The EDC4-XRN1 interaction controls P-body dynamics to link mRNA decapping with decay.

Deadenylation-dependent mRNA decapping and decay is the major cytoplasmic mRNA turnover pathway in eukaryotes. Many mRNA decapping and decay factors are associated with each other via protein-protein interaction motifs. For example, the decapping enzyme DCP2 and the 5'-3' exonuclease XRN1 interact with the enhancer of mRNA-decapping protein 4 (EDC4), a large scaffold that has been reported to stimulate mRNA decapping. mRNA decapping and decay factors are also found in processing bodies (P-bodies), evolutionarily conserved ribonucleoprotein granules that are often enriched with mRNAs targeted for decay, yet paradoxically are not required for mRNA decay to occur. Here, we show that disrupting the EDC4-XRN1 interaction or altering their stoichiometry inhibits mRNA decapping, with microRNA-targeted mRNAs being stabilized in a translationally repressed state. Importantly, we demonstrate that this concomitantly leads to larger P-bodies that are responsible for preventing mRNA decapping. Finally, we demonstrate that P-bodies support cell viability and prevent stress granule formation when XRN1 is limiting. Taken together, these data demonstrate that the interaction between XRN1 and EDC4 regulates P-body dynamics to properly coordinate mRNA decapping with 5'-3' decay in human cells.

Microbiome analysis reveals the differences in gut fungal community between Dutch Warmblood and Mongolian horses.

Similar to gut bacterial community, gut fungal community are also an important part of the gut microbiota and play crucial roles in host immune regulation and metabolism. However, most studies have focused on the gut bacterial community, and research on the gut fungal community has been limited. Dutch Warmblood (DWH) and Mongolian horses (MGH) are important equine breeds, but little research has been done on their gut fungal community. Here, we assessed differences in gut fungal community between two horse species. Results showed that a total of 2159 OTUs were found in the Dutch Warmblood and Mongolian horses, of which 308 were common. Between-group analyzes of microbial diversity showed no differences in the alpha and beta diversity of gut fungal community between the two horse species. Microbiological taxonomic surveys showed that the dominant fungal phyla (Neocallimastigomycota and Ascomycota) and genera (unclassified_Neocallimastigaceae and Anaeromyces) were the same without being affected by species. Although the types of dominant fungal phyla did not change, the abundances of some fungal genera changed significantly. Results of Metastats analysis showed that there were a total of 206 fungal genera that were significantly different between the two horses, among which 78 genera showed an increase and 127 genera significantly decreased in Dutch Warmblood horses compared with Mongolian horses. In conclusion, this study investigated the composition and structure of the gut fungal community of Dutch Warmblood and Mongolian horses and found significant differences in gut fungal community between both breeds. Notably, this is the first exploration of the differences in the gut fungal community of both breeds, which may help to understand the distribution characteristics of the gut fungal community of different breeds of horses and reveal the differences in the traits of different horses.

Response to COVID-19 in Lebanon: update, challenges and lessons learned.

The COVID-19 pandemic remains a public health problem threatening national and global health security. The socio-economic impact of COVID-19 was more severe on developing countries including Lebanon, especially due to the fragile healthcare system, weak surveillance infrastructure and lack of comprehensive emergency preparedness and response plans. Lebanon has been struggling with plethora of challenges at the social, economic, financial, political and healthcare levels prior to the COVID-19 pandemic. The COVID-19 pandemic in Lebanon revealed gaps and challenges across the spectrum of preparedness and response to emergencies. Despite these challenges, the Lebanese response was successful in delaying the steep surge of COVID-19 cases and hospitalisations through imposing strict public health and social measures. The deployment of the national vaccination plan in Lebanon in February 2021 coincided with the reduction in the number of cases and hospitalisation rates. The aim of this manuscript is to advance the epidemiologic evolution of COVID-19 in Lebanon pre- and post-vaccination, the challenges affecting the response and recovery, and the lessons learned.

Effects of 25(OH)D3 supplementation during late gestation on the serum biochemistry and reproductive performance of aged sows and newborn piglets.

