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Abstract The widespread use of oxidative hair colouring cosmetics threatens public health. Phenylenediamine derivatives serve as the main pigment in permanent hair colours. They interact with biological macromolecules, altering their functional and structural physiology. The study aimed to investigate the effect of a typical synthetic hair dye pigment, 4-Chloro-orthophenylenediamine (4-Cl-OPD), under a nitrating environment of DEANO on the calf thymus DNA molecule. The results showed single-stranded regions, base/sugar-phosphate backbone alterations, molecular changes, and nitro-oxidative lesions. These modifications are referred to as neo-epitopes on the DNA molecule. IgGs from cancer patients with a history of permanent hair dye use were screened for the recognition of neo-epitopes on DNA molecules. Hepatocellular carcinoma IgG showed the highest binding with 56% inhibition in the competition ELISA. The immune complex formation was observed through electrophoretic mobility shift assay. In conclusion, synthetic hair dye users are likely to present with heightened immunological triggers under elevated nitric oxide levels. The study reports chronic hair dye exposure as one of the factors responsible for altering the intricacies of the DNA’s microarchitectural structure and inducing neo-epitopes on the molecule. The physiological status of NO may define the susceptibility towards 4-Cl-OPD and humoral response in hair dye users. Persistent nitro-oxidative stress due to 4-Cl-OPD and NO may induce a heightened immune response against neoepitopes in the nitro-oxidatively modified DNA. Therefore, chronic hair dye exposure may be identified as a risk to human health. These findings may contribute to a better understanding and reinforcement of hair dye as one of the modifiable risk factors responsible for the pro-inflammatory carcinogenic environment.

Abstract Transesophageal echocardiography (TEE) has been the preferred imaging modality to help guide left atrial appendage closure. Newer technologies such as the Nuvision 4D Intracardiac echocardiography (ICE) catheter allow for real-time 3D imaging of cardiac anatomy. There are no direct comparison studies for procedural imaging between TEE and 4D ICE. To evaluate the performance and safety of left atrial appendage (LAA) closure procedures with the Watchman FLX and Amulet, guided by the Nuvision 4D ICE Catheter. This retrospective observational analysis was conducted on institutional LAAO National Cardiovascular Data Registry from January 2022 to March 2023. Patients had undergone LAA closure procedures with the Watchman FLX or Amulet device guided by TEE or a 4D ICE Catheter. The primary outcome evaluated was successful LAAO device placement. A total of 121 patients underwent LAAO device placement with 46 (38.0%) patients guided by 4D ICE during LAAO implantation. The 4D ICE group had a shorter procedural time compared with TEE guidance. Post procedural 45-day TEE post implant was also comparable for both groups with no patients in either group having incomplete closure of the left atrial appendage and peri-device leak > 5 mm. No device related complications (device related access, stroke, or pericardial effusion) occurred in either group at follow-up. There was no significant difference in device implant success or post procedural outcomes at 45 days in either the TEE or 4D ICE group. However, there was a noticeable improvement in procedural time with the 4D ICE catheter.

Therapeutic Area: CVD Prevention – Primary and Secondary Background: Cholesterol-lowering medications such as HMG-CoA reductase inhibitors or statins are a guideline recommendation for the prevention of cardiovascular events in patients with diabetes over the age of 40. High-intensity statins can reduce low-density lipoprotein LDL cholesterol levels by as much as 50%. The optimal LDL level for statin medication patients has not been well studied. Our study aimed to determine the optimal LDL range for cardiovascular outcomes for primary and secondary prevention among patients with diabetes taking a statin. Methods: A retrospective observational study of patients diagnosed with type 2 diabetes mellitus receiving statin therapy was evaluated and separated into groups based on their low-density lipoprotein (LDL) values, 100 mg/dL. The primary outcome of acute coronary syndrome and ischemic cerebrovascular accidents were analyzed in primary prevention and secondary prevention groups. A chi-squared analysis was used to determine which LDL range was deemed more effective and whether the LDL range was dependent on prevention outcomes. Additionally, a multinomial logistic regression was used to determine predictors for successful prevention management. Results: Of the 11,529 patients, most of the patients were male (52.2%) and had an LDL range of >100 mg/dL (50.98%), followed by 71-100 mg/dL (26.90%), 51-70 mg/dL (12.23%), and < 50mg/dL (9.87%). Primary prevention and LDL range were statistically dependent (χ2=12.92, p=0.044), with the LDL range of 56-70 mg/dL displaying a lower-than-expected frequency for outcomes in primary prevention (z=-2.91). On multinomial logistic regression for cardiovascular outcomes LDL group was not a significant predicator (OR , 95% CI 0.86-1.60, p

Pentachlorophenol (PCP) is an excessively used wood preservative and pesticide, which has resulted in human exposure raising concerns about its potential toxic effects. This study is designed to evaluate the hemotoxicity of PCP in adult rats. Wistar rats were orally administered PCP (25–150 mg/kg bw) for five days while untreated (control) rats received corn oil. Animals were sacrificed, blood was taken and fractionated into plasma and red blood cells (RBC). PCP administration increased methemoglobin formation but decreased methemoglobin reductase activity. Significantly increased hydrogen peroxide level indicates initiation of oxidative stress condition in blood. PCP increased the oxidation of thiols, proteins and lipids, lowered glutathione levels, and compromised the antioxidant status of RBC in treated rats. Enzymes of the pathways of glucose breakdown, glycolysis and phosphogluconate pathway, were inhibited. Markers of liver damage were increased in the plasma of PCP-treated rats suggesting hepatotoxicity. This was confirmed by histopathological analysis of stained liver sections. Activity of xanthine oxidase, a reactive oxygen species (ROS) generating pro-oxidant enzyme, was increased. These hematological changes could be a result of the increased generation of ROS or direct chemical transformation by transient reaction species. These results show that PCP induces redox imbalance, diminishes antioxidant potential, inhibits metabolic pathways, and oxidizes cellular components in rat blood.This study suggests an elaborated possible molecular mechanism of PCP toxicity, and similar compounds so that methods can be devised to minimize its damaging effect.

Abstract Bioallethrin is a synthetic pesticide that is widely used to control insect pests. The wide use of bioallethrin has resulted in inevitable human exposure. In this study we report the effect of different concentrations of bioallethrin (10 to 200 µM, 2 h at 37 °C) on human lymphocytes under in vitro conditions. Bioallethrin treatment resulted in loss of cell viability (> 30% at 200 µM bioallethrin). Oxidative stress markers like lipid peroxidation and protein oxidation were significantly increased accompanied by lower ratio of reduced to oxidized glutathione. Enhanced ROS generation was observed through fluorescence spectroscopy and microscopy. Bioallethrin-induced oxidative stress also compromised the antioxidant defence as it reduced antioxidant capacity of cells and inhibited major antioxidant enzymes. Biomolecular modifications and systemic toxicity by bioallethrin resulted in plasma membrane damage with mitochondrial depolarization. Comet assay showed nuclear DNA fragmentation and strand scission with significant increase in tail length and olive tail moment. Apoptosis and necrosis of cells was confirmed through acridine orange/ethidium bromide dual staining and visualization under fluorescence microscope. Thus, bioallethrin causes oxidative damage and compromises the antioxidant system leading to DNA damage, cellular and organelle toxicity, resulting in apoptosis and necrosis of human lymphocytes.

