Functional divergence of FTL9 and FTL10 in flowering control in rice.

BACKGROUND: Floral transition in cereals is a critical phenomenon influenced by exogenous and endogenous signals, determining crop yield and reproduction. Flowering Locus T-like (FT-like) genes encode a mobile florigen, the main signaling molecule for flowering. RESULTS: In this study, we characterized two FT-like genes, FTL9 and FTL10, to study their functional diversity in flowering control in rice. We compared independent mutant lines of ftl10 with WT and observed negligible differences in the flowering phenotype, or agronomic traits implying potentially redundant roles of FTL10 loss-of-function in flowering control in rice. Nevertheless, we found that overexpression of FTL10, but not FTL9, substantially accelerated flowering, indicating the flowering-promoting role of FTL10 and the divergent functions between FTL9 and FTL10 in flowering. Besides flowering, additive agronomic roles were observed for FTL10-OE regulating the number of effective panicles per plant, the number of primary branches per panicle, and spikelets per panicle without regulating seed size. Mechanistically, our Y2H and BiFC analyses demonstrate that FTL10, in contrast to FTL9, can interact with FD1 and GF14c, forming a flowering activation complex and thereby regulating flowering. CONCLUSION: Altogether, our results elucidate the regulatory roles of FTL9 and FTL10 in flowering control, unveiling the molecular basis of functional divergence between FTL10 and FTL9, which provides mechanistic insights into shaping the dynamics of flowering time regulation in rice.

Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia.

PURPOSE: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive. METHODS: We studied 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing. RESULTS: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from 2 unrelated families segregated 2 homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of 2 affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process. CONCLUSION: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.

Molecular genetics, neuroimaging outcomes, and structural analyses of novel and recurrent variants of WDR62 gene in two consanguineous Pakistani families with autosomal recessive primary microcephaly.

BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD below mean) and often results in varying degree of intellectual disability. Thirty genes have been identified for the etiology of this disorder due to its clinical and genetic heterogeneity. METHODS AND RESULTS: Here, we report two consanguineous Pakistani families affected with MCPH exhibiting mutation in WDR62 gene. The investigation approach involved Next Generation Sequencing (NGS) gene panel sequencing coupled with linkage analysis followed by validation of identified variants through automated Sanger sequencing and Barcode-Tagged (BT) sequencing. The molecular genetic analysis revealed one novel splice site variant (NM_001083961.2(WDR62):c.1372-1del) in Family A and one known exonic variant NM_001083961.2(WDR62):c.3936dup (p.Val1313Argfs*18) in Family B. Magnetic Resonance Imaging (MRI) scans were also employed to gain insights into the structural architecture of affected individuals. Neurological assessments showed the reduced gyral and sulcal patterns along with normal corpus callosum in affected individuals harboring novel variant. In silico assessments of the identified variants were conducted using different tools to confirm the pathogenicity of these variants. Through In silico analyses, both variants were identified as disease causing and protein modeling of exonic variant indicates subtle conformational alterations in prophesied protein structure. CONCLUSION: This study identifies a novel variant (c.1372-1del) and a recurrent pathogenic variant c.3936dup (p.Val1313Argfs*18) in the WDR62 gene among the Pakistani population, expanding the mutation spectrum for MCPH. These findings emphasize the importance of genetic counseling and awareness to reduce consanguinity and address the burden of this disorder.

Investigating the effects of a single ASPM variant (c.8508_8509) on brain architecture among siblings in a consanguineous Pakistani family.

