers Over 5 years

Supplemental Digital Content is Available in the Text. Objective: This study aimed to evaluate the risk of developing hip pain, cartilage defects, and retirement in hypermobile ballet dancers over 5 years. Design: Prospective cohort study. Setting: Professional Ballet Company. Participants: Forty ballet dancers (57.5% women) were assessed at baseline and 21 dancers at 5 years. Independent Variable: Baseline evaluation of generalised joint hypermobility (GJH) (GJH = Beighton score ≥5/9). Outcome Measures: Cartilage defects on hip 3T magnetic resonance imaging and pain (the Copenhagen Hip and Groin Outcome Score: HAGOS) at baseline and follow-up, hip-related injury incidence, and retirement over 5 years. Results: Twelve dancers retired by follow-up, none due to hip injury or GJH. At baseline, 17 (42.5%) dancers were hypermobile, 18 (45%) had cartilage defects, and 15 (37.5%) reported hip pain (HAGOS pain <100). Cartilage defect prevalence was lower in GJH (n = 1) than non-GJH dancers (n = 17, P < 0.001). Beighton scores <5/9 were predictive of cartilage defect presence at baseline, independent of age and sex (P = 0.006). At follow-up, cartilage defects progressed in 2 dancers, one was hypermobile. Baseline and follow-up HAGOS pain scores were similar in GJH and non-GJH dancers (P > 0.05 for all). Hip-related injury over 5 years was reported by a similar number of GJH (n = 7) and non-GJH dancers (n = 6, P = 0.7). Hypermobility was more prevalent in active dancers (n = 12) than dancers who retired (n = 2), independent of age, rank, and sex (P = 0.03). Conclusions: Hypermobile dancers are at no greater risk of reporting hip pain and injury or retirement over 5 years, and cartilage defect prevalence was much lower in GJH than non-GJH dancers.
The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.
Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery.
Predicting Volume of Distribution in Humans: Performance of In Silico Methods for a Large Set of Structurally Diverse Clinical Compounds

Volume of distribution at steady state (VD,ss) is one of the key pharmacokinetic parameters estimated during the drug discovery process. Despite considerable efforts to predict VD,ss, accuracy and choice of prediction methods remain a challenge, with evaluations constrained to a small set (<150) of compounds. To address these issues, a series of in silico methods for predicting human VD,ss directly from structure were evaluated using a large set of clinical compounds. Machine learning (ML) models were built to predict VD,ss directly and to predict input parameters required for mechanistic and empirical VD,ss predictions. In addition, log D, fraction unbound in plasma (fup), and blood-to-plasma partition ratio (BPR) were measured on 254 compounds to estimate the impact of measured data on predictive performance of mechanistic models. Furthermore, the impact of novel methodologies such as measuring partition (Kp) in adipocytes and myocytes (n = 189) on VD,ss predictions was also investigated. In predicting VD,ss directly from chemical structures, both mechanistic and empirical scaling using a combination of predicted rat and dog VD,ss demonstrated comparable performance (62%–71% within 3-fold). The direct ML model outperformed other in silico methods (75% within 3-fold, r2 = 0.5, AAFE = 2.2) when built from a larger data set. Scaling to human from predicted VD,ss of either rat or dog yielded poor results (<47% within 3-fold). Measured fup and BPR improved performance of mechanistic VD,ss predictions significantly (81% within 3-fold, r2 = 0.6, AAFE = 2.0). Adipocyte intracellular Kp showed good correlation to the VD,ss but was limited in estimating the compounds with low VD,ss. SIGNIFICANCE STATEMENT This work advances the in silico prediction of VD,ss directly from structure and with the aid of in vitro data. Rigorous and comprehensive evaluation of various methods using a large set of clinical compounds (n = 956) is presented. The scale of techniques evaluated is far beyond any previously presented. The novel data set (n = 254) generated using a single protocol for each in vitro assay reported in this study could further aid in advancing VD,ss prediction methodologies.
Nucleoporin 210 Serves a Key Scaffold for SMARCB1 in Liver Cancer