Abstract Background Gardenia gummifera L.f. (Family: Rubeacea) is used in indigenous system of medicine to cure many diseases. To authenticate the traditional medicinal claim investigation has been under taken to evaluate the antioxidant and hepatoprotective activities of Gardenia gummifera L.f. fruit methanol extract (GFME). Method GFME was evaluated using various antioxidant assays, including DPPH and Nitric oxide radical scavenging assays. The protective effects of GFME were studied in carbon tetrachloride reduced biochemical markers of hepatic injury such as serum glutamyl oxaloacetate transaminase (SGOT), serum glutamyl pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total protein (TP), total bilirubin (TB) and direct bilirubin (DB) and in silico studies were carried out to screen the GFME phytocompounds. Results The extract showed significant antioxidant activity in DPPH and Nitric oxide radical scavenging with IC50 value of 131.11 and 175.95 respectively. Quantitative phytochemical assay determines the presence of alkaloids 69.1 μg/1 mg and phenolics 76.5 μg/1 mg. GC-MS analysis of aromatic extract resulted in 36 compounds. Among them, compounds 2, 3-Dihydro-3,5-dihydroxy-6-methyl-4 h-pyran-4-one, 2-furancarboxaldehyde 5-(hydroxymethyl) and Quinic acid are the major ones. The fruit methanol extract showed significant in vivo hepatoprotective activity by altering the levels of liver function biochemical parameters such as SGOT, SGPT, ALP, TP, TB and DB. Histology of the liver section also confirms the hepatoprotective activity of GFME. Molecular docking of GC-MS profiled phytocompounds with the target protein TGF-β1and PPARα also confirmed the therapeutic effect with good hydrogen bonding and hydrophobic interactions. Conclusion Thus the present study clearly strengthened the traditional medicinal claim of the plant Gardenia gummifera L.f. possessing the hepatoprotective drug.

Introduction. Hypereosinophilic syndrome (HES) is a rare disease characterized by unexplained peripheral eosinophilia along with evidence of end-organ damage. Cardiac involvement is the most life-threatening consequence and is frequently underreported with a prevalence of around 5%. The gold standard for diagnosis is myocardial biopsy, but less-invasive imaging such as cardiac MR (CMR) has been frequently used to help with the diagnosis. We are presenting a unique case of a patient diagnosed with Eosinophilic myocarditis (EM) supported by CMR with rapid improvement after starting steroid treatment. Case Presentation. A 67-year-old African American female with extensive cardiovascular disease history presenting with chest pain was diagnosed with EM secondary to hypereosinophilic syndrome (HES). Lab workup revealed absolute eosinophils of 4.70×103/μL (normal 0–0.75×103/μL). Transthoracic echocardiography showed mild reduction in left ventricular function and a large obliterating thrombus in the right ventricular apex. CMR showed increased signal intensity at the left ventricular and right ventricular apex, consistent with myocardial edema. Subsequently, the patient was placed on dexamethasone 10 mg daily with significant symptomatic improvement. Discussion. EM is a rare complication of hypereosinophilic syndrome and can mimic common cardiovascular diseases such as acute exacerbation of heart failure or myocardial infarction. A high index of suspicion is essential especially in the setting of suggestive lab workup. CMR is a promising noninvasive and cost-effective alternative for myocardial biopsy in diagnosis.

Fluoride is a widespread environmental pollutant that at high levels exerts numerous deleterious effects on human health. The toxic effects of fluoride are a matter of serious concern since many countries have regions of endemic fluorosis. The main source of fluoride exposure for humans is intake of contaminated groundwater. Fluoride is absorbed from the gastrointestinal tract and enters the circulating blood, where the abundant red blood cells (RBC) are an early and major target of fluoride toxicity. Chronic fluoride exposure generates free radicals, reactive species which leads to redox imbalance, cytotoxicity and hematological damage. This study aimed to determine the effect of sodium fluoride (NaF) on human RBC under in vitro conditions. Isolated RBC were incubated with different concentrations of NaF (10–500 µM) for 8 h at 37 °C. Several biochemical parameters were determined in hemolysates or whole cells. Treatment of RBC with NaF enhanced the generation of reactive oxygen and nitrogen species. This increased the oxidation of hemoglobin to yield methemoglobin and oxoferrylhemoglobin, which are inactive in oxygen transport. NaF treatment increased the degradation of heme causing release of free iron from its porphyrin ring. Cellular antioxidant power was significantly decreased in NaF-treated RBC, lowering the metal reducing and free radical quenching ability of cells. The two pathways of glucose metabolism in RBC i.e. glycolysis and hexose monophosphate shunt, were inhibited. NaF also inhibited the plasma membrane redox system, and its associated ascorbate free radical reductase, to disrupt transmembrane electron transport. These results suggest that fluoride generates reactive species that cause extensive oxidative modifications in human RBC.

Objective: The plantCassia fistula L. (Caesalpiniaceae) is traditionally used to treat heart diseases, abdominal pain and fever. The present study was aimed to investigate the toxic effects acute and sub-acute administration of ethanol extract of C. fistula fruit (CFE) in male Wistar rats. Materials and Methods: In acute toxicity, the effects of a single oral dose (1000, 3000 and 5000 mg/kg) of CFE have been determined. Animal behaviour and mortality were determined for up to 14 days. In sub-acute study, the effects of CFE in daily single oral administration at the doses of 250, 500 and 1000 mg/kg during 28 days were determined. The blood haematological and biochemical parameters, as well as the histopathological examination of the liver, heart and kidneys were studied. Results: In acute study, a single administration of the CFE up to a dose of 5000 mg/kg did not induce mortality. Thus, the LD50 of the CFE has been estimated higher than 5000 mg/kg. In sub-acute toxicity study, administration of CFE at the doses of 250, 500 and 1000 mg/kg to rats did not induce mortality. No significant differences were found in relative organ weight, and haematological and biochemical analyses in treated groups compared to control group. No noticeable histological changes were observed in organs of CFE-treated rats compared to controls. Conclusion: These results have shown that oral administration of C. fistula fruit did not produce any significant toxic effect in male rats. Hence, C. fistula fruit could be regarded as a safe natural product for therapeutic use.

Thevetia peruviana is a medicinal plant used in the treatment of external wounds, infected area, ring worms, tumours etc. in traditional system of medicine. The aim of the study was to evaluate the wound healing potentials of T. peruviana leaves hexane (LH) and fruit rind (FW) water extracts and to prove the folkloric claims. The antimicrobial, antioxidant and anti-inflammatory potentials could be important strategies in defining potent wound healing drug. Based on these approaches the current study was designed using incision, excision and dead space wound models with the biochemical, antioxidant enzymes and inflammatory marker analysis. The fruit rind water extract showed highest WBS of 1133 ± 111.4 g. The extracts in excision model retrieved the excised wound i.e. complete healing of wound at day 14. The hydroxyproline content of FW and LH treated dry granuloma tissue was increased to 65.73 ± 3.2 mg/g and 53.66 ± 0.38 mg/g, accompanied by elevations of hexosamine and hexauronic acid with upregulation of GSH, catalase, SOD, peroxidase and the down regulation of the inflammatory marker (NO) and oxidative stress marker (LPO) in wet granulation tissue was documented. Conclusively, both the extracts showed enhanced WBS, rate of wound contraction, skin collagen tissue development, and early epithelisation. Therapeutic wound healing effect was further proven by reduced free radicals and inflammatory makers associated with enhanced antioxidants and connective tissue with histological evidence of more collagen formation. The present research could establish T. peruviana as potential source of effective wound healing drugs.

Standardised MedDRA Queries (SMQs) have been developed since the early 2000's and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA).We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed.A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with "narrow terms" to enhance specificity over strategies using "broad terms" to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision-making process.SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions.

Industrialization and unchecked use of nitrate/nitrite salts for various purposes has increased human exposure to high levels of sodium nitrite (NaNO2) which can act as a pro-oxidant and pro-carcinogen. Oral exposure makes the gastrointestinal tract particularly susceptible to nitrite toxicity. In this work, the effect of administration of a single acute oral dose of NaNO2 on rat intestine was studied. Animals were randomly divided into four groups and given single doses of 20, 40, 60 and 75 mg NaNO2/kg body weight. Untreated animals served as the control group. An NaNO2 dose-dependent decline in the activities of brush border membrane enzymes, increase in lipid peroxidation, protein oxidation, hydrogen peroxide levels and decreased thiol content was observed in all treated groups. The activities of various metabolic and antioxidant defense enzymes were also altered. NaNO2 induced a dose-dependent increase in DNA damage and DNA-protein crosslinking. Histopathological studies showed marked morphological damage in intestinal cells. The intestinal damage might be due to nitrite-induced oxidative stress, direct action of nitrite anion or chemical modification by reaction intermediates.