BACKGROUND: Autosomal Recessive Primary Microcephaly (MCPH) is a rare, neurodevelopmental disorder associated with mild to severe mental retardation. It is characterized by reduced cerebral cortex that ultimately leads to reduction in skull size less than - 3 S.D below the mean for normal individuals having same age and sex. Till date, 30 known loci have been reported for MCPH. METHODS: In the present study, Sanger sequencing was performed followed by linkage analysis to validate the mutation in ASPM gene of the consanguineous Pakistani clans. Bioinformatics tools were also used to confirm the pathogenicity of the diseased variant in the gene. MRI scan was used to compare the brain structure of both the affected individuals (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023). RESULTS: Our study described a consanguineous family with two patients with a known ASPM (MCPH5) variant c.8508_8509delGA causing a frameshift mutation in exon 18 which located in calmodulin-binding IQ domain of the ASPM protein. The salient feature of this study is that a single variant led to significantly distinct changes in the architecture of brain of both siblings which is further confirmed by MRI results. The computation analysis showed that the change in the conservation of this residue cause this variant highly pathogenic. Carrier screening and genetic counselling were also remarkable features of this study (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023). CONCLUSION: This study explores the extraordinary influence of a single ASPM variant on divergent brain structure in consanguineous siblings and enable us to reduce the incidence of further microcephalic cases in this Pakistani family (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023).

Phytoremediation through microstructural and functional alterations in alkali weed (Cressa cretica L.) in the hyperarid saline desert.

Salt excretory halophytes are the major sources of phytoremediation of salt-affected soils. Cressa cretica is a widely distributed halophyte in hypersaline lands in the Cholistan Desert. Therefore, identification of key physio-anatomical traits related to phytoremediation in differently adapted C. cretica populations was focused on. Four naturally adapted ecotypes of non-succulent halophyte Cressa cretica L. form hyper-arid and saline desert Cholistan. The selected ecotypes were: Derawar Fort (DWF, ECe 20.8 dS m-1) from least saline site, Traway Wala Toba (TWT, ECe 33.2 dS m-1) and Bailah Wala Dahar (BWD, ECe 45.4 dS m-1) ecotypes were from moderately saline sites, and Pati Sir (PAS, ECe 52.4 dS m-1) was collected from the highly saline site. The natural population of this species was collected and carefully brought to the laboratory for different structural and functional traits. As a result of high salinity, Na+, Cl-, K+, and Ca2+ content significantly increased at root and shoot level. At root level, some distinctive modifications such as increased sclerification in vascular bundles, enlarged vascular bundles, metaxylem vessels, phloem region, and storage parenchyma (cortex) are pivotal for water storage under extreme arid and osmotic condition. At the stem level, enhanced sclerification in outer cortex and vascular bundles, stem cellular area, cortical proportion, metaxylem and phloem area, and at the leaf level, very prominent structural adaptations were thicker and smaller leaves with increased density of salt glands and trichomes at surface, few and large stomata, reduced cortical and mesophyll parenchyma, and narrow xylem vessels and phloem area represent their non-succulent nature. The ecotype collected from hypersaline environments was better adapted regarding growth traits, ion uptake and excretion, succulence, and phytoremediation traits. More importantly, structural and functional traits such as root length and biomass, accumulation of toxic ions along with K+ in root and shoot, accumulation of Ca2+ in shoot and Mg2+ in root, excretion of toxic ions were the highest in this ecotype. In conclusion, all these alterations strongly favor water conservation, which certainly contributes to ecotypes survival under salt-induced physiological drought.

Naturally adapted salt tolerant plants provide exceptional material for exploring adaptive mechanisms they use to confront high salt concentrations. Cressa cretica is a hypersaline hyperarid desert colonizer, which was previously underexplored. In the present study, we focused on the new insight on relationship among anatomical modifications, salt accumulation and excretion and phytoremediation potential of this rare species.

Recurrence mutation in RBBP8 gene causing non-syndromic autosomal recessive primary microcephaly; geometric simulation approach for insight into predicted computational models.

