Clinical and genetic investigation of 14 families with various forms of short stature syndromes.

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population.

Calcium Channel Inhibitory Effect of Marjoram (Origanum majorana L.): Its Medicinal Use in Diarrhea and Gut Hyperactivity.

BACKGROUND: The leaves of Origanum majorana (O. majorana) are traditionally renowned for treating diarrhea and gut spasms. This study was therefore planned to evaluate its methanolic extract. METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to identify the phytochemicals, and Swiss albino mice were used for an in vivo antidiarrheal assay. Isolated rat ileum was used as an ex vivo assay model to study the possible antispasmodic effect and its mechanism(s). RESULTS: The GC-MS analysis of O. majorana detected the presence of 21 compounds, of which alpha-terpineol was a major constituent. In the antidiarrheal experiment, O. majorana showed a substantial inhibitory effect on diarrheal episodes in mice at an oral dosage of 200 mg/kg, resulting in 40% protection. Furthermore, an oral dosage of 400 mg/kg provided even greater protection, with 80% effectiveness. Similarly, loperamide showed 100% protection at oral doses of 10 mg/kg. O. majorana caused complete inhibition of carbachol (CCh, 1 µM) and high K+ (80 mM)-evoked spasms in isolated ileal tissues by expressing significantly higher potency (p < 0.05) against high K+ compared to CCh, similar to verapamil, a Ca++ antagonist. The verapamil-like predominant Ca++ ion inhibitory action of O. majorana was further confirmed in the ileal tissues that were made Ca++-free by incubating the tissues in a physiological salt solution having ethylenediaminetetraacetic acid (EDTA) as a chelating agent. The preincubation of O. majorana at increasing concentrations (0.3 and 1 mg/mL) shifted towards the right of the CaCl2-mediated concentration-response curves (CRCs) with suppression of the maximum contraction. Similarly, verapamil also caused non-specific suppression of Ca++ CRCs towards the right, as expected. CONCLUSIONS: Thus, this study conducted an analysis to determine the chemical constituents of the leaf extract of O. majorana and provided a detailed mechanistic basis for the medicinal use of O. majorana in hyperactive gut motility disorders.

Pharmacological Basis for the Antidiarrheal and Antispasmodic Effects of Cuminaldehyde in Experimental Animals: In Silico, Ex Vivo and In Vivo Studies.

BACKGROUND: Medicinal herbs are frequently used for the management of gastrointestinal disorders because they contain various compounds that can potentially amplify the intended therapeutic effects. Cuminaldehyde is a plant-based constituent found in oils derived from botanicals such as cumin, eucalyptus, myrrh, and cassia and is responsible for its health benefits. Despite the utilization of cuminaldehyde for several medicinal properties, there is currently insufficient scientific evidence to support its effectiveness in treating diarrhea. Hence, the present investigation was carried out to evaluate the antidiarrheal and antispasmodic efficacy of cuminaldehyde, with detailed pharmacodynamics explored. METHODS: An in vivo antidiarrheal test was conducted in mice following the castor oil-induced diarrhea model, while an isolated small intestine obtained from rats was used to evaluate the detailed mechanism(s) of antispasmodic effects. RESULTS: Cuminaldehyde, at 10 and 20 mg/kg, exhibited 60 and 80% protection in mice from episodic diarrhea compared to the saline control group, whereas this inhibitory effect was significantly reversed in the pretreated mice with glibenclamide, similar to cromakalim, an ATP-dependent K+ channel opener. In the ex vivo experiments conducted in isolated rat tissues, cuminaldehyde reversed the glibenclamide-sensitive low K+ (25 mM)-mediated contractions at significantly higher potency compared to its inhibitory effect against high K+ (80 mM), thus showing predominant involvement of ATP-dependent K+ activation followed by Ca++ channel inhibition. Cromakalim, a standard drug, selectively suppressed the glibenclamide-sensitive low K+-induced contractions, whereas no relaxation was observed against high K+, as expected. Verapamil, a Ca++ channel inhibitor, effectively suppressed both low and high K+-induced contractions with similar potency, as anticipated. At higher concentrations, the inhibitory effect of cuminaldehyde against Ca++ channels was further confirmed when the preincubated ileum tissues with cuminaldehyde (3 and 10 mM) in Ca++ free medium shifted CaCl2-mediated concentration-response curves (CRCs) towards the right with suppression of the maximum peaks, similar to verapamil, a standard Ca++ ion inhibitor. CONCLUSIONS: Present findings support the antidiarrheal and antispasmodic potential of cuminaldehyde, possibly by the predominant activation of ATP-dependent K+ channels followed by voltage-gated Ca++ inhibition. However, further in-depth assays are recommended to know the precise mechanism and to elucidate additional unexplored mechanism(s) if involved.