The purpose of this study was to investigate the effects of diet type (normal or low Ca and P diets) and 25(OH)D3 supplementation (with or with not 2000 IU/kg 25(OH)D3 ) during late gestation on the serum biochemistry and reproductive performance of aged sows and newborn piglets. A total of 40 sows, which are at their 7th parity, were divided into four groups: control group (standard diet), low Ca group, 25(OH)D3 group and low Ca plus 25(OH)D3 group respectively (10 in each group). The blood of sows on day 100 and 114 of gestation and newborn piglets was collected for serum biochemical analyses. Results showed that the reproductive performance of sows was not influenced by diet type or 25(OH)D3 supplementation (p > 0.05). And the addition of 25(OH)D3 to diet low Ca group caused that the content of serum TG in sows on day 100 of gestation was not different from that of the control group (p > 0.05). The addition of 25(OH)D3 significantly decreases the content of serum TG in sows on day 114 of gestation (p < 0.05). The addition of 25(OH)D3 significantly increased the content of serum UREA and CREA in newborn piglets (p < 0.05). Overall, feeding 2000 IU/kg 25(OH)D3 to aged sows at late gestation had no effects on reproductive performance, but partly contributed to keeping serum TG balance in sows and may indicate increased pressure on kidneys in newborn piglets.

A PROSPECTIVE STUDY OF COMMONLY UTILIZED REGIMENS OF VITAMIN D REPLACEMENT AND MAINTENANCE THERAPY IN ADULTS.

OBJECTIVE: To determine which vitamin D dose, formulation, and schedule most effectively and safely achieves a 25-hydroxyvitamin D (25[OH]D) level of >30 ng/mL (75 nmol/L). METHODS: In this prospective study, 100 subjects from the NY Harbor HCS Brooklyn Campus, ages 25 to 85 years, with 25(OH)D <30 ng/mL (<75 nmol/L), were randomized into four groups: cholecalciferol (D3) 2,000 international units (IU) daily; D3 3,000 IU daily; ergocalciferol (D2) 50,000 IU weekly; and D2 50,000 IU twice weekly. All were supplemented with 500 mg calcium carbonate daily. 25(OH)D, parathyroid hormone (PTH), urinary calcium, urinary creatinine, and other variables were measured during 7 visits over 12 months. RESULTS: All groups achieved a mean vitamin D level >30 ng/mL (>75 nmol/L) by visit 4 (5 months). Those receiving 50,000 IU D2 twice weekly displayed the most rapid and robust response, with 25(OH)D reaching >30 ng/mL (>75 nmol/L) after only 1 month and plateauing at 60 ng/mL (150 nmol/L) by 7 months. Although no statistically significant difference was seen in mean 25(OH)D levels between groups 1 through 3, subjects on 50,000 IU D2 weekly more consistently showed higher mean levels than either groups 1 or 2. No episodes of significant hypercalcemia occurred. There was a negative correlation in mean PTH levels and mean vitamin D levels in group 4 and all groups combined. CONCLUSION: All four schedules of vitamin D replacement were effective in safely achieving and maintaining 25(OH)D >30 ng/mL (>75 nmol/L). D2 50,000 IU twice weekly provided the most rapid attainment and highest mean levels of vitamin D. ABBREVIATIONS: 25(OH)D = 25-hydroxyvitamin D; BMI = body mass index; BUN = blood urea nitrogen; Ca/Cr = calcium/creatinine; D2 = ergocalciferol; D3 = cholecalciferol; IU = international units; PTH = parathyroid hormone.

Pathophysiology of peste des petits ruminants in sheep (Dorper & Kajli) and goats (Boer & Beetal).

