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In this study, we have identified multiple mutations in the IL-12R1 gene among Pakistani patients who have inherited them through consanguineous marriages. These patients have experienced severe Bacille-Calmette-Guérin (BCG) infection as well as recurrent tuberculosis. We will demonstrate the pivotal role of interleukin (IL)-12/interferon (IFN)-γ axis in the regulation of mycobacterial diseases. First, we checked the patients' medical records, and then afterward, we assessed interferon-gamma (IFN-γ) production through ELISA. Following that, DNA was extracted to investigate IL-12/IFN- abnormalities. Whole exome sequencing was conducted through Sanger sequencing. Secretory cytokine levels were compared from healthy control of the same age groups and they were found to be considerably less in the disease cohort. To evaluate the probable functional impact of these alterations, an in silico study was performed. The study found that the patients' PBMCs produced considerably less IFN-γ than expected. Analysis using flow cytometry showed that activated T cells lacked surface expression of IL-12Rβ1. Exon 7 of the IL-12Rβ1 gene, which encodes a portion of the cytokine binding region (CBR), and exon 10, which encodes the fibronectin-type III (FNIII) domain, were found to have the mutations c.641 A > G; p.Q214R and c.1094 T > C; p.M365T, respectively. In silico analysis showed that these mutations likely to have a deleterious effect on protein function. Our findings indicate the significant contribution of the IL-12/IFN-γ is in combating infections due to mycobacterium. Among Pakistani patients born to consanguineous marriages, the identified mutations in the IL-12Rβ-1 gene provide insights into the genetic basis of severe BCG infections and recurrent tuberculosis. The study highlights the potential utility of newborn screening in regions with mandatory BCG vaccination, enabling early detection and intervention for primary immunodeficiencies associated with mycobacterial infections. Moreover, the study suggests at the potential role of other related genes such as IL-23Rβ1, TYK2, or JAK2 in IFN-γ production, warranting further investigation. • Deleterious mutations in the IL-2Rβ-1gene among patients born to consanguineous marriages. • The study highlights the pivotal role of the interleukin (IL)-12/interferon (IFN)-γ axis in regulating mycobacterial diseases. • Secretory cytokine levels are compared with healthy controls of the same age group, revealing significant differences in the disease cohort. • Flow cytometry analysis reveals that activated T cells lack surface expression of IL-12Rβ1. • The study demonstrates application of these mutations to be screened in newborns. [ABSTRACT FROM AUTHOR]

Background: The IL-12/IFN-γ axis plays a vital role in the control of intramacrophagic pathogens including Leishmania infections. Objective: The aim of this study was to investigate genetic defects in the IL-12/IFN-γ axis in cutaneous leishmaniasis patients, using immunological and genetic evaluation. Methods: Enzyme-linked immunosorbent assay was used to quantify IFN-γ , while flow cytometry was performed to analyze surface IL-12Rβ1/IL-12Rβ2 expression and phosphorylation of signal transducers as well as the activator of transcription 4 (pSTAT4). Sequencing was carried out for genetic analysis. Results: The peripheral blood mononuclear cells from the two patients (P1 and P2) demonstrated impaired production of IFN-γ. Furthermore, abolishment of the surface expression of Il-12Rβ1 was observed in lymphocytes, with consequent impairment of STAT4 phosphorylation in the lymphocytes of P1 and P2. IL-12Rβ1 deficiency was identified, which was caused by a novel homozygous missense mutation (c.485>T/p.P162L) and a novel homozygous nonsense mutation (c.805G>T/P.E269*) in the IL-12R β 2 gene of P1 and P2, respectively. In silico analyses predicted these novel mutations as being pathogenic, causing truncated proteins, with consequent inactivation. Conclusion: Our data have expanded the phenotype and mutation spectra associated with IL-12Rβ1 deficiency, and suggest that patients with CL should be screened for mutations in genes of the IL-12/IFN-γ axis. [ABSTRACT FROM AUTHOR]