Predictive insights into plant-based compounds as fibroblast growth factor receptor 1 inhibitors: a combined molecular docking and dynamics simulation study.

The discovery of novel therapeutic agents with potent anticancer activity remains a critical challenge in drug development. Natural products, particularly bioactive phytoconstituents derived from plants, have emerged as promising sources for anticancer drug discovery. In this study, we used virtual screening techniques to explore the potential of bioactive phytoconstituents as inhibitors of fibroblast growth factor receptor 1 (FGFR1), a key signaling protein implicated in cancer progression. We used virtual screening techniques to analyze phytoconstituents extracted from the IMPPAT 2.0 database. Our primary objective was to discover promising inhibitors of FGFR1. To ensure the selection of promising candidates, we initially filtered the molecules based on their physicochemical properties. Subsequently, we performed binding affinity calculations, PAINS, ADMET, and PASS filters to identify nontoxic and highly effective hits. Through this screening process, one phytocompound, namely Mundulone, emerged as a potential lead. This compound demonstrated an appreciable affinity for FGFR1 and exhibited specific interactions with the ATP-binding site residues. To gain further insights into the conformational dynamics of Mundulone and the reference FGFR1 inhibitor, Lenvatinib, we conducted time-evolution analyses employing 200 ns molecular dynamics simulations (MDS) and essential dynamics. These analyses provided valuable information regarding the dynamic behavior and stability of the compounds in complexes with FGFR1. Overall, the findings indicate that Mundulone exhibits promising binding affinity, specific interactions, and favorable drug profiles, making it a promising lead candidate. Further experimental analysis will be necessary to confirm its effectiveness and safety profiles for therapeutic advancement in the cancer field.Communicated by Ramaswamy H. Sarma.

Exploring progress in iron supplement formulation approaches for treating iron deficiency anemia through bibliometric and thematic analysis.

Anemia is a severe health issue that affects around one-third of the global population. Therefore, the present study aims to conduct a bibliometric analysis to investigate the research trends regarding advancements on iron formulations in treating iron deficiency anemia via oral or parenteral route. This study adopts thematic and bibliometric methods on existing research on novel iron formulations. It also provides perspective into the existing understanding on treatment strategies for iron deficiency anemia. This study is conducted on 543 papers on various ferrous and ferric formulations used in the treatment of iron deficiency anemia. The study period is from 1977 to 2022, and the papers are identified from the Scopus database. The bibliometric analysis was carried out using the R tool's Bibliometrix package. The study discusses performance analysis, including annual publications, geographic analysis, relevant affiliations, journal analysis, and citation analysis. In addition, the conceptual structure, including the co-occurrence network, thematic map, thematic evolution, intellectual structure highlighting co-citation analysis, and social structure depicting the collaboration network and collaboration world map, are presented. The results showed increased research on formulation strategies for the treatment of iron deficiency anemia from 2010 onwards. The top 5 contributing countries are the USA, Italy, India, Germany, and the UK, and peer-reviewed journals from the area of nutrition. The most trending areas of study are iron deficiency anemia in pregnancy, chronic kidney diseases, inflammatory bowel diseases, and various intravenous formulations used in its treatment. The authors from Europe collaborate the most with authors from other countries. The study concludes that a safer and more effective iron formulation is needed to reduce the prevalence of anemia. The findings of the study are helpful in advancing research on innovative formulations for treating iron deficiency anemia. The insights from the study are helpful to policymakers in designing specific health policies and investing more in research and development of novel formulations for the treatment of iron deficiency anemia.

Spectrum of infections in different regimens of post-induction chemotherapy in acute myeloid leukemia (de-novo): A comparative retrospective study.