A series of 5-{[(6-substituted-2-hydroxyquinolin-3-yl)methylidene]/5-[(7-substitutedtetrazolo[1,5-a]quinoline-4-yl)methylidene]}-2-[(4-substitutedphenyl)amino]-1,3-thiazol-4(5H)-one was successfully synthesized under solvent free conditions by microwave irradiation in high yield. Structures of these newly synthesized compounds were established on the basis of spectral and analytical data. These novel compounds were also evaluated for their in vitro antioxidant, antibacterial and antifungal activity.

During winter 2004 and 2005, two field and glasshouse experiments were conducted to evaluate the response of 471 chickpea genotypes to Ascochyta rabiei, as Ascochyta blight (AB) disease in Chickpea (Cicer aurietimum). Frequent rainfall at flowering and pod formation stages made favorite conditions conducive for the infection and symptoms expression. So, the genotypes with high level of tolerance at seedling stage proved response to the pathogen under field condition. Disease at seedling and adult plant stage exhibited high association, although level of infection was higher at adult plant stage. In glasshouse 65 genotypes at seedling stage and in field experiment 14 genotypes at pod formation stage were resistant to the pathogen. Following green house and field screening methods, six genotypes FLIP98-229C, FLIP82-150C,NCS 950204, NCS 950219, NCS 9903 and PaidarxParbat from NARC and six lines (FLIP 00-20C, FLIP 02-18C, FLIP 02-44C, FLIP 97-120C, FLIP 02-39C and FLIP 97-102C) from ICARDA found resistant for multilocational / agronomic evaluation and use as resistant parent trials for high yielding AB resistance breeding varieties.

Creatine (Cr) is naturally produced in the body and stored in muscles where it is involved in energy generation. It is widely used, especially by athletes, as a staple supplement for improving physical performance. Recent reports have shown that Cr displays antioxidant activity which could explain its beneficial cellular effects. We have evaluated the ability of Cr to protect human erythrocytes and lymphocytes against oxidative damage. Erythrocytes were challenged with model oxidants, 2, 2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and hydrogen peroxide (H2O2) in the presence and absence of Cr. Incubation of erythrocytes with oxidant alone increased hemolysis, methemoglobin levels, lipid peroxidation and protein carbonyl content. This was accompanied by decrease in glutathione levels. Antioxidant enzymes and antioxidant power of the cell were compromised while the activity of membrane bound enzyme was lowered. This suggests induction of oxidative stress in erythrocytes by AAPH and H2O2. However, Cr protected the erythrocytes by ameliorating the AAPH and H2O2 induced changes in these parameters. This protective effect was confirmed by electron microscopic analysis which showed that oxidant-induced cell damage was attenuated by Cr. No cellular alterations were induced by Cr alone even at 20 mM, the highest concentration used. Creatinine, a by-product of Cr metabolism, was also shown to exert protective effects, although it was slightly less effective than Cr. Human lymphocytes were similarly treated with H2O2 in absence and presence of different concentrations of Cr. Lymphocytes incubated with oxidant alone had alterations in various biochemical and antioxidant parameters including decrease in cell viability and induction of DNA damage. The presence of Cr attenuated all these H2O2-induced changes in lymphocytes. Thus, Cr can function as a blood antioxidant, protecting cells from oxidative damage, genotoxicity and can potentially increase their lifespan.

Potassium bromate (KBrO3) is widely used as a food additive and is a major water disinfection by-product. It induces multiple organ toxicity in humans and experimental animals and is a probable human carcinogen. The present study reports the protective effect of dietary antioxidant taurine on KBrO3-induced damage to the rat intestine. Animals were randomly divided into four groups: control, KBrO3 alone, taurine alone and taurine+ KBrO3. Administration of KBrO3 alone led to decrease in the activities of intestinal brush border membrane enzymes while those of antioxidant defence and carbohydrate metabolism were also severely altered. There was increase in DNA damage and DNA-protein cross-linking. Treatment with taurine, prior to administration of KBrO3, resulted in significant attenuation in all these parameters but the administration of taurine alone had no effect. Histological studies supported these biochemical results showing extensive intestinal damage in KBrO3-treated animals and greatly reduced tissue injury in the taurine+ KBrO3 group. These results show that taurine ameliorates bromate induced tissue toxicity and oxidative damage by improving the antioxidant defence, tissue integrity and energy metabolism. Taurine can, therefore, be potentially used as a therapeutic/protective agent against toxicity of KBrO3 and related compounds.

Abiotic stress often causes a series of morphological, physiological, biochemical and molecular changes that affect plant growth, development and productivity. To cope with abiotic stresses, it is necessary to understand plant responses to stresses that disturb homeostatic equilibrium at the cellular and molecular level. Genomic information on Capsicum annuum has been explored to identify microsatellite markers associated with abiotic stress tolerance and assign them to cognate functional groups related to specific stress responses. Several in silico methods have been used to identify simple sequence repeats associated with stress responsive gene candidates in Capsicum annuum. In this study, a microsatellite marker has been identified in Capsicum annuum associated with Nucleoside Diphosphate Kinase (NDK) having multiple environmental stress tolerance (oxidative, high temperature and salt stress) and which is also highly conserved in crops of Solanaceae. These are house-keeping enzymes that maintain intracellular levels of all nucleoside triphosphates (NTP) with the exception of adenosine triphosphate (ATP). These are also involved in phytochrome A response, UV-B signaling, auxin responses and oxidative stress signaling.

Poor regeneration is one of the limiting factors in the development of transgenic crops since Agrobacterium as a plant pathogen can disturb the fragile in vitro conditions with wounding and infection regimes. We have tried to optimize the transformation system in two important varieties of brinjal after Agrobacterium infection to the explants. The effect of explant was studied and hypocotyls were found to be better than cotyledonary leaves. High BAP during the preconditioning period was found to further enhance the regeneration rate. Therefore, use of hypocotyls and high BAP during preconditioning can improve the regeneration of transformed cells and recovery of transformants in vegetables especially brinjal.

The changes in endometrial cells, both in the eutopic endometrium of patients with and without endometriosis and in lesions at ectopic sites, are frequently described and often compared to tumorigenesis. In tumorigenesis, the concept of "seed and soil" is well established. The seed refers to tumor cells with metastatic potential, and the soil is any organ or tissue that provides a suitable environment for the seed to grow. In this systematic review (PRISMA-S), we specifically compared the development of endometriosis with the "seed and soil" hypothesis. To determine changes in the endometrial seed, we re-analyzed the mRNA expression data of the eutopic and ectopic endometrium, paying special attention to the epithelial-mesenchymal transition (EMT). We found that the similarity between eutopic endometrium without and with endometriosis is extremely high (~99.1%). In contrast, the eutopic endometrium of patients with endometriosis has a similarity of only 95.3% with the ectopic endometrium. An analysis of EMT-associated genes revealed only minor differences in the mRNA expression levels of claudin family members without the loss of other cell-cell junctions that are critical for the epithelial phenotype. The array data suggest that the changes in the eutopic endometrium (=seed) are quite subtle at the beginning of the disease and that most of the differences occur after implantation into ectopic locations (=soil)., Competing Interests: The authors declare no conflicts of interest.

There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the main reasons is the scarcity of protocols enabling prolonged epithelial cell culture. Even though it is possible to culture HPEECs in 3D over a longer period of time, it is technically demanding. In this study, we successfully established a highly pure, stable, and long-term viable human conditionally reprogrammed endometrial epithelial cell line, designated as eCRC560. These cells stained positive for epithelial markers, estrogen and progesterone receptors, and epithelial cell-cell contacts but negative for stromal and endothelial cell markers. Estradiol (ES) reduced the abundance of ZO-1 in a time- and dose-dependent manner, in contrast to the dose-dependent increase with the progestin dienogest (DNG) when co-cultured with HPESCs. Moreover, ES significantly increased cell viability, cell migration, and invasion of the eCRC560 cells; all these effects were inhibited by pretreatment with DNG. DNG withdrawal led to a significantly disrupted monolayer of eCRC560 cells in co-culture with HPESCs, yet it markedly increased the adhesion of eCRC560 to the human mesothelial MeT-5A cells. The long-term viable eCRC560 cells are suitable for in vitro analysis of HPEECs to study the epithelial compartment of the human endometrium and endometrial pathologies.