There is evidence for a dramatic relationship between depression and alcohol consumption. Depressed patients may abuse ethanol because this agent reduces the symptoms of depression. In the current study, we aimed to investigate the NMDA/nitric oxide/cGMP pathway in the antidepressant-like effect of ethanol in an animal model of behavioral despair. Animals were subjected to locomotor activity in an open-field test separately, followed by a forced swimming test. During the forced swimming test (FST), ethanol (2 and 2.5 g/kg) significantly decreased the immobility time without altering the locomotor activity of animals. The antidepressant-like effect of ethanol (2.5 g/kg) was reversed by co-administration of N-methyl-D-aspartate (NMDA, 75 mg/kg), L-arginine (750 mg/kg), or sildenafil (5 mg/kg). In contrast, co-administration of MK-801 (0.05 mg/kg), ketamine (1 mg/kg), and ifenprodil (0.5 mg/kg) as antagonists of NMDAR, and NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), 7-nitroindazole (7-NI, 30 mg/kg), and methylene blue (10 mg/kg) as inhibitors of nitric oxide synthase (NOS), or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (20 mg/kg), a nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) inhibitor, with a subeffective dose of ethanol (1.5 g/kg), significantly decreased the immobility time in the FST. Furthermore, injection of ethanol 2.5 g/kg alone or 1.5 g/kg with a 7-NI subeffective dose, significantly decreased the nitrite levels in the hippocampus and prefrontal cortex. Hence, it is concluded that blockade of NMDA receptors and the nitric oxide/cyclic-guanosine monophosphate (NO-cGMP) pathway might be involved in the antidepressant-like effect of ethanol in mice. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance In remote areas, medicinal plants have an imperative role in curing various livestock's ailments. In Pakistan, people residing in remote areas including South Waziristan Agency and Bajaur Agency depend on traditional herbal remedies for treating their domestic animals. Medicinal plants are an important part of the medical system in these Agencies. The prime goal of the current study is to explore the ethnoveterinary practices in the two regions and discuss cross-cultural consensus on the use of medicinal plants. In this study, we have given detailed description on the ethnoveterinary usage of certain medicinal plants and their recipes. Moreover, we have also elaborated the ethnoveterinary potential of certain plants in relation to their ethnomedicinal, pharmacological and phytochemicals reports. Methodology Fieldwork comprised of two fields surveys conducted at South Waziristan Agency and Bajaur Agency. A total of 75 informants from South Waziristan Agency and 80 informants from Bajaur Agency were interviewed with the help of semi-structured questionnaires. Use reports (URs) were recorded for all the documented taxa. Data were quantitatively analyzed by using informant consensus factor (F ic ) index in order to find out information homogeneity provided by the informants. To analyze the cross-cultural consensus, the recorded data were tabulated as well as shown by Venn diagram. Results Overall, 94 medicinal plant taxa were recorded in the comparative analysis. Out of these, most of the plants species (72 species) were used at Bajaur Agency than South Waziristan Agency (37 species). Cross-cultural analysis showed that only 15 medicinal plants were used in common by the indigenous communities in both Agencies, which indicates a low interregional consensus with regard to the ethnoveterinary practices of medicinal plants. Apiaceae was the dominant family in both regions by representing maximum number of plant species (11 species). Gastro intestinal complexities were common in both regions having higher F ic values (above 90). Moreover, the current investigation reported new ethnoveterinary uses of medicinal plants from South Waziristan Agency, which were Sideroxylon mascatense, Raphanus sativus, Salix babylonica, Solanum nigrum, Sophora mollis, Taraxacum campylodes and Tulipa stellata . On the other hand from Bajaur Agency, Boerhavia erecta, Celtis australis , Chamaecyparis obtusa var. obtuse , Eryngium biehersteinianum , Gossypium arboreum , Narcissus tazetta , Opuntia littoralis , Streblus asper were reported with new ethnoveterinary uses. Conclusions The current study has an important contribution towards the preservation of indigenous plants’ based knowledge. Several plants are carrying important ethnoveterinary uses being practiced by the local people mostly against the gastrointestinal disorders in both regions. Importantly, the cross-cultural approach has reported some new traditional uses of plants against livestock's diseases. Hence, this is an opportunity to investigate such plants phytopharmacologically and toxicologically for the discovery of new drug sources. [ABSTRACT FROM AUTHOR]