Background: Patients diagnosed with acute myeloid leukemia (AML) face a heightened susceptibility to infections, which significantly elevates their risk of mortality and disability. The intensity of the chemotherapy treatment and its specific focus on inhibiting myeloid cell divisions render patients especially vulnerable, particularly during the early stages of chemotherapy. This vulnerability is compounded by the occurrence of repeated episodes of prolonged neutropenia, leaving patients highly susceptible to infections. The compromised immune systems of these individuals make them more susceptible to infections, which adversely affect their physical health and overall well-being. Consequently, our study aimed to investigate the range of infections experienced by patients with newly diagnosed AML undergoing different induction chemotherapy. Methods: This was a comparative retrospective study, conducted at a tertiary hospital providing comprehensive cancer care in North India. All newly diagnosed patients with AML, who received induction chemotherapy from January 1, 2012 to November 1, 2022, were identified from the hospital database and included in this study. Results: Four hundred and twenty AML patients treated with either high-intensity or low-intensity induction chemotherapy was observed in this study. It was found that patients who received high-intensity treatment had a higher rate of clinically and microbiologically documented infections, fever without a known cause, and more cases of febrile neutropenia than those who got low-intensity treatment. These differences between the two groups were particularly evident on day 14 (p = 0.0002) and persisted through day 28 (p = 0.005). Conclusions: These findings underscore the effectiveness and downside of high-intensity induction chemotherapy regimens, as evidenced by the higher incidence of infections observed. Further investigation through prospective clinical studies is warranted to better evaluate and validate the efficacy of this approach.

Management of triple-negative breast cancer by natural compounds through different mechanistic pathways.

Triple-negative breast cancer (TNBC) is the most severe form of breast cancer, characterized by the loss of estrogen, progesterone, and human epidermal growth factor receptors. It is caused by various genetic and epigenetic factors, resulting in poor prognosis. Epigenetic changes, such as DNA methylation and histone modification, are the leading mechanisms responsible for TNBC progression and metastasis. This review comprehensively covers the various subtypes of TNBC and their epigenetic causes. In addition, the genetic association of TNBC with all significant genes and signaling pathways linked to the progression of this form of cancer has been enlisted. Furthermore, the possible uses of natural compounds through different mechanistic pathways have also been discussed in detail for the successful management of TNBC.

Novel pathogenic variants in HR underlie atrichia with papular lesions in a cohort of 10 families.

Atrichia with papular lesions (APL) is a hair abnormality characterized by loss of hair on the scalp and rest of the body. In a few cases, hair loss is accompanied by the appearance of keratotic papules on the body. It is inherited in an autosomal recessive manner. Sequence variants in the HR (hairless) gene are responsible for this hair abnormality. Here, we present nine consanguineous families and one nonconsanguineous family with clinical manifestations of APL. Whole exome followed by Sanger sequencing and/or direct Sanger sequencing was performed to identify pathogenic variants. The study revealed seven novel pathogenic variants c.794del;p.(Pro265Argfs*98), c.2921-2936del;p.(Tyr974Leufs*16), c.2889C>A;p.(Cys963*), c.2689C>T;p.(Gln897*), c.3186_3187dup;p.(Gln1063Profs*43), c.560dup;p.(Tyr188Ilefs*131), c.2203+5G>C, c.2776+5G>A, and the previously reported variant c.1837C>T;p.(Arg613*) in HR in these families. The study not only expands the mutational spectrum in the HR gene but also highlights the unusual phenotypic findings and will facilitate genetic counseling of families with members showing various types of hair loss disorders in the local population.

New nematode Tahaminaindica gen. nov., sp. nov. (Nematoda, Dorylaimida, Tylencholaimoidea) from the tropical rainforest, Western Ghats.

During a nematological survey in the Western Ghats a new nematode belonging to the superfamily Tylencholaimoida (Dorylaimida) extracted from the rhizosphere of the soil of grasses, is described and illustrated. Tahaminaindicagen. nov., sp. nov. is characterized by females with a body length of 1.3-1.4 mm; lip region 8.0 µm wide, approximately one-fourth of the body diameter at the pharyngeal base; amphidial fovea cup-shaped, about one-half as wide as the lip region diameter. Odontostyle 8.0-9.0 µm long, 1.0-1.1 times lip region diameter; guiding ring simple; odontophore rod-like, 10.5-11.5 µm long with basal thickening or minute knobs-like structure; pharynx consisting of a weakly muscular anterior part, expanding abruptly into a cylindrical basal bulb, occupying about two-fifths to one-half of the total pharyngeal length; female genital system monodelphic-opisthodelphic with anterior uterine sac; vulval opening pore-like, and tail elongated with a slight dorsally curved tip. Males not found.

