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Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles (5a–m) has been described by reacting hydrazine-1-carbothioamides (3a–k) with α-chloro- or bromo-acetophenones (4a–d) in refluxing ethanol in good to excellent yields (65–86%). Structural confirmation was based upon spectroscopic techniques such as 1H-NMR, 13C-NMR, FT-IR and mass spectrometry. The biological application of these motifs has been demonstrated in terms of their strong urease inhibition activity. The results of in vitro study revealed that all the compounds are the potent inhibitors of urease. The IC50 (ranging in between 110 and 440 nM) values were higher as compared to that of standard, i.e., thiourea (IC50 = 490 ± 10 nM). The synthesized compounds were docked at the active sites of the Jack bean urease enzyme in order to explore the possible binding interactions of enzyme–ligand complexes; the results reinforced the in vitro biological activity results.Graphic abstract

Background Influenza and tuberculosis both cause significant morbidity and mortality worldwide. Therefore, this study aimed to estimate the burden of influenza A (H1N1)pdm09 virus infection among human tuberculosis patients and the general population. Methods A prospective cohort study was conducted among a cohort group (TB positive patients) as exposed and a comparison group (general population) as non-exposed. A total of 304 participants were recruited in both groups and followed for a period of 12 weeks. Of the 304 concurrently enrolled individuals, 152 were TB-positive patients (cohort group) and 152 were from the general population (comparison group).To calculate the sample size, the power of study was kept at 80% for detecting a difference at 5% alpha level assuming the 25% prevalence of respiratory viruses in cohort group compared to 12.5% in general population. An oropharyngeal swab was taken from a participant with symptoms of influenza-like illness (ILI). Samples were tested by conventional reverse transcription polymerase chain reaction (RT-PCR) for the detection of influenza A (H1N1)pdm09. All statistical analyses were conducted using R software. Results A total of 95 participants developed influenza-like illness (ILI) symptoms. Among these, 64 tested positive for influenza A(H1N1)pdm09, of which 39 were from the exposed group and 25 were from the non-exposed group. During the 12-week period of follow-up, the influenza A (H1N1)pdm09 incidence rate was 20 per 1000 people. The risk of testing positive for influenza A (H1N1)pdm09 was 1.66 times higher in the exposed group compared to the non-exposed group. The cumulative incidence indicated that 25% of the TB cohort and 16% of the comparison group were at risk of getting influenza A (H1N1)pdm09 during the 12 weeks of follow-up. Conclusion Participants from the TB cohort had a higher incidence of influenza A (H1N1)pdm09 than the general population suggesting that they should be prioritized for influenza vaccination.

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.Clonal evolution and genomic alterations in the Eµ-TCL1 mouse model mirror human CLL and identify Myc as oncogenic hit associated with disease progression in patients.

Background Co-morbidity with respiratory viruses including influenza A, cause varying degree of morbidity especially in TB patients compared to general population. This study estimates the risk factors associated with influenza A (H1N1)pdm09 in TB patients with ILI. Methods A cohort of tuberculosis (TB) patients who were admitted to and enrolled in a TB Directly Observed Therapy Program (DOTs) in tertiary care hospitals of Lahore (Mayo Hospital and Infectious Disease Hospital) were followed for 12 weeks. At the start of study period, to record influenza-like illness (ILI), a symptom card was provided to all the participants. Every participant was contacted once a week, in person. When the symptoms were reported by the participant, a throat swab was taken for the detection of influenza A (H1N1)pdm09. A nested case control study was conducted and TB patients with ILI diagnosed with influenza A (H1N1)pdm09 by conventional RT-PCR were selected as cases, while those who tested negative by conventional RT-PCR were enrolled as controls. All cases and controls in the study were interviewed face-to-face in the local language. Epidemiological data about potential risk factors were collected on a predesigned questionnaire. Logistic analysis was conducted to identify associated risk factors in TB patients with ILI. Results From the main cohort of TB patients ( n  = 152) who were followed during the study period, 59 (39%) developed ILI symptoms; of them, 39 tested positive for influenza A (H1N1)pdm09, while 20 were detected negative for influenza A (H1N1)pdm09. In univariable analysis, four factors were identified as risk factors ( p  < 0.05). The final multivariable model identified one risk factor (sharing of towels, P  = 0.008)) and one protective factor (wearing a face mask, p = < 0