This study reveals a novel protumorigenic role for SMARCB1 and describes valuable links between nucleoporins and chromatin remodelers in cancer by identifying NUP210 as a critical coregulator of SMARCB1 chromatin remodeling activity. The roles of chromatin remodelers and their underlying mechanisms of action in cancer remain unclear. In this study, SMARCB1, known initially as a bona fide tumor suppressor gene, was investigated in liver cancer. SMARCB1 was highly upregulated in patients with liver cancer and was associated with poor prognosis. Loss- and gain-of-function studies in liver cells revealed that SMARCB1 loss led to reduced cell proliferation, wound healing capacity, and tumor growth in vivo. Although upregulated SMARCB1 appeared to contribute to switch/sucrose nonfermentable (SWI/SNF) complex stability and integrity, it did not act using its known pathways antagonism with EZH2 or association between TP53 or AMPK. SMARCB1 knockdown induced a mild reduction in global H3K27 acetylation, and chromatin immunoprecipitation sequencing of SMARCB1 and acetylated histone H3K27 antibodies before and after SMARCB1 loss identified Nucleoporin210 (NUP210) as a critical target of SMARCB1, which bound its enhancer and changed H3K27Ac enrichment and downstream gene expression, particularly cholesterol homeostasis and xenobiotic metabolism. Notably, NUP210 was not only a putative tumor supporter involved in liver cancer but also acted as a key scaffold for SMARCB1 and P300 to chromatin. Furthermore, SMARCB1 deficiency conferred sensitivity to doxorubicin and P300 inhibitor in liver cancer cells. These findings provide insights into mechanisms underlying dysregulation of chromatin remodelers and show novel associations between nucleoporins and chromatin remodelers in cancer. Significance: This study reveals a novel protumorigenic role for SMARCB1 and describes valuable links between nucleoporins and chromatin remodelers in cancer by identifying NUP210 as a critical coregulator of SMARCB1 chromatin remodeling activity.
Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies

On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, and the reality of the situation has finally caught up to the widespread reach of the disease. The presentation of the disease is highly variable, ranging from asymptomatic carriers to critical COVID-19. The availability of angiotensin-converting enzyme 2 (ACE2) receptors may reportedly increase the susceptibility and/or disease progression of COVID-19. Comorbidities and risk factors have also been noted to increase COVID-19 susceptibility. In this paper, we hereby review the evidence pertaining to ACE2’s relationship to common comorbidities, risk factors, and therapies associated with the susceptibility and severity of COVID-19. We also highlight gaps of knowledge that require further investigation. The primary comorbidities of respiratory disease, cardiovascular disease, renal disease, diabetes, obesity, and hypertension had strong evidence. The secondary risk factors of age, sex, and race/genetics had limited-to-moderate evidence. The tertiary factors of ACE inhibitors and angiotensin II receptor blockers had limited-to-moderate evidence. Ibuprofen and thiazolidinediones had limited evidence.
Transcriptome Analysis of Pyrus betulaefolia Seedling Root Responses to Short-Term Potassium Deficiency

Potassium (K) plays a crucial role in multiple physiological and developmental processes in plants. Its deficiency is a common abiotic stress that inhibits plant growth and reduces crop productivity. A better understanding of the mechanisms involved in plant responses to low K could help to improve the efficiency of K use in plants. However, such responses remain poorly characterized in fruit tree species such as pears (Pyrus sp). We analyzed the physiological and transcriptome responses of a commonly used pear rootstock, Pyrus betulaefolia, to K-deficiency stress (0 mM). Potassium deprivation resulted in apparent changes in root morphology, with short-term low-K stress resulting in rapidly enhanced root growth. Transcriptome analyses indicated that the root transcriptome was coordinately altered within 6 h after K deprivation, a process that continued until 15 d after treatment. Potassium deprivation resulted in the enhanced expression (up to 5-fold) of a putative high-affinity K+ transporter, PbHAK5 (Pbr037826.1), suggesting the up-regulation of mechanisms associated with K+ acquisition. The enhanced root growth in response to K-deficiency stress was associated with a rapid and sustained decrease in the expression of a transcription factor, PbMYB44 (Pbr015309.1), potentially involved in mediating auxin responses, and the increased expression of multiple genes associated with regulating root growth. The concentrations of several phytohormones including indoleacetic acid (IAA), ABA, ETH, gibberellin (GA3), and jasmonic acid (JA) were higher in response to K deprivation. Furthermore, genes coding for enzymes associated with carbon metabolism such as SORBITOL DEHYDROGENASE (SDH) and SUCROSE SYNTHASE (SUS) displayed greatly enhanced expression in the roots under K deprivation, presumably indicating enhanced metabolism to meet the increased energy demands for growth and K+ acquisition. Together, these data suggest that K deprivation in P. betulaefolia results in the rapid re-programming of the transcriptome to enhance root growth and K+ acquisition. These data provide key insights into the molecular basis for understanding low-K-tolerance mechanisms in pears and in other related fruit trees and identifying potential candidates that warrant further analyses.
KCC2 Chloride Transport Contributes to the Termination of Ictal Epileptiform Activity