Integration of federated learning with IoT for smart cities applications, challenges, and solutions.

In the past few years, privacy concerns have grown, making the financial models of businesses more vulnerable to attack. In many cases, it is hard to emphasize the importance of monitoring things in real-time with data from Internet of Things (IoT) devices. The people who make the IoT devices and those who use them face big problems when they try to use Artificial Intelligence (AI) techniques in real-world applications, where data must be collected and processed at a central location. Federated learning (FL) has made a decentralized, cooperative AI system that can be used by many IoT apps that use AI. It is possible because it can train AI on IoT devices that are spread out and do not need to share data. FL allows local models to be trained on local data and share their knowledge to improve a global model. Also, shared learning allows models from all over the world to be trained using data from all over the world. This article looks at the IoT in all of its forms, including "smart" businesses, "smart" cities, "smart" transportation, and "smart" healthcare. This study looks at the safety problems that the federated learning with IoT (FL-IoT) area has brought to market. This research is needed to explore because federated learning is a new technique, and a small amount of work is done on challenges faced during integration with IoT. This research also helps in the real world in such applications where encrypted data must be sent from one place to another. Researchers and graduate students are the audience of our article.

Phytochemicals as potential inhibitors of interleukin-8 for anticancer therapy: in silico evaluation and molecular dynamics analysis.

Within the realm of soluble factors that have emerged as potential targets for therapeutic intervention, the chemokine interleukin-8 (IL-8) has garnered attention as a potential contributor to treatment responses in various cancer types. The utilization of naturally occurring anticancer compounds for treating cancer patients has shown substantial advancements in survival rates across early and advanced stages of the disease. In silico research findings provide support for the application of phytochemicals as potential inhibitors of IL-8, and phytochemicals exhibiting a high binding free energy and crucial interactions display promising anticancer properties, positioning them as candidates for future drug development. Noteworthy phytochemicals such as IMPHY006634 (Isohydnocarpin), IMPHY007957 (Chitranone) and IMPHY013015 (1-Hydroxyrutaecarpine) were predicted to possess inhibitory activity against IL-8, with calculated energies ranging from -9.9 to -9.1 kcal/mol, respectively. Several hydrogen bonds, including common amino acid residues Lys9 and CYS48, were identified. Molecular dynamics calculations conducted on these potent inhibitors demonstrated their stability throughout a 200 ns simulation, as indicated by metrics such as RMSD, RMSF, Rg, SASA, H-bonds, PCA and FEL analysis. Moreover, PASS analysis and adherence of these natural compounds to drug-likeness rules like Lipinski's further strengthen their candidacy. Considering these calculations and various parameters, these three prominent natural compounds emerge as promising candidates for anti-IL-8 therapy in the management of cancer.Communicated by Ramaswamy H. Sarma.

A novel homozygous nonsense mutation in NECTIN4 gene in a Pakistani family with ectodermal dysplasia syndactyly syndrome 1

Abstract Background Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene. Objective The main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers. Methods In the present study, the authors have investigated a large consanguineous family of Pakistani origin segregating autosomal recessive EDSS1. All the coding exons of the NECTIN4 gene were directly sequenced using gene-specific primers. Results The affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. Sequence analysis of the coding region of the NECTIN4 identified a novel nonsense variant [c.163C>T; p.(Arg55*)] in exon-2 of the gene. Computational analysis of protein structure revealed that the variant induced premature termination at Arg55 located in Ig-like V-loop region leading to loss of Ig-C2 type domains and transmembrane region, and most likely Nectin-4 function will be lost. Study limitation Gene expression studies are absent that would have strengthened the findings of computational analysis. Conclusion The present study expanded the phenotypic and mutation spectrum of the NECTIN4 gene. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation

Abstract Split-hand/split-foot malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1-q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/foot malformation.