Primary microcephaly is a rare, congenital, and genetically heterogeneous disorder in which occipitofrontal head circumference is reduced by a minimum of three standard deviations (SDs) from average because of the defect in fetal brain development. OBJECTIVE: Mapping of RBBP8 gene mutation that produce autosomal recessive primary microcephaly. Insilco RBBP8 protein models prediction and analysis. METHODS: Consanguineous Pakistani family affected with non-syndromic primary microcephaly was mapped a biallelic sequence variant (c.1807_1808delAT) in the RBBP8 gene via whole-exome sequencing. The deleted variant in the RBBP8 gene in affected siblings (V:4, V:6) of primary microcephaly was confirmed by sanger sequencing. RESULTS: Identified variant c.1807_1808delAT that truncated the protein translation p. Ile603Lysfs*7 and impaired the functioning of RBBP8 protein. This sequence variant was only reported previously in Atypical Seckel syndrome and Jawad syndrome, while we mapped it in the non-syndromic primary microcephaly family. We predicted 3D protein models by using Insilco tools like I TASSER, Swiss model, and phyre2 of wild RBBP8 protein of 897 amino acids and 608 amino acids of the mutant protein. These models were validated through the online SAVES server and Ramachandran plot and refined by using the Galaxy WEB server. A predicted and refined wild protein 3D model was deposited with accession number PM0083523 in Protein Model Database. A normal mode-based geometric simulation approach was used through the NMSim program, to find out the structural diversity of wild and mutant proteins which were evaluated by RMSD and RMSF. Higher RMSD and RMSF in mutant protein reduced the stability of the protein. CONCLUSION: The high possibility of this variant results in nonsense-mediated decay of mRNA, leading to the loss of protein functioning which causes primary microcephaly.

Diagnostic evaluation of upper tract urothelial carcinoma: can we safely omit diagnostic ureteroscopy?

OBJECTIVE: To identify clinicopathological or radiological factors that may predict a diagnosis of upper urinary tract urothelial cell carcinoma (UTUC) to inform which patients can proceed directly to radical nephroureterectomy (RNU) without the delay for diagnostic ureteroscopy (URS). PATIENTS AND METHODS: All consecutive patients investigated for suspected UTUC in a high-volume UK centre between 2011 and 2017 were identified through retrospective analysis of surgical logbooks and a prospectively maintained pathology database. Details on clinical presentation, radiological findings, and URS/RNU histopathology results were evaluated. Multivariate regression analysis was performed to evaluate predictors of a final diagnosis of UTUC. RESULTS: In all, 260 patients were investigated, of whom 230 (89.2%) underwent URS. RNU was performed in 131 patients (50.4%), of whom 25 (9.6%) proceeded directly without URS - all of whom had a final histopathological diagnosis of UTUC - and 15 (11.5%) underwent RNU after URS despite no conclusive histopathological confirmation of UTUC. Major surgery was avoided in 77 patients (33.5%) where a benign or alternative diagnosis was made on URS, and 14 patients (6.1%) underwent nephron-sparing surgery. Overall, 178 patients (68.5%) had a final diagnosis of UTUC confirmed on URS/RNU histopathology. On multivariate logistic regression analysis, a presenting complaint of visible haematuria (hazard ratio [HR] 5.17, confidence interval [CI] 1.91-14.0; P = 0.001), a solid lesion reported on imaging (HR 37.8, CI = 11.7-122.1; P < 0.001) and a history of smoking (HR 3.07, CI 1.35-6.97; P = 0.007), were predictive of a final diagnosis of UTUC. From this cohort, 51 (96.2%) of 53 smokers who presented with visible haematuria and who had a solid lesion on computed tomography urogram had UTUC on final histopathology. CONCLUSION: We identified specific factors which may assist clinicians in selecting which patients may reliably proceed to RNU without the delay of diagnostic URS. These findings may inform a prospective multicentre analysis including additional variables such as urinary cytology.

Comparative evaluation of cell-mediated immune response in calves immunized with live-attenuated and killed Theileria annulata vaccines.