Visual Abstract Recurrent seizures intensely activate GABAA receptors (GABAA-Rs), which induces transient neuronal chloride ([Cl–]i) elevations and depolarizing GABA responses that contribute to the failure of inhibition that engenders further seizures and anticonvulsant resistance. The K+-Cl– cotransporter KCC2 is responsible for Cl– extrusion and restoration of [Cl–]i equilibrium (ECl) after synaptic activity, but at the cost of increased extracellular potassium which may retard K+-Cl– extrusion, depolarize neurons, and potentiate seizures. Thus, KCC2 may either diminish or facilitate seizure activity, and both proconvulsant and anticonvulsant effects of KCC2 inhibition have been reported. It is now necessary to identify the loci of these divergent responses by assaying both the electrographic effects and the ionic effects of KCC2 manipulation. We therefore determined the net effects of KCC2 transport activity on cytoplasmic chloride elevation and Cl– extrusion rates during spontaneous recurrent ictal-like epileptiform discharges (ILDs) in organotypic hippocampal slices in vitro, as well as the correlation between ionic and electrographic effects. We found that the KCC2 antagonist VU0463271 reduced Cl– extrusion rates, increased ictal [Cl–]i elevation, increased ILD duration, and induced status epilepticus (SE). In contrast, the putative KCC2 upregulator CLP257 improved chloride homeostasis and reduced the duration and frequency of ILDs in a concentration-dependent manner. Our results demonstrate that measuring both the ionic and electrographic effects of KCC2 transport clarify the impact of KCC2 modulation in specific models of epileptiform activity. Anticonvulsant effects predominate when KCC2-mediated chloride transport rather than potassium buffering is the rate-limiting step in restoring ECl and the efficacy of GABAergic inhibition during recurrent ILDs.
Metal-organic frameworks : design and application

Preface. Contributors. 1 From Hofmann Complexes to Organic Coordination Networks (Makoto Fujita). 2 Insight into the Development of Metal-Organic Materials (MOMs): At Zeolite-like Metal-Organic Frameworks (ZMOFs) (Mohamed Eddaoudi and Jarrod F. Eubank). 3 Topology and Interpenetration (Stuart Batten). 4 Highly-Connected Metal-Organic Frameworks (Peter Hubberstey, Kiang Lin, Neil R. Champness and Martin Schroder). 5 Surface Pore Engineering of Porous Coordination Polymers (Sujit K. Ghosh and Susumu Kitagawa). 6 Rational Design of Non-centrosymmetric Metal-Organic Frameworks for Second-Order Nonlinear Optics (Wenbin Lin and Shuting Wu). 7 Selective Sorption of Gases and Vapors in Metal-Organic Frameworks (Hyumuk Kim, Hyungphil Chun and Kimoon Kim). 8 Hydrogen and Methane Storage in Metal Oorganic Frameworks (David J. Collins, Shengquin Ma and Hong-Cai Zhou). 9 Towards Mechanochemical Synthesis of Metal-Organic Frameworks: From Coordination Polymers and Lattice Inclusion Compounds to Porous Materials (Tomislav Fri i ). 10 Metal-Organic Frameworks with Photochemical Building Units (Saikat Dutta, Ivan F. Georgiev and Leonard R. MacGillivray). 11 Molecular Modeling of Adsorption and Diffusion in Metal-Organic Frameworks (Randall Q. Snurr, A. Ozgur Yazaydin, David Dubbeldam and Houston Frost). Index.