Peste des petits ruminants (PPR), an economically important viral transboundary disease of small ruminants is not only prevalent in Pakistan but also in other countries where people rely on agriculture and animal products. The present study was aimed at describing the pathology and antigen localization in natural PPR infections in local (Kajli sheep; Beetal goats) as well as imported small ruminant breeds (Dorper sheep; Australian Boer goat). Morbidity and mortality rates were significantly (P < 0.001) higher in indigenous Kajli sheep (75.37 and 32.80%) and Beetal goats (81.10 and 37.24%) as compared to Dorper sheep (6.99 and 1.48%) and Australian Boer goat (5.01 and 2.23%). Affected animals exhibited high fever, severe diarrhea, abdominal pain, respiratory distress and nodular lesions on lips and nostrils. Thick mucous discharge was oozing out from nostrils. On necropsy, lungs were congested and pneumonic, with nodular and cystic appearance. Intestines were hemorrhagic with zebra stripping. Characteristic histopathological lesions of PPR were noted in intestines, lymphoid organs and lungs. In GI tract, stunting and blunting of villi, necrotic enteritis, and infiltration of mononuclear cells in duodenum, jejunum and ileum. Small intestines exhibited diffuse edema of the submucosa along with proliferation of fibrocytes leading to thickened submucosa which has not been reported previously. Lymphoid organs showed partial to complete destruction of lymphoid follicles. Lesions of the respiratory tract included depictive of bronchopneumonia, severe congestion of trachea and apical lobe of lungs with deposition of fibrinous materials. Histopathological lesions of respiratory tract were severe and characteristic of broncho-interstitial pneumonia, bronchopneumonia, interstitial pneumonia and fibrinous pneumonia. The alveoli were filled with edematous fluid mixed with fibrinous exudate, numerous alveolar macrophages, mononuclear cells along with thickened interalveolar septa and presence of intranuclear eosinophilic inclusion bodies. One-Step RT-PCR using NP3 and NP4 primers confirmed a PPR virus of 352 bp size in spleen, lungs and mesenteric and brachial lymph node samples. It was concluded that morbidity and mortality due to PPR were significantly higher in indigenous breeds of sheep and goat as compared to imported sheep and goat breeds. PPR has rendered various lesions in GI and respiratory tract which are characteristic in nature for the diagnosis of the disease under field condition.

Fibroblast growth factor-23 in obese, normotensive adolescents is associated with adverse cardiac structure.

OBJECTIVES: Fibroblast growth factor-23 (FGF23) is a biomarker for cardiovascular disease. Obesity may promote FGF23 production in the absence of chronic kidney disease. We sought to determine among normotensive African American adolescents whether FGF23 levels are greater in obese compared with normal-weight adolescents and to determine the relationship of FGF23 with markers of cardiac structure and insulin resistance. STUDY DESIGN: Cross-sectional data were obtained from a cohort of 130 normotensive, African American adolescents ages 13-18 years without chronic kidney disease; 74 were obese; 56 were normal weight. Plasma C-terminal FGF23, fasting glucose and insulin, and high-sensitivity C-reactive protein were measured; participants underwent M-mode echocardiography. RESULTS: FGF23 was skewed and approximately normally distributed after natural log transformation (logFGF23). FGF23 levels were greater in obese vs normal-weight participants (geometric mean 43 vs 23 RU/mL, P < .01). FGF23 values were significantly greater in participants with eccentric or concentric cardiac hypertrophy compared with those without hypertrophy P < .01). LogFGF23 directly correlated with body mass index, body mass index z-score, waist circumference, fasting insulin levels, and homeostasis model assessment scores. Regression models adjusted for age, sex, and high-sensitivity C-reactive protein suggest that each 10% increase in FGF23 is associated with a 1.31 unit increase in left ventricular mass (P < .01), a 0.29-unit increase in left ventricular mass index (P < .01), and a 0.01-unit increase in left atrial dimension indexed to height (P = .02). CONCLUSIONS: In this sample of obese African American adolescents, FGF23 blood levels were associated with abnormal cardiac structure. We postulate that FGF23 may be an early marker of cardiac injury in obese but otherwise-healthy African American adolescents.

Clinico-hematological and tissue changes induced by butachlor in male Japanese quail (Coturnix japonica).

The present experiment was executed to determine the pathological effects induced by concurrent feeding of butachlor (chloroacetanilide herbicide) in male Japanese quail. For this purpose mature male quail about 4-5weeks of age were procured from the local market and randomly divided into six equal groups (A-F). Butachlor was mixed in corn oil and administered orally for 30days using crop tube. Four birds from each group were killed at day 10, 20 and 30 of the experiment and blood was collected with and without anticoagulant. The birds in groups (A-D) did not reveal any clinical and behavioral alterations. Clinical signs like watery droppings, dullness, ruffled feather, depression, decrease frequency of crowing, mounting with pen mates and foam production were observed. Maximum intensity of these clinical signs and behavioral alterations were observed in group F throughout the experiment. Significant lower values of erythrocytes, hematocrit percent and hemoglobin were recorded. Significantly increased numbers of erythrocytes with micronuclei, lobed and notched nuclei were observed. Histopathologically, enlarged intertubular space, fewer numbers of round spermatids, necrotic spermatids and admixture of dead spermatids were observed in testes. The results revealed significant increase in serum lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT) and urea concentrations. The results of present experimental study indicated that butachlor induces hematobiochemical and testicular changes in birds.