Tropical theileriosis is a tick-borne disease caused by the protozoan Theileria annulata and transmitted by numerous species of Ixodid ticks of the genus Hyalomma. The main clinical signs are fever, lymphadenopathy, and anemia responsible for heavy economic losses, including mortality, morbidity, vaccination failure, and treatment cost. Development of poor cell-mediated immunity (CMI) has been observed in the case of many bovine pathogens (bacteria, viruses, and parasites). Quantification of CMI is a prerequisite for evaluating vaccine efficacy against theileriosis caused by T. annulata. The current study evaluated the CMI in calves administered with two types of T. annulata vaccine (live attenuated and killed). We prepared a live attenuated T. annulata vaccine by attenuation in a rabbit model and also prepared killed vaccine from non-attenuated T. annulata. For the evaluation of immune response in experimental groups including control, 20 calves were divided into four different groups (A, B, C, and D). They were either inoculated subcutaneously with live rabbit-propagated-Theileria-infected RBCs (5 × 106) (group A) or with killed T. annulata vaccine (2 × 109 schizonts) with Freund's adjuvant (group B), along with an infected group (group C) and a healthy control group (group D). The protection of vaccinated calves was estimated with challenge infection. Our results showed that with a single shot of live-attenuated and killed vaccine with a booster dose elicited cell-mediated immune responses in immunized calves. We observed a significant elevation in CD4 + and CD8 + T cells in immunized calves. A significant difference in the CD8 + T cell response between the post-challenge stage of killed and live vaccine (p < 0.0001) was observed, whereas no other difference was found at both pre- and post-immunization stages. A similar finding was recorded for the CD4 + T cells at a post-challenge stage, where a significant difference was seen between killed and live vaccine (p < 0.0001). Another significant difference was observed between the CD8 + T cells and CD4 + T cells at the post-challenge stage in the live vaccine group, where there was a significantly higher induction of CD4 + T cell response (p < 0.0001).

Ion homeostasis in differently adapted populations of Suaeda vera Forssk. ex J.F. Gmel. for phytoremediation of hypersaline soils.

Salt-accumulator species are of great interest for the phytoremediation of salt-affected soils to reclaim soil salinization, a major constraints causing germination retardation and growth restriction of plants as well as habitat degradation. Higher biomass production at ECe 23-36 dS m-1 indicated that this species grows better in high to moderate salinity that was linked to osmotic adjustment through higher ion accumulation (Na+, Cl‒, and Ca2+) and organic osmolytes (free amino acids and proline). Plants from highly and moderately saline habitats exhibited broader metaxylem vessels, which was associated with eased conduction of solutes leading to better growth. Leaf anatomical characteristics generally increased with increasing salinity except at the highest ECe 55 dS m-1. The increased leaf lamina thickness contributed to succulence because of increased storage parenchymatous spongy tissues (that can store high amounts of water), water contents and it is a reflection of maintaining ion homeostasis and colonizing hyper-saline soil. Reduced stomatal density and area under high salinity are critical to cope with environmental hazards. Under high salinity, compartmentalization of excessive Na+ and Cl- ions and accumulation of compatible osmolytes are directly related to high degree of salinity tolerance, and hence are useful for phyto-amelioration of salinity-impacted lands.

Salinity tolerance mechanism in Suaeda vera have been explored extensively, but these mechanisms have not been addressed in the context of soil-plant interaction and functioning connection between structural and functional features with respect to phytoremediation. This work aims to provide mechanistic insight into how different morphological and physio-anatomical mechanisms in differently adapted population of Suaeda vera operate in coordinated manner to maintain ionic homeostasis under high salinity that are useful for phytoremediation.

Structural determinants of phytoremediation capacity in saltmarsh halophyte Diplachne fusca (L.) P. Beauv. ex Roem. & Schult. subsp. fusca.

Micro and macro-morphological features contribute to plants' tolerance to a variety of environmental pollutants. The contribution of such structural modifications in the phytoremediation potential of Diplachne fusca populations collected from five saline habitats were explored when treated with 100 to 400 mM NaCl for 75 days along with control. Structural modifications in the populations from the highest salinity included development of aerenchyma in stem instead of chlorenchyma, absence of excretory hairs in stem, and exceptionally large trichomes on the leaf surface to help excretion of excess salt. Large parenchyma cells provided more space for water and solute storage, while broad metaxylem vessels were linked to better conduction water and nutrients, which ultimately excreted via glandular hairs, microhairs, and vesicular hairs. Broad metaxylem vessels and exceptionally long hairs observed in the populations collected from 52 dS m-1. In conclusion, large stem aerenchyma, exceptionally large trichomes on the leaf surface, and tightly packed outer cortical region in roots with intensive sclerification just inside the epidermis accompanied with salt excretion via glandular hairs, microhairs, and vesicular hairs were the main anatomical modifications involved in the phytoremediation potential of D. fusca in hyper-saline environments.