The emergence of nano innovations in membrane distillation (MD) has garnered increasing scientific interest. This enables the exploration of state-of-the-art nano-enabled MD membranes with desirable properties, which significantly improve the efficiency and reliability of the MD process and open up opportunities for achieving a sustainable water-energy-environment (WEE) nexus. This comprehensive review provides broad coverage and in-depth analysis of recent innovations in nano-enabled MD membranes, focusing on their role in achieving desirable properties, such as strong liquid-repellence, high resistance to scaling, fouling, and wetting, as well as efficient self-heating and self-cleaning functionalities. The recent developments in nano-enhanced photothermal-catalytic applications for water-energy co-generation within a single MD system are also discussed. Furthermore, the bottlenecks are identified that impede the scale-up of nanoenhanced MD membranes and a future roadmap is proposed for their sustainable commercialiation. This holistic overview is expected to inspire future research and development efforts to fully harness the potential of nano-enabled MD membranes to achieve sustainable integration of water, energy, and the environment., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Introduction: Baseline frailty status has been utilized to predict a wide range of outcomes and guide preoperative decision making in neurosurgery. This systematic review aims to analyze existing literature on the utilization of frailty as a predictor of neurosurgical outcomes., Evidence Acquisition: We conducted a systematic review following PRISMA guidelines. Studies that utilized baseline frailty status to predict outcomes after a neurosurgical intervention were included in this systematic review. Studies that utilized sarcopenia as the sole measure of frailty were excluded. PubMed, EMBASE, and Cochrane library was searched from inception to March 1 st , 2023, to identify relevant articles., Evidence Synthesis: Overall, 244 studies met the inclusion criteria. The 11-factor modified frailty index (mFI-11) was the most utilized frailty measure (N.=91, 37.2%) followed by the five-factor modified Frailty Index (mFI-5) (N.=80, 32.7%). Spine surgery was the most common subspecialty (N.=131, 53.7%), followed by intracranial tumor resection (N.=57, 23.3%), and post-operative complications were the most reported outcome (N.=130, 53.2%) in neurosurgical frailty studies. The USA and the Bowers author group published the greatest number of articles within the study period (N.=176, 72.1% and N.=37, 15.2%, respectively)., Conclusions: Frailty literature has grown exponentially over the years and has been incorporated into neurosurgical decision making. Although a wide range of frailty indices exist, their utility may vary according to their ability to be incorporated in the outpatient clinical setting.

Background: Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder debilitating mainly in adults., Objective: This study aimed to assess the trends in HD-related mortality regarding various demographic factors., Methods: Death certificates from the CDC WONDER were studied from 1999 to 2019, for HD-related mortality in adults aged 25 + years. Age-adjusted Mortality Rate (AAMR) per 100,000 persons and Annual Percentage Change (APC) were calculated and stratified by year, age groups, gender, race/ethnicity, state, census region, urbanization, and place of death., Results: Between 1999 to 2019, 22,595 deaths occurred in adults due to HD. The AAMR increased from 0.43 to 0.54 during this period (APC = 0.50; 95% CI: 0.18 to 0.84). Old adults (65-85 + years) had the highest overall AAMR, followed by middle-aged adults (45-64 years) and young adults (25-44 years) (AAMR old: 1.01 vs. AAMR middle-age: 0.68 vs. AAMR young: 0.16). Men had slightly greater overall AAMRs than women (AAMR men: 0.54 vs. AAMR women: 0.48). When stratified by race, non-Hispanic (NH) Whites had significantly higher mortality rates than NH African Americans (AAMR NH White: 0.61 vs. NH African American: 0.35), while the AAMR were lowest in Hispanic/Latino (0.28). The AAMRs also showed variation by region (overall AAMR: Midwest: 0.63, Northeast: 0.47, West: 0.48, South: 0.46), and non-metropolitan areas had higher HD-related AAMR (0.66) than metropolitan areas (0.47)., Conclusions: HD-related mortality in US adults has increased since 1999. Reflecting on the variations in trends observed, new strategies are required to optimize the quality of care in long-term care facilities.

Okra (Abelmoschus esculentus L.) is the most consumed vegetable worldwide with the potential for diverse ecological adaptation. However, increasing salinization and changing climatic conditions are posing serious threats to the growth, yield, and quality of okra. Therefore, to mitigate increasing soil salinization and ensure sustainable okra production under rapidly changing climatic conditions, evaluation of new okra germplasm to develop salt tolerant cultivars is direly needed. The present study was designed to evaluate the genetic resources of okra genotypes for salt tolerance at growth and reproductive phases. Based on mophological and physio-biochemical responses of plants under stress condition, genotypes were divided into salt tolerant and succeptible groups. The experiment was comprised of 100 okra genotypes and each genotype was grown under control conditions and 6.5 dS m -1 NaCl concentration in a pot having 10 kg capacity. The experiment was conducted in a completely randomized design and each treatment was replicated three times. The results showed vast genetic variability among the evaluated okra germplasm traits like days to emergence, pod length, pod diameter, plant height, stem girth, and other yield-related parameters. Correlation analysis showed a highly significant positive association among the number of leaves at first flower and plant height at first flower.Likewise, pod weight also revealed a highly significant positive relationship for pod weight plant -1 , pod length, and K + : Na + . Principal Component Analysis (PCA) revealed that out of 16 principal components (PCs), five components showed more than one eigenvalue and the first six PCs contributed 67.2% of the variation. Bi-plot analysis illustrated that genotypes 95, 111, 133, 99, and 128, under salt stress conditions, exhibited both high yield per plant and salt-tolerant behavior in other yield-related traits. On the basis of all studied traits, a salt susceptible group and a salt-tolerant group were formed. The salt tolerant group comprised of 97, 68, 95, 114, 64, 99, 111, 133, 128, and 109 genotypes, whereas, the salt susceptible group contained 137, 139, 130, 94, and 125 genotypes. Salt-tolerant okra genotypes were suggested to be used in further breeding programs aimed to develop salt tolerance in okra. These insights will empower precision breeding, underscore the importance of genetic diversity, and bear the potential to address the challenges of salt-affected soils while promoting broader agricultural resilience, economic prosperity, and food security., (© 2023. The Author(s).)

Objective: The "leaky academic pipeline" describes how female representation in leadership positions has remained stagnant despite an increase in the number of female trainees. Female mentorship to female mentees, and female role models at higher academic positions have been shown to positively influence academic productivity. To the authors' knowledge, the impact of female editorial board representation on authorship trends in neurosurgical journals remains undescribed. This study aimed to analyze trends in the representation of female topic editors and its impact on female authorship within Neurosurgical Focus over a 10-year period., Methods: Publicly available data were collected from the journal's website, inclusive from January 2013 to December 2022. The articles were grouped into technical and nontechnical themes based on their relevance to specific technical details regarding surgical techniques. Female gender-concordant publications were defined as publications having a female first author (or co-first author) and a female senior author. Linear regression analysis determined trends in publishing. Odds ratios and 95% CIs were calculated using logistic regression analysis. Pearson correlation and cross-correlation analyses were used to examine each pairwise comparison of time series. The statistical significance of associations was evaluated using t-tests and chi-square and Fisher's exact tests., Results: The number of female topic editors and gender-concordant authors increased over time (p < 0.05). Women accounted for ≥ 50% of the topic editors on nontechnical themes relevant to education and gender diversity. Having a female senior author was associated with higher publication productivity for original research and review articles among female authors (OR 13.73, 95% CI 1.75-394.31; p < 0.05). Female authors had higher odds of publishing editorials with a female topic editor (OR 3.81, 95% CI 1.37-11.02; p < 0.01). Publications with female first and senior authors were significantly more likely to have female topic editors (OR 4.05, 95% CI 1.38-12.92; p < 0.01). A positive association was observed between female senior authors and female topic editors at lag -8, with a correlation coefficient of 0.19 (p = 0.03)., Conclusions: Female attending-to-female trainee mentorship and female representation among editorial boards play a crucial role in enhancing academic productivity among women. Efforts to sustain academic productivity during the early-career period would presumably help increase female representation in neurosurgery.