The Potential of Infrared Thermography for Early Pregnancy Diagnosis in Nili-Ravi Buffaloes.

This study was designed to explore the potential of infrared thermography (IRT) as an alternate approach for early pregnancy diagnosis in buffaloes. The surface temperature (ST) of different regions (eyes, muzzle, flanks, and vulva) was determined in 27 buffaloes using IRT from the day of artificial insemination (AI; Day 0), and measurement was repeated every fourth day until Day 24 post-AI. From all regions, the ST in each thermograph was recorded at three temperature values (maximum, average, minimum). Pregnancy status was confirmed through ultrasonography on Day 30, and animals were retrospectively grouped as pregnant or non-pregnant for analysis of thermographic data. In pregnant buffaloes, all three values of ST were significantly greater (p ≤ 0.05) for the left flank, while, in the left eye and vulva, only the maximum and average values were significantly greater. By contrast, the maximum ST of the muzzle was significantly lower (p ≤ 0.05) in pregnant buffaloes compared to non-pregnant buffaloes. However, the ST of the right eye and right flank did not show significant temperature variation at any value. These findings suggest that IRT has the potential to identify thermal changes associated with pregnancy in buffaloes at an early stage.

Eosinophilic cystitis mimics bladder tumor: A rare case report.

Eosinophilic cystitis is a rare inflammatory condition of the bladder characterized by eosinophils infiltrating the bladder wall. It affects people of all ages and with no gender difference. Eosinophilic cystitis can mimic bladder tumors and other chronic cystitis, which makes it a challenging condition to diagnose. In this article, we will discuss the causes, symptoms, diagnosis, and treatment of eosinophilic cystitis, as well as how it might be mistaken for bladder tumors.

Sodium acetate and sodium butyrate attenuate diarrhea in yak calves by regulating gut microbiota and metabolites.

Diarrhea is a severe issue in calves that causes fertility problems and economic issues worldwide. Sodium acetate/sodium butyrate (SA/SB) alleviates diarrhea in mice; however, little information is available about the preventive effect of SA/SB on diarrheic yak calves living on the Tibet plateau. Yak calves (n = 19) of age ≥4 months and weight 37 ± 2 Kg were randomly divided into control (C, n = 10) and supplement groups (S, n = 9). Yaks belonging to the supplement group were given sodium butyrate (10 g/kg) and sodium acetate (5 g/kg) for 28 days, along with normal feed, seasonal grasses, pasture, and water. The blood and fecal samples from yak calves were collected for assessment of antioxidant capacity, inflammatory cytokines, microbiome, and short-chain fatty acids (SCFAs) concentration analysis. Results of this study revealed that a lower diarrhea rate, higher weight, and net weight gain were recorded in yaks belonging to group S supplemented with SA/SB. Similarly, increased antioxidant capacity with higher levels of T-AOC, SOD, and GSH-px and decreased inflammatory reactions by decreasing both TNF-α and IL-1ß concentrations were recorded in yaks of group S. The concentration of SCFAs was significantly higher (p < 0.05) in yaks from group S than group C. Microbiome analysis revealed that 8 phyla and 54 genera were significantly different (p < 0.05) in both yak groups, with increased probiotics (Akkermansia, Oscillospira), SCFAs producing genera (Oscillospira, ASF356, Anaerosporobacter and Phascolarctobacterium), and decreased inflammatory related genus (Flavonifractor, Fournierella) and harmful bacteria (Oscillibacter, Achromobacter) in group S. In conclusion, the results demonstrated that SA and SB could decrease diarrhea rates in yak calves on the plateau via increasing antioxidant ability and SCFAs, while decreasing inflammatory responses in yaks by moderating gut microbiota. The current results provide new insights for the prevention and treatment of diarrhea in yaks.

Corrigendum to "Sodium acetate and sodium butyrate attenuate diarrhea in yak calves by regulating gut microbiota and metabolites original research A"[Heliyon Volume 10, Issue 5, March, 2024, Article e26564].

[This corrects the article DOI: 10.1016/j.heliyon.2024.e26564.].

Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers.

Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.

Preoperative plasma FGF23 levels predict acute kidney injury in children: results of a pilot study.