Morpho-anatomical characteristics of the differently adapted populations of Diplachne fusca has never been reported. In particular, structural variation in their mechanism of adaptation for salinity tolerance was investigated for the first time in current study.

Removal of pharmaceutically active compounds from water sources using nanofiltration and reverse osmosis membranes: Comparison of removal efficiencies and in-depth analysis of rejection mechanisms.

Trace organic compounds from effluent streams are not completely removed by conventional purification techniques and hence, contaminating groundwater sources. Herein, we report the removal efficiency and rejection mechanisms of three common pharmaceutically active compounds (PhACs); caffeine (CFN), omeprazole (OMZ), and sulfamethoxazole (SMX), using commercial nanofiltration (NF) and reverse osmosis (RO) membranes with different surface characteristics. The RO membranes showed near-complete removal of all PhACs with rejection rates >99%. On the other hand, retention capabilities for the NF membranes varied and were influenced by the characteristics of the PhACs, membranes, and the feed solution. In general, during long-term testing, the rejection did not show much variation and followed a trend compatible with the size exclusion (steric hindrance) mechanism. When a real matrix was used, the rejection of CFN by the more tight NF membranes, HL TFC and NFW decreased by ∼10%, whereas the removal of SMX by the loose NF membrane, XN45, increased by the same ratio. In short-term testing, the rejection of negatively charged SMX increased significantly (∼20-40%) at a higher pH of ∼8 and in the presence of salts. Fouling by the PhACs was more severe on the high-flux NF membranes, HL TFC and XN45, as witnessed by the significant change in Contact angle (CA) values (∼25-50°) as well as the flux decline (∼15%) during long-term testing. To summarize, the removal of PhACs by membranes is a complex phenomenon and depends upon a combination of several factors.

Resveratrol Mitigates Bisphenol A-Induced Metabolic Disruptions: Insights from Experimental Studies.

The aim of this study was to investigate the disruptions of metabolic pathways induced by bisphenol A (BPA) and explore the potential therapeutic intervention provided by resveratrol (RSV) in mitigating these disruptions through the modulation of biochemical pathways. Wistar albino rats were divided into three groups: group 1 served as the control, group 2 received 70 mg/Kg of BPA, and group 3 received 70 mg/kg of BPA along with 100 mg/Kg of RSV. After the treatment period, various biomarkers and gene expressions were measured to assess the effects of BPA and the potential protective effects of RSV. The results revealed that BPA exposure significantly increased the serum levels of α-amylase, α-glucosidase, G6PC, insulin, HbA1c, HMG-CoA reductase, FFAs, TGs, DPP-4, MDA, and proinflammatory cytokines such as TNF-α and IL-6. Concurrently, BPA exposure led to a reduction in the levels of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), as well as GLUT4 and HDL cholesterol. However, the administration of RSV along with BPA significantly ameliorated these alterations in the biomarker levels induced through BPA exposure. RSV treatment effectively reduced the elevated levels of α-amylase, α-glucosidase, G6PC, insulin, HbA1c, HMG-CoA reductase, FFAs, TGs, DPP-4, MDA, and proinflammatory cytokines, while increasing the levels of antioxidant enzymes, GLUT4, and HDL cholesterol. Furthermore, BPA exposure suppressed the mRNA expression of glucokinase (GCK), insulin-like growth factor 1 (IGF-1), and glucose transporter 2 (GLUT2) and up-regulated the mRNA expression of uncoupling protein 2 (UCP2), which are all critical biomarkers involved in glucose metabolism and insulin regulation. In contrast, RSV treatment effectively restored the altered mRNA expressions of these biomarkers, indicating its potential to modulate transcriptional pathways and restore normal metabolic function. In conclusion, the findings of this study strongly suggest that RSV holds promise as a therapeutic intervention for BPA-induced metabolic disorders. By mitigating the disruptions in various metabolic pathways and modulating gene expressions related to glucose metabolism and insulin regulation, RSV shows potential in restoring normal metabolic function and counteracting the adverse effects induced by BPA exposure. However, further research is necessary to fully understand the underlying mechanisms and optimize the dosage and duration of RSV treatment for maximum therapeutic benefits.

Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling.

PURPOSE: LEF1 encodes a transcription factor acting downstream of the WNT-ß-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 variants. METHODS: High-throughput sequencing was employed to delineate the genetic underpinnings of the disease. Cellular consequences were characterized by immunofluorescence, immunoblotting, pulldown assays, and/or RNA sequencing. RESULTS: Monoallelic variants in LEF1 were detected in 11 affected individuals from 4 unrelated families, and a biallelic variant was detected in an affected individual from a consanguineous family. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Depending on the type and location of LEF1 variants, the inheritance of this novel Mendelian condition can be either autosomal dominant or recessive. Our functional data indicate that 2 molecular mechanisms are at play: haploinsufficiency or loss of DNA binding are responsible for a mild to moderate phenotype, whereas loss of ß-catenin binding caused by biallelic variants is associated with a severe phenotype. Transcriptomic studies reveal an alteration of WNT signaling. CONCLUSION: Our findings establish mono- and biallelic variants in LEF1 as a cause for a novel syndrome comprising limb malformations and ectodermal dysplasia.

A novel missense variant of SCN4A co-segregates with congenital essential tremor in a consanguineous Kurdish family.

Essential tremor (ET) is a neurological disorder characterized by bilateral and symmetric postural, isometric, and kinetic tremors of forelimbs produced during voluntary movements. To date, only a single SCN4A variant has been suggested to cause ET. In continuation of the previous report on the association between SCN4A and ET in a family from Spain, we validated the pathogenicity of a novel SCN4A variant and its involvement in ET in a second family affected by this disease. We recruited a Kurdish family with four affected members manifesting congenital tremor. Using whole-exome sequencing, we identified a novel missense variant in SCN4A, NM_000334.4:c.4679C>T; p.(Pro1560Leu), thus corroborating SCN4A's role in ET. The residue is highly conserved across vertebrates and the substitution is predicted to be pathogenic by various in silico tools. Western blotting and immunocytochemistry performed in cells derived from one of the patients showed reduced immunoreactivity of SCN4A as compared to control cells. The study provides supportive evidence for the role of SCN4A in the etiology of ET and expands the phenotypic spectrum of channelopathies to this neurological disorder.

Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease.

Type 2 diabetes mellitus and Alzheimer's disease (AD), both are chronic and progressive diseases. Many cardiovascular and genetic risk factors are considered responsible for the development of AD and diabetes mellitus (DM). Genetic risk factor such as apolipoprotein E (APOE) plays a critical role in the progression of AD. Specifically, APOEε4 is genetically the strongest isoform associated with neuronal insulin deficiency, altered lipid homeostasis, and metabolism, decreased glucose uptake, impaired gray matter volume, and cerebrovascular functions. In this article, we have summarized the mechanisms of cardiovascular disturbances associated with AD and DM, impact of amyloid-ß aggregation, and neurofibrillary tangles formation in AD. Moreover, cardiovascular risk factors leading to insulin resistance (IR) and amyloid-ß aggregation are highlighted along with the effects of APOE risk alleles on cerebral, lipid, and cholesterol metabolism leading to CVD-mediated IR. Correspondingly, the contribution of IR, genetic and cardiovascular risk factors in amyloid-ß aggregation, which may lead to the late onset of AD and DM, has been also discussed. In short, IR is related to significantly lower cerebral glucose metabolism, which sequentially forecasts poorer memory performance. Hence, there will be more chances for neural glucose intolerance and impairment of cognitive function in cardiac patients, particularly APOEε4 carriers having IR. Hence, this review provides a better understanding of the corresponding crosstalk among different pathways. This will help to investigate the rational application of preventive measures against IR and cognitive dysfunction, specifically in APOEε4 carriers' cardio-metabolic patients.