Background: Membrane type-matrix metalloproteinases (MT-MMPs) are a subgroup of the matrix metalloproteinases (MMPs) family and are key molecules in the degradation of the extracellular matrix. Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP14) is often deregulated in different cancer tissues and body fluids of human cancer patients; however, MT1-MMP levels in endometriosis and adenomyosis patients are currently unknown., Materials and Methods: Tissue samples from patients with and without endometriosis or adenomyosis were analyzed with immunohistochemistry for the localization of MT1-MMP. Serum and endocervical mucus samples from patients with and without endometriosis or adenomyosis were investigated with MT1-MMP ELISAs., Results: MT1-MMP was localized preferentially in the glands of eutopic and ectopic endometrium. MT1-MMP protein levels are significantly reduced in ovarian endometriosis (HSCORE = 31) versus eutopic endometrium (HSCORE = 91) and adenomyosis (HSCORE = 149), but significantly increased in adenomyosis (HSCORE = 149) compared to eutopic endometrium (HSCORE = 91). Similarly, analysis of the levels of MT1-MMP using enzyme-linked immune assays (ELISAs) demonstrated a significant increase in the concentrations of MT1-MMP in the serum of endometriosis patients (1.3 ± 0.8) versus controls (0.7 ± 0.2), but not in the endocervical mucus. Furthermore, MT1-MMP levels in the endocervical mucus of patients with endometriosis were notably reduced in patients using contraception (3.2 ± 0.4) versus those without contraception (3.8 ± 0.2)., Conclusions: Taken together, our findings showed an opposite regulation of MT1-MMP in the tissue of ovarian endometriosis and adenomyosis compared to eutopic endometrium without endometriosis but increased serum levels in patients with endometriosis.

Objectives: Are other pain symptoms in addition to dysmenorrhea, dyspareunia, dyschezia, dysuria, and chronic pelvic pain correlated to endometriosis and suitable for a clinical prediction model?, Methods: We conducted a prospective study from 2016 to 2022, including a total of 269 women with numerous pain symptoms and other parameters. All women filled out two questionnaires and were examined by palpation and transvaginal ultrasound (TVUS). In cases of suspected deep endometriosis, magnetic resonance imaging (MRI) was performed. After the operation, endometriosis was diagnosed by histological examination., Results: All in all, 30 significant parameters and 6 significant numeric rating scale (NRS) scores associated with endometriosis could be identified: 7 pain adjectives, 8 endometriosis-associated pain symptoms, 5 pain localizations, 6 parameters from the PainDETECT, consumption of analgesics, and allergies. Furthermore, longer pain duration (before, during, and after menstruation) was observed in women with endometriosis compared to women without endometriosis (34.0% vs. 12.3%, respectively). Although no specific pain for endometriosis could be identified for all women, a subgroup with endometriosis reported radiating pain to the thighs/legs in contrast to a lower number of women without endometriosis (33.9% vs. 15.2%, respectively). Furthermore, a subgroup of women with endometriosis suffered from dysuria compared to patients without endometriosis (32.2% vs. 4.3%, respectively). Remarkably, the numbers of significant parameters were significantly higher in women with endometriosis compared to women without endometriosis (14.10 ± 4.2 vs. 7.75 ± 5.8, respectively). A decision tree was developed, resulting in 0.904 sensitivity, 0.750 specificity, 0.874 positive predictive values (PPV), 0.802 negative predictive values (NPV), 28.235 odds ratio (OR), and 4.423 relative risks (RR). The PPV of 0.874 is comparable to the positive prediction of endometriosis by the clinicians of 0.86 (177/205)., Conclusions: The presented predictive model will enable a non-invasive diagnosis of endometriosis and can also be used by both patients and clinicians for surveillance of the disease before and after surgery. In cases of positivety, as evaluated by the questionnaire, patients can then seek advice again. Similarly, patients without an operation but with medical therapy can be monitored with the questionnaire.

Synthetic insecticides have been an inevitable part of plant protection throughout the world. Sublethal effects of these chemicals on beneficial insect species are one of the contemporary issues these days. Using the age-stage, two-sex life table model, this study evaluated the sublethal and transgenerational effects of six synthetic insecticides (imidacloprid, thiamethoxam, lambda-cyhalothrin, cypermethrin, chlorpyrifos and profenofos) commonly applied to winter vegetables, on the fitness and predation of the seven-spotted ladybeetle, Coccinella septempunctata , which is an efficient predator of aphids worldwide. According to results, all insecticides at their sublethal doses (LC 30 ) significantly suppressed the emergence of adults, adult weight, fertility and fecundity of the parental generation compared to control treatment. The larval stage was prolonged and oviposition, fecundity and total longevity of the adult beetles were decreased in unexposed progeny whose parents were exposed to sublethal doses of all insecticides. Moreover, the biological parameters of adults, including the intrinsic rate of increase ( r ), finite rate of increase ( λ ) and net reproductive rate ( R 0 ) were significantly reduced when exposed to sublethal doses of insecticides. The predation rate of the F 1 generation adults was also decreased after exposure to the sublethal doses of insecticides. However, chlorpyrifos, profenofos, lambda-cyhalothrin and cypermethrin exhibited more deleterious effects on the fitness and population parameters of beetles than imidacloprid and thiamethoxam., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Afza, Afzal, Riaz, Majeed, Idrees, Qadir, Afzal, Hassan and Li.)

The blood testis barrier (BTB) is often studied with isolated immature Sertoli cells (SCs), transepithelial resistance (TER) measurements and FITC dextran diffusion assays. Recently, it was found that even in the absence of SCs, only few immune cells enter the seminiferous tubules. Thus, in this study, we evaluated the testicular immunological barrier (TIB) in vitro by transmigration of macrophages through SCs with and without peritubular cells (PCs) and with or without matrigel (MG). Primary PCs were isolated from adult rat testis and kept in mono- or co-cultures with the conditionally reprogrammed primary adult Sertoli cell line (PASC1) from rat that has been recently generated by our group. Rat monocytes isolated from fresh blood were differentiated into M0 macrophages, and after polarization to M1 or M2 macrophages characterized by gene expression of CXCL11 and TNF-α for M1, or CCL17 and CCL22 for M2. Transmigration of LeukoTracker-labeled M0, M1, and M2 macrophages through mono- and co-cultures of PCs/SCs with and without MG demonstrated that SCs are the main constituent of the TIB in vitro with only a negligible contribution of PCs or MG. Moreover, M2 macrophages showed less migration activity compared to M0 or M1. Treatment of SCs with testosterone (T) showed positive effects on the barrier in contrast to negative effects by interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α). The new transmigration model is suitable to evaluate transmigration of macrophages through a barrier consisting of testicular cells and can be applied to study the integrity of testicular barriers with respect to immunological aspects.

The TGF-β superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-β type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-β signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-β superfamily ligands in endometrial cells in vitro., Competing Interests: The authors declare no conflict of interest.

Claudins, as the major components of tight junctions, are crucial for epithelial cell-to-cell contacts. Recently, we showed that in endometriosis, the endometrial epithelial phenotype is highly conserved, with only minor alterations. For example, claudin-11 is strongly expressed; however, its localization in the endometriotic epithelial cells was impaired. In order to better understand the role of claudins in endometrial cell-to-cell contacts, we analyzed the tissue expression and localization of claudin-10 by immunohistochemistry analysis and two scoring systems. We used human tissue samples (n = 151) from the endometrium, endometriosis, and adenomyosis. We found a high abundance of claudin-10 in nearly all the endometrial (98%), endometriotic (98−99%), and adenomyotic (90−97%) glands, but no cycle-specific differences and no differences in the claudin-10 positive endometrial glands between cases with and without endometriosis. A significantly higher expression of claudin-10 was evident in the ectopic endometrium of deep-infiltrating (p < 0.01) and ovarian endometriosis (p < 0.001) and in adenomyosis in the cases with endometriosis (p ≤ 0.05). Interestingly, we observed a shift in claudin-10 from a predominant apical localization in the eutopic endometrium to a more pronounced basal/cytoplasmic localization in the ectopic endometria of all three endometriotic entities but not in adenomyosis. Significantly, despite the impaired endometriotic localization of claudin-10, the epithelial phenotype was retained. The significant differences in claudin-10 localization between the three endometriotic entities and adenomyosis, in conjunction with endometriosis, suggest that most of the aberrations occur after implantation and not before. The high similarity between the claudin-10 patterns in the eutopic endometrial and adenomyotic glands supports our recent conclusions that the endometrium is the main source of endometriosis and adenomyosis.

The poultry sector is the most vibrant segment of the agriculture system plays a vital role in the supply of healthy meat products. Broiler production effectiveness is greatly associated with feed formulation. Although, broiler exhibits a relatively fast growth rate, the nutritional profile of its meat has been criticized under conventional human dietary regimes. In the current study, the dietary inclusion of quinoa was assessed to improve broiler growth performance, carcass quality, and health by analyzing different growth, hematological and biochemical, immunological parameters. In the present study, the chicken was fed with 50 g/kg, 100 g/kg, and 200 g/kg quinoa enriched diets in two different experimental groups during the growth phase or finisher phase while chicken fed with diet without quinoa were as control. The 50 g/kg quinoa supplemented chicken group revealed a substantial difference in growth performance in comparison with the control group. In addition, the examination of quinoa dietary supplementation on carcass quality exhibited variable behavior. Further, all the study groups fed with quinoa during the growth phase revealed no remarkable difference in the hematological profile in contrast to the control group except for the chicken group fed (50 g/Kg) during the finisher phase for hemoglobin levels. Likewise, all the quinoa enriched diet given chicken groups showed no significant difference in serum biochemical profile in contrast to the control group except for the 50 g/Kg quinoa fed chicken group during the finisher phase for total globulin levels. In addition, the examination of quinoa dietary supplementation on the broiler serum lipid profile was also assessed and birds exhibited variable behavior as the result of quinoa dietary supplementation. Evaluation of short-term immune response after quinoa supplementation assessed and birds exhibited no marked significance on expression outcomes of interleukin/cytokines (IL 1 beta, IL-6, IL-10) assessed by qRT-PCR analysis. In conclusion, the dietary supplementation of broiler fed with quinoa seeds can enhance the growth performance and the carcass quality of broiler., Competing Interests: The authors have declared that no competing interests exist.

The tele-presence robot is designed to set forth an economic solution to facilitate day-to-day normal activities in almost every field. There are several solutions to design tele-presence robots, e.g., Skype and team viewer, but it is pretty inappropriate to use Skype and extra hardware. Therefore, in this article, we have presented a robust implementation of the tele-presence robot. Our proposed omnidirectional tele-presence robot consists of (i) Tricon ultrasonic sensors, (ii) Kalman filter implementation and control, and (iii) integration of our developed WebRTC-based application with the omnidirectional tele-presence robot for video transmission. We present a new algorithm to encounter the sensor noise with the least number of sensors for the estimation of Kalman filter. We have simulated the complete model of robot in Simulink and Matlab for the tough paths and critical hurdles. The robot successfully prevents the collision and reaches the destination. The mean errors for the estimation of position and velocity are 5.77% and 2.04%. To achieve efficient and reliable video transmission, the quality factors such as resolution, encoding, average delay and throughput are resolved using the WebRTC along with the integration of the communication protocols. To protect the data transmission, we have implemented the SSL protocol and installed it on the server. We tested three different cases of video resolutions (i.e., 320×280, 820×460 and 900×590) for the performance evaluation of the video transmission. For the highest resolution, our TPR takes 3.5 ms for the encoding, and the average delay is 2.70 ms with 900 × 590 pixels.

H 2 O 2 sensing is required in various biological and industrial applications, for which electrochemical sensing is a promising choice among various sensing technologies. Electrodes and electrocatalysts strongly influence the performance of electrochemical H 2 O 2 sensors. Significant efforts have been devoted to electrode nanostructural designs and nanomaterial-based electrocatalysts. Here, we review the design strategies for electrodes and electrocatalysts used in electrochemical H 2 O 2 sensors. We first summarize electrodes in different structures, including rotation disc electrodes, freestanding electrodes, all-in-one electrodes, and representative commercial H 2 O 2 probes. Next, we discuss the design strategies used in recent studies to increase the number of active sites and intrinsic activities of electrocatalysts for H 2 O 2 redox reactions, including nanoscale pore structuring, conductive supports, reducing the catalyst size, alloying, doping, and tuning the crystal facets. Finally, we provide our perspectives on the future research directions in creating nanoscale structures and nanomaterials to enable advanced electrochemical H 2 O 2 sensors in practical applications.

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shh tm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1 , suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

Endometriosis is characterized by the presence of ectopic endometrium most often in the pelvis. The transforming growth factor-beta (TGF-β) superfamily is also involved in the pathogenesis; however, betaglycan (BG, syn. TGF-β type III receptor) as an important co-receptor was not studied. We analyzed mainly BG ectodomain shedding because released soluble BG (sBG) often antagonizes TGF-β signaling. Furthermore, we studied the role of TGF-βs and BG in wound healing and evaluated the suitability of BG measurements in serum and endocervical mucus for non-invasive diagnosis of endometriosis. Evaluation of the BG shedding and signaling pathways involved as well as wound healing was performed with enzyme-linked immune assays (ELISAs), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), small interfering RNA (siRNA) knockdown, and scratch assays with human endometriotic epithelial cells. TGF-β1/2 stimulation resulted in a significant dose-dependent reduction in BG shedding in endometriotic cells, which was TGF-β/activin receptor-like kinase-5 (ALK-5)/mother against decapentaplegic homolog3 (SMAD3)- but not SMAD2-dependent. Inhibition of matrix metalloproteinases (MMPs) using the pan-MMP inhibitor GM6001 and tissue inhibitor of MMPs (TIMP3) equally attenuated BG shedding, signifying the involvement of MMPs in shedding. Likewise, recombinant BG moderately reduced the secretion of TGF-β1/2 and wound healing of endometriotic cells. TGF-β1 significantly enhanced the secretion of MMP2 and MMP3 and moderately promoted wound healing. In order to evaluate the role of BG in endometriosis, serum (n = 238) and mucus samples (n = 182) were analyzed. Intriguingly, a significant reduction in the levels of sBG in endocervical mucus but not in the serum of endometriosis patients compared to controls was observed. Collectively, these observations support a novel role for BG in the pathophysiology of endometriosis.

Matrix metalloproteinases (MMPs) play an important role in menstruation and endometriosis; however, the membrane-type matrix metalloproteinases (MT-MMPs) are not well studied in endometriosis and adenomyosis. We analyzed MT2-MMP (MMP15) and MT3-MMP (MMP16) in eutopic endometrium with and without endometriosis and with and without adenomyosis and ectopic endometrium of deep infiltrating endometriosis (DIE), peritoneal endometriosis (PE), and ovarian endometriosis (Ov) by immunohistochemistry. Preferential expression of both proteins was observed in the glandular and luminal epithelial cells of the eutopic endometrium of patients with and without endometriosis with a ~2.5-fold stronger expression of MT3-MMP compared to MT2-MMP. We did not observe any differences during menstrual cycling and in eutopic endometrium of patients with and without endometriosis. Similarly, eutopic endometrium and adenomyotic tissue with and without endometriosis showed similar protein levels of MT2-MMP and MT3-MMP. In contrast, MT2-MMP and MT3-MMP protein was decreased in ectopic compared to eutopic endometrium and adenomyosis. The similar expression of MT2-MMP and MT3-MMP in eutopic endometrium in patients with and without endometriosis in contrast to the impaired expression in ectopic endometrium suggests that alterations occur after and not before endometrial implantation possibly by distinct interactions with the different environments. The differential protein expression of MT2/3-MMP in adenomyosis compared to endometriosis might suggest a different pathogenesis pathway for the two diseases.

This review comprises the inorganic compounds particularly metal coordinated complexes, as drugs play a relevant role in medicinal chemistry. It has been observed that copper complexes are potentially attractive as medicinal importance. In this review, the most remarkable achievements of copper complexes undertaken over the past few decades as antimicrobial, antioxidant, enzyme inhibition activity, and anti-cancer agents are discussed. This work was motivated by the observation that no comprehensive surveys of the diversity of biological activities of copper complexes were available in the literature., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors., (© TÜBİTAK.)

A protocol for the isolation and long-term propagation of adult rat Sertoli cells (SCs) using conditional reprogramming (CR) was developed and the formation of tight junctions as an in vitro model for the blood testis barrier (BTB) was studied. Three pure primary SC lines were isolated successfully and maintained for several months without significant changes in expression levels of SC-typical markers such as SRY-box transcription factor 9 (SOX9), transferrin, clusterin, androgen receptor (AR), and GATA binding protein 1 (GATA1). In addition to AR expression, the tight junction proteins, zonula occludens-1 (ZO-1) and the junctional adhesion molecule-3 (JAM-3), were upregulated and the SC barrier integrity was enhanced by testosterone. Peritubular/myoid cells did not increase the tightness of the SC. The cytokines, interleukin-6 (IL-6), bone morphogenetic protein-2 (BMP2), and transforming growth factor beta-3 (TGF-β3), negatively affected the tightness of the SC barrier. We have established a protocol for the isolation and long-term propagation of highly pure primary adult rat SCs, which are able to respond to androgen treatments, to form tight junctions and to maintain the mRNA expression of SC-specific genes. By applying this new method, adult SCs can now be analyzed in more detail and might serve as an in vitro model for the study of many SC functions.

Resistance to chemical insecticides including pyrethroids, the main insecticide class used against mosquitoes, has re-kindled interest in the use of neonicotinoids. In this context, the present study aimed to characterize the molecular basis of neonicotinoid resistance in the mosquito Aedes aegypti. Resistance mechanisms were studied by combining transcriptomic and genomic data obtained from a laboratory strain selected at the larval stage after 30 generations of exposure to imidacloprid (Imida-R line). After thirty generations of selection, larvae of the Imida-R line showed an 8-fold increased resistance to imidacloprid and a significant cross-tolerance to the pyrethroids permethrin and deltamethrin. Cross-resistance to pyrethroids was only observed in adults when larvae were previously exposed to imidacloprid suggesting a low but inducible expression of resistance alleles at the adult stage. Resistance of the Imida-R line was associated with a slower larval development time in females. Multiple detoxification enzymes were over-transcribed in larvae in association with resistance including the P450s CYP6BB2, CYP9M9 and CYP6M11 previously associated with pyrethroid resistance. Some of them together with their redox partner NADPH P450 reductase were also affected by non-synonymous mutations associated with resistance. Combining genomic and transcriptomic data allowed identifying promoter variations associated with the up-regulation of CYP6BB2 in the resistant line. Overall, these data confirm the key role of P450s in neonicotinoid resistance in Ae. aegypti and their potential to confer cross-resistance to pyrethroids, raising concerns about the use of neonicotinoids for resistance management in this mosquito species., (Copyright © 2021. Published by Elsevier B.V.)

Thoracic endometriosis (TE) is a rare type of endometriosis, where endometrial tissue is found in or around the lungs and is frequent among extra-pelvic endometriosis patients. Catamenial pneumothorax (CP) is the most common form of TE and is characterized by recurrent lung collapses around menstruation. In addition to histology, immunohistochemical evaluation of endometrial implants is used more frequently. In this review, we compared immunohistochemical (CPE) with histological (CPH) characterizations of TE/CP and reevaluated arguments in favor of the implantation theory of Sampson. A summary since the first immunohistochemical description in 1998 until 2019 is provided. The emphasis was on classification of endometrial implants into glands, stroma, and both together. The most remarkable finding is the very high percentage of stromal endometriosis of 52.7% (CPE) compared to 10.2% (CPH). Chest pain, dyspnea, right-sided preference, and diaphragmatic endometrial implants showed the highest percentages in both groups. No significant association was found between the recurrence rate and the various appearances of endometriosis. Sometimes in CPE (6.8%) and CPH (30.6%) no endometrial implants were identified underlining the importance of sensitive detection of endometriosis during and after surgery. We suggest that immunohistochemical evaluation should become mandatory and will improve diagnosis and classification of the disease.

Dechlorane Plus (DP) is an unregulated, highly chlorinated flame retardant. It has been manufactured from past 40 years but its presence in the environment was initially reported in 2006. Later, it has been found in various biotic and abiotic environmental matrices. However, little attention has been paid to monitor its presence in Asia. Many studies have reported the occurrence of DP in the environment of Asia, yet the data are scarce, and studies are limited to few regions. The objective of present review is to summarize the occurrence, distribution, and toxicity of this ubiquitous pollutant in various environmental matrices (biotic and abiotic). DP has also been reported in the areas with no emission sources, which proves its long-range transport. Moreover, urbanization and industrialization also affect the distribution of DP, i.e., high levels of DP have been found in urban areas relative to the rural. Tidal movement also incorporates in transport of DP across the aquatic system. Further, bioaccumulation trend of DP in various tissues is kidney > liver > muscle tissues, whereas, blood brain barrier resists its accumulation in brain tissues. Additionally, gender-based accumulation trends revealed high DP levels in females in comparison to males due to strong metabolism of males. Furthermore, methodological aspects and instrumental analysis used in previous studies have also been summarized here. However, data on biomagnification in aquatic ecosystem and bioaccumulation of DP in terrestrial food web are still scarce. Toxicity behavior of syn-DP and anti-DP is still unknown which might gain the interest for future studies.

Fruits are the valuable and important components of human diet. Among them, Prunus persica is a rich source of different minerals and dietary fibers. In Pakistan, the total annual production of P. persica is approximately 837,000 tons. In order to enhance agricultural yield and quality, the plant protection agents are employed during fruit production. Ultimately, this in turn leads to the incorporation of pesticide residues in fruits. In present study, an effort has been made for the determination of three selected pesticide residues, i.e., chlorpyrifos (CPF), difenoconazole (DFN), and carbendazim (CRB) in samples of P. persica collected from Swat territory. Samples were analyzed through high performance liquid chromatography (HPLC). Results revealed the occurrence of all three pesticides in studied samples; however, levels of CPF and DFN were found to be higher than MRLs. Moreover, the effects of different mitigation techniques revealed that highest reduction of CPF, DFN, and CRB (86%, 97%, 89%) residues was obtained by treatment with 10% CH 3 COOH followed by 10% NaCl (74%, 78%, 84%). The lowest reduction was obtained by treatment with 10% solution of NaOH (52%, 55%, 63%).

Background: Presence of good size perforators are mandatory to design perforator based pedicelledflaps specially in lower limb as flap failure rate isrelativelyhigh. We have explored the use ofsmartphonebaseddynamic thermal imagingand compared it with doppler to devise a protocol forplanning and executionof pedicled perforator flaps anddescribedits use in deciding delay of flap. We have also compared the time required for detecting dominant perforators., Methods: This prospective case series was done atJinnah burn and reconstructive surgery center Lahore from July to September 2018and included patients requiring pedicled fasciocutaneous or musculocutaneous flapfor lower extremity reconstruction. Smartphonebased dynamic thermal imaging and doppler wereused to map out suitable perforators and confirmed intraoperatively. Comparison was made regarding their ability to locatedominant perforatorsandtotal time required.Utility of thermal imaging to ascertain flap perfusion postoperatively was also assessed.Flaps were designed according to thermal mapping. Clinical judgement supplemented with thermal imaging was usedto ascertain flap survival., Results: The study included 15 patientsin which22 out 23 dominant perforators as located withthermal imaging were confirmed intra-operatively (positive predictive value = 95.7%) as compared to 22 out of 32 with doppler(positive predictive value=68.8%). Mean time required with doppler was 591.27±252.48, compared to 598.47±192.94 seconds with thermal imaging. In two cases flap was delayed. Partial flap necrosis occurred in one case., Conclusion: Dynamic thermal imaging can be reliably usedin planning of pedicled perforator flaps for lower limb reconstruction. We have found itmore reliable than handhelddoppler in locating dominant perforators.

Bacterial insecticidal proteins, such as the Bin toxin from Lysinibacillus sphaericus, could be used more extensively to control insecticide resistant mosquitoes. This study was aimed at identification of mosquito cell proteins binding Bin toxin. Results showed that purified toxin was toxic to Anopheles gambiae larvae and Ag55 cultured cells. Clathrin heavy chain (an endocytosis protein) and glycolytic enzymes such as pyruvate kinase, enolase and dihydrolipoamide dehydrogenase were identified as binders of Bin toxin. The viability of Ag55 cells in the presence of endocytosis inhibitor, pitstop2, was significantly decreased upon Bin treatment, while the inhibitor chlorpromazine did not affect Bin toxicity. Bin toxin treatment decreased ATP production and mitochondrial respiration in Ag55 cells, whereas non-mitochondrial oxygen consumption significantly increased after Bin toxin treatment. These findings are steps towards understanding how Bin toxin kills mosquitoes. SIGNIFICANCE: Mosquitoes are vectors of pathogens causing human diseases such as dengue fever, yellow fever, zika virus and malaria. An insecticidal toxin from Lysinibacillus sphaericus called Binary, or Bin, toxin could be used more extensively to control insecticide resistant mosquitoes. Bin toxin enter cells in susceptible mosquitoes and induces apoptosis or autophagy. In the current research, we used the malaria mosquito Anopheles gambiae Ag55 cell line as a model. A proteomic-based approach identified proteins that interact with Bin toxin. Interacting proteins include clathrin heavy chain (endocytosis protein) and glycolysis enzymes such as pyruvate kinase, enolase and dihydrolipoamide dehydrogenase. In Ag55 cell toxicity assays, an endocytosis inhibitor, pitstop2, increased Bin toxicity. Real time assays with a Seahorse™ flux analyzer showed that Bin significantly affects mitochondrial respiration, a result consistent with cell death via apoptosis or autophagy. These research findings add insights into how an unusual binary protein exploits cellular machinery to kill mosquitoes., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tannery wastewater mainly comes from leather industries. It has high organic load, high salinity, and many other pollutants, including chromium (Cr). Tannery wastewater is generally used for crop irrigation in some areas of Pakistan and worldwide, due to the low availability of good quality of irrigation water. As tannery wastewater has many nutrients in it, its lower concentration benefits the plant growth, but at a higher concentration, it damages the plants. Chromium in tannery wastewater accumulates in plants, and causes stress at physiological and biochemical levels. In recent times, the role of micronutrient-amino acid chelated compounds has been found to be helpful in reducing abiotic stress in plants. In our present study, we used lysine chelated zinc (Zn-lys) as foliar application on maize ( Zea mays L.), growing in different concentrations of tannery wastewater. Zinc (Zn) is required by plants for growth, and lysine is an essential amino acid. Maize plants were grown in tannery wastewater in four concentrations (0, 25%, 50%, and 100%) and Zn-lys was applied as a foliar spray in three concentrations (0 mM, 12.5 mM, and 25 mM) during plant growth. Plants were cautiously harvested right after 6 weeks of treatment. Foliar spray of Zn-lys on maize increased the biomass and improved the plant growth. Photosynthetic pigments such as total chlorophyll, chlorophyll a, chlorophyll b and contents of carotenoids also increased with Zn-lys application. In contrast to control plants, the hydrogen peroxide (H 2 O 2 ) contents were increased up to 12%, 50%, and 68% in leaves, as well as 16%, 51% and 89% in roots at 25%, 50%, and 100% tannery water application, respectively, without Zn-lys treatments. Zn-lys significantly reduced the damages caused by oxidative stress in maize plant by decreasing the overproduction of H 2 O 2 and malondialdehyde (MDA) in maize that were produced, due to the application of high amount of tannery wastewater alone. The total free amino acids and soluble protein decreased by 10%, 31% and 64% and 18%, 61% and 122% at 25%, 50% and 100% tannery water treatment. Zn-lys application increased the amino acids production and antioxidant activities in maize plants. Zn contents increased, and Cr contents decreased, in different parts of plants with Zn-lys application. Overall, a high concentration of tannery wastewater adversely affected the plant growth, but the supplementation of Zn-lys assertively affected the plant growth and enhanced the nutritional quality, by enhancing Zn and decreasing Cr levels in plants simultaneously irrigated with tannery wastewater.

Epithelial-mesenchymal transition (EMT) is an important process of cell remodeling characterized by the gradual loss of the epithelial phenotype and progressive gain of a mesenchymal phenotype. EMT is not an all-or-nothing process, but instead a transition of epithelial to mesenchymal cells with intermediate cell states. Recently, EMT was described in endometriosis, and many EMT-specific pathways like Twist, Snail, Slug, Zinc finger E-box-binding homeobox 1/2 (ZEB1/2), E/N-cadherin, keratins, and claudins are involved. However, as pointed out in this review, a comparison of the eutopic endometrium of women with and without endometriosis yielded only subtle changes of these EMT markers. Furthermore, only very few alterations in cell-cell contacts could be found but without changes in the epithelial phenotype. This suggests only a partial EMT which is not a prerequisite for the detachment of endometrial cells and, thus, not critical for the first step(s) in the pathogenesis of endometriosis. In contrast, the majority of changes in the EMT-related marker expression were found in the ectopic endometrium, especially in the three endometriotic entities, ovarian, peritoneal, and deep infiltrating endometriosis (DIE), compared with the eutopic endometrium. In this review, we examine the most important EMT pathways described in endometriosis and propose that partial EMT might result from the interaction of endometrial implants with their surrounding microenvironment.

Diabetes is a complex metabolic disorder and different environmental toxicants including heavy metals have been involved in diabetes induction. Therefore, assessment of the environmental risk factors and heavy metals induced toxicity have become critical for reducing the consequences of metals pollutants. Previously, we reported heavy metals induced nephrotoxicity in non-diabetic and diabetic rats. Here, we extended our analysis by examining the heavy metals induced organs (heart, kidney, liver, pancreas, and spleen) damage in diabetic and non-diabetic Wistar rats using histopathology and quantitative real-time PCR (qRT-PCR). Following the generation of the diabetic rat model, the animals were exposed to heavy metals including lead (Pb), arsenic (As), manganese (Mn) and cadmium (Cd). Both non-diabetic and diabetic rats were exposed to heavy metals for 30 days and subsequently, the heart, kidney, liver, pancreas and spleen tissues were examined. Heavy metal treatment resulted in irregularly arranged myofibrils and vacuolization in the heart tissue of metal treated groups as evident from hematoxylin and eosin (H & E) staining. The kidney tissue of rats treated with heavy metals showed tubular degeneration, fibrosis, hemorrhage, and vacuolation. The liver of the heavy metals treated rats exhibited cellular degeneration and necrosis. The pancreatic tissue of streptozotocin injected untreated and metal treated rats revealed severe degeneration, necrosis, degranulation, shrinkage, and depression in the islets of Langerhans. Increased red pulp area and congestion were observed in the spleen of the metal mixture treated non-diabetic and diabetic rats. In line with the histological data, the qRT-PCR analysis showed downregulated expression of Bcl 2 and upregulation of Caspase-3 in non-diabetic and diabetic metal treated rats as compared to the non-diabetic untreated rats. In conclusion, the present study revealed, diabetic rats are more prone to metal alone as well as metal mixture induced organ damage as compared to non-diabetic rats.