BACKGROUND: Acute kidney injury (AKI) carries a large burden of morbidity and mortality. Early diagnosis may lead to better strategies of clinical care. Cardiac surgery involving cardiopulmonary bypass is associated with a significant incidence of AKI. The study objective was to determine whether or not preoperative fibroblast growth factor-23 (FGF23) levels differed among pediatric patients who did or did not develop AKI following cardiac surgery. METHODS: A nested case-control study was performed. FGF23 levels were measured pre- and post-operatively in 19 children without chronic kidney disease (CKD) who underwent cardiopulmonary bypass. Five patients developed AKI and 14 patients served as controls. RESULTS: FGF23 levels in patients who developed AKI following cardiac surgery were elevated above normal levels, both pre-operatively and post-operatively compared with those patients who did not develop AKI. Relative risk of developing AKI when the pre-operative FGF23 level was >86 RU/mL was 2.0 (p = 0.033). Preoperative FGF23 levels correlated with post-operative fluid gain (correlation coefficient 0.607, p = 0.0059). CONCLUSIONS: FGF23 may serve as a pre-operative prognostic indicator of the development of AKI following cardiopulmonary bypass surgery in pediatric patients without CKD. Identifying patients more likely to have AKI following surgery provides a means of achieving closer clinical management of AKI and fluid balance.

Treatment of childhood nephrotic syndrome with long-term, low-dose tacrolimus.

AIM: Children with steroidresistant (SR) and steroid-dependent (SD) nephrotic syndrome (NS) pose a treatment challenge. Literature on the use of tacrolimus (TAC), a calcineurin inhibitor, for maintenance treatment of NS is sparse. We aimed to evaluate the efficacy and safety of low-dose, long-term TAC for inducing and sustaining remission in children with SD/SR NS. METHODS: Data from patients treated at our center from 1999 to 2009 were analyzed. RESULTS: 40 patients with NS were treated with TAC for 3 - 80-month periods (median 25.2 months). Diagnoses included focal segmental glomerulosclerosis (FSGS) (60%), IgM nephropathy (15%), minimal change disease (20%) and membrano-proliferative glomerulonephritis (MPGN) (5%). 58% of patients had been previously treated with alternate agents. After 1, 2, and 3 years on TAC, complete remission was achieved in 26%, 48%, and 29% of patients; complete or partial remission was achieved in 85%, 100%, and 86%, respectively (p < 0.05). Median time to remission was 41 days (range: 10 - 270 days). FSGS and SR diseases were associated with lower likelihood of remission (p < 0.05). Remission was equally likely in both treatment naïve patients and those who had received prior second-line agents. CONCLUSION: Our results demonstrate that TAC treatment for children with SR/SD NS is associated with high rates of sustained remission, even when prior second-line agents failed.

Infrared Thermography as a Potential Non-Invasive Tool for Estrus Detection in Cattle and Buffaloes.

The productivity of dairy animals has significantly increased over the past few decades due to intense genetic selection. However, the enhanced yield performance of milk animals caused a proportional increase in stress and compromised reproductive efficiency. Optimal reproductive performance is mandatory for the sustainable production of dairy animals. Reproductive efficiency is marked by proper estrus detection and precise breeding to achieve maximum pregnancies. The existing conventional methods of estrus detection are somewhat labor intensive and less efficient. Similarly, the modern automated methods that rely on detecting physical activity are expensive, and their efficiency is affected by factors such as type of housing (tie stall), flooring, and environment. Infrared thermography has recently emerged as a technique that does not depend on monitoring physical activity. Furthermore, infrared thermography is a non-invasive, user-friendly, and stress-free option that aids in the detection of estrus in dairy animals. Infrared thermography has the potential to be considered a useful non-invasive tool for detecting temperature fluctuations to generate estrus alerts without physical contact in cattle and buffaloes. This manuscript highlights the potential use of infrared thermography to understand reproductive physiology and practical implementation of this technique through discussing its advantages, limitations, and possible precautions.

Synthesis of Chitosan-TiO2 Nanocomposite for Efficient Cr(VI) Removal from Contaminated Wastewater Sorption Kinetics, Thermodynamics and Mechanism.