Versatile role of sirtuins in metabolic disorders: From modulation of mitochondrial function to therapeutic interventions.

Sirtuins (SIRT1-7) are distinct histone deacetylases (HDACs) whose activity is determined by cellular metabolic status andnicotinamide adenine dinucleotide (NAD+ ) levels. HDACs of class III are the members of the SIRT's protein family. SIRTs are the enzymes that modulate mitochondrial activity and energy metabolism. SIRTs have been linked to a number of clinical and physiological operations, such as energy responses to low-calorie availability, aging, stress resistance, inflammation, and apoptosis. Mammalian SIRT2 orthologs have been identified as SIRT1-7 that are found in several subcellular sections, including the cytoplasm (SIRT1, 2), mitochondrial matrix (SIRT3, 4, 5), and the core (SIRT1, 2, 6, 7). For their deacetylase or ADP-ribosyl transferase action, all SIRTs require NAD+ and are linked to cellular energy levels. Evolutionarily, SIRT1 is related to yeast's SIRT2 as well as received primary attention in the circulatory system. An endogenous protein, SIRT1 is involved in the development of heart failure and plays a key role in cell death and survival. SIRT2 downregulation protects against ischemic-reperfusion damage. Increase in human longevity is caused by an increase in SIRT3 expression. Cardiomyocytes are also protected by SIRT3 from oxidative damage and aging, as well as suppressing cardiac hypertrophy. SIRT4 and SIRT5 perform their roles in the heart. SIRT6 has also been linked to a reduction in heart hypertrophy. SIRT7 is known to be involved in the regulation of stress responses and apoptosis in the heart.

Blockchain-Based Smart Home Networks Security Empowered with Fused Machine Learning.

Security and privacy in the Internet of Things (IoT) other significant challenges, primarily because of the vast scale and deployment of IoT networks. Blockchain-based solutions support decentralized protection and privacy. In this study, a private blockchain-based smart home network architecture for estimating intrusion detection empowered with a Fused Real-Time Sequential Deep Extreme Learning Machine (RTS-DELM) system model is proposed. This study investigates the methodology of RTS-DELM implemented in blockchain-based smart homes to detect any malicious activity. The approach of data fusion and the decision level fusion technique are also implemented to achieve enhanced accuracy. This study examines the numerous key components and features of the smart home network framework more extensively. The Fused RTS-DELM technique achieves a very significant level of stability with a low error rate for any intrusion activity in smart home networks. The simulation findings indicate that this suggested technique successfully optimizes smart home networks for monitoring and detecting harmful or intrusive activities.

Impact of Gamma Irradiation and Kale Leaf Powder on Amino Acid and Fatty Acid Profiles of Chicken Meat under Different Storage Intervals.

The present study was planned to determine the effect of kale leaf powder and gamma rays on variations in the pH, amino acid and fatty acid profiles of chicken meat at different storage intervals. Significant changes (p ≤ 0.05) in the pH, amino acid and fatty acid profiles of chicken meat following different treatments (KLP (1% and 2%) and gamma irradiation (3k Gy)) were reported at 0, 7 and 14 days of storage. The pH value of the chicken meat sample decreased with the addition of kale leaf powder, whereas the value increased following a gamma irradiation dose of 3 kGy and with the passage of time. During different storage intervals, the minimum reduction in the amino acid and fatty acid quantities in the chicken meat samples was reported after gamma irradiation treatment. However, with the addition of KLP, the amount of amino acids and fatty acids in the chicken meat samples increased. Conclusively, the pH was observed to be reduced in the meat following combined treatment (irradiation + KLP), whereas the 2% KLP treatment improved the amino acid and fatty acid profiles of the chicken samples.

Effect of Antimicrobial and Antioxidant Rich Pomegranate Peel Based Edible Coatings on Quality and Functional Properties of Chicken Nuggets.

The current study evaluated the effect of pomegranate peel-based edible coating on chicken nuggets in order to develop a functional and safe product, high in nutritional value. For this purpose, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and total phenolic content (TPC) assays were performed to check the potential antioxidant activity of chicken nuggets; microbial control, including total aerobic count and coliforms population, was performed for quality and safety purposes; and thiobarbituric acid reactive substances (TBARS) and peroxide value (POV) were performed to determine the oxidative stability of chicken nuggets. Different treatments were applied at different storage periods (0th, 7th, 14th and 21st day). The higher value of total aerobic count (5.09 ± 0.05 log CFU/g) and coliforms (3.91 ± 0.06 log CFU/g) were obtained for the uncoated samples, while the lower population was enumerated in the combination of sodium alginate (SA) and pomegranate peel powder (PPP). However, DPPH (64.65 ± 2.15%) and TPC (135.66 ± 3.07 GAE/100 g) values were higher in the coated chicken nuggets (SA (1.5%) and PPP (1.5%)) and lowest in the control samples. The higher value of TBARS (1.62 ± 0.03 MDA/kg) and POV (0.92 ± 0.03 meq peroxide/kg) were observed in the uncoated chicken nuggets. In the Hunter color system, L*, a*, and b* peak values were determined in the coated chicken nuggets with SA (1.5%) + PPP (1.5%) at the 21st day of storage. The uncoated chicken nuggets had different sensory characteristics (appearance, color, taste, texture, and overall acceptability) compared to the coated samples. Conclusively, coating based on the combination of SA (1.5%) and PPP (1.5%) increased the quality, safety, and nutritional properties of chicken nuggets.

Comprehensive Phytochemical Profiling, Biological Activities, and Molecular Docking Studies of Pleurospermum candollei: An Insight into Potential for Natural Products Development.

The purpose of this study was to find the biological propensities of the vegetable plant Pleurospermum candollei by investigating its phytochemical profile and biological activities. Phytochemical analysis was done by spectroscopic methods to investigate the amount of total polyphenols, and biological evaluation was done by the different antioxidant, enzyme inhibitory (tyrosinase, α-amylase, and α-glucosidase), thrombolytic, and antibacterial activities. The highest amount of total phenolic and flavonoid contents was observed in methanolic extract (240.69 ± 2.94 mg GAE/g and 167.59 ± 3.47 mg QE/g); the fractions showed comparatively less quantity (57.02 ± 1.31 to 144.02 ± 2.11 mg GAE/g, and 48.21 ± 0.75 to 96.58 ± 2.30 mg QE/g). The effect of these bioactive contents was also related to biological activities. GCMS analysis led to the identification of bioactive compounds with different biological effects from methanolic extract (antioxidant; 55.07%, antimicrobial; 56.41%), while the identified compounds from the n-hexane fraction with antioxidant properties constituted 67.86%, and those with antimicrobial effects constituted 82.95%; however, the synergetic effect of polyphenols may also have contributed to the highest value of biological activities of methanolic extract. Molecular docking was also performed to understand the relationship of identified secondary metabolites with enzyme-inhibitory activities. The thrombolytic activity was also significant (40.18 ± 1.80 to 57.15 ± 1.10 % clot lysis) in comparison with streptokinase (78.5 ± 1.53 to 82.34 ± 1.25% clot lysis). Methanolic extract also showed good activity against Gram-positive strains of bacteria, and the highest activity was observed against Bacillus subtilis. The findings of this study will improve our knowledge of phytochemistry, and biological activities of P. candollei, which seems to be a ray of hope to design formulations of natural products for the improvement of health and prevention of chronic diseases; however, further research may address the development of novel drugs for use in pharmaceuticals.