A photolysis method was used to prepare a nanocomposite adsorbent (Chitosan-TiO2) and was tested for Cr(VI) removal from aqueous solution. The produce nanocomposite was investigated using, XRD, BET, FTIR, FESEM-EDX and TEM before and after Cr(VI) adsorption. The XRD results shows prepared anatase phase of TiO2 with 12 nm. According to BET measurements, the surface area of the TiO2/chitosan nanocomposite was lower and archived to 26 m2/g, while the TEM and FESEM images show a uniform distribution of TiO2 throughout the chitosan matrix. Adsorption and kinetic experiments were run in batch system under different conditions of pH, contact time, adsorbent dosage and temperature. Experimental Cr(VI) adsorption equilibrium and kinetics data fitted well to Langmuir model. The calculated Langmuir maximum adsorption capacity (qmax) value of nanocomposite was 488 mg/g. Moreover, the highest quantity of Cr(VI) uptake was achieved of pH = 2 and 45℃ and TiO2 and CS-TiO2 had respective removal efficiencies of 94 and 87.5%. The thermodynamic parameters of Cr(VI) adsorption by nanocomposite affirm the spontaneous and endothermic nature of process. Chromium adsorption mechanism by CS-TiO2 nanocomposite were proposed and discussed.

Economic and Health Care Resource Use Burden of Systemic Sclerosis.

OBJECTIVE: To describe the health care resource use (HCRU) and costs of patients with systemic sclerosis (SSc) prior to and after diagnosis. METHODS: This retrospective study used a claims data set (Merative MarketScan; 2015-2019). Eligible patients with SSc were identified by diagnosis codes and required at least 24 months of enrollment without an SSc diagnosis before their first SSc claim and at least 12 months of enrollment thereafter. Total HCRU and costs were reported for three intervals: 2 years and 1 year before and 1 year after index diagnosis. A general population cohort without SSc was matched 1:1 to the SSC cohort on age and sex for comparison. RESULTS: Eligibility criteria identified 902 patients with SSc (mean age: 54 years old; 85% female). Mean per-member per year costs increased each year from $22,383 to $29,708 to $47,095, 2 years before, 1 year before, and 1 year after index diagnosis versus $10,232 to $9656 to $9714 in the general population cohort. Outpatient settings represented the largest proportion of cost 1 year after SSc diagnosis ($16,392), followed by prescription drugs ($10,692), physician office ($10,523), and inpatient ($9448) settings. CONCLUSION: Patients with SSC accrued greater costs and required more services than a general population cohort. These elevated expenditures and HCRU were observed at least 2 years before an SSc diagnosis and increased over time, reflecting both the progressive, multisystem nature of SSc and potential challenges in diagnosis. These findings suggest that SSc poses a substantial burden on the US health care system and highlights the need for early diagnosis and effective therapies.

A computational study of structural analysis of Class I human glucose-6-phosphate dehydrogenase (G6PD) variants: Elaborating the correlation to chronic non-spherocytic hemolytic anemia (CNSHA).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect that affects more than 500 million people worldwide. Individuals affected with G6PD deficiency may occasionally suffer mild-to-severe chronic hemolytic anemia. Chronic non-spherocytic hemolytic anemia (CNSHA) is a potential result of the Class I G6PD variants. This comparative computational study attempted to correct the defect in variants structure by docking the AG1 molecule to selected Class I G6PD variants [G6PDNashville (Arg393His), G6PDAlhambra (Val394Leu), and G6PDDurham (Lys238Arg)] at the dimer interface and structural NADP+ binding site. It was followed by an analysis of the enzyme conformations before and after binding to the AG1 molecule using the molecular dynamics simulation (MDS) approach, while the severity of CNSHA was determined via root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen bonds, salt bridges, radius of gyration (Rg), solvent accessible surface area analysis (SASA), and principal component analysis (PCA). The results revealed that G6PDNashville (Arg393His) and G6PDDurham (Lys238Arg) had lost the direct contact with structural NADP+ and salt bridges at Glu419 - Arg427 and Glu206 - Lys407 were disrupted in all selected variants. Furthermore, the AG1 molecule re-stabilized the enzyme structure by restoring the missing interactions. Bioinformatics approaches were also used to conduct a detailed structural analysis of the G6PD enzyme at a molecular level to understand the implications of these variants toward enzyme function. Our findings suggest that despite the lack of treatment for G6PDD to date, AG1 remains a novel molecule that promotes activation in a variety of G6PD variants.

Design and synthesis of polyethylene glycol-modified biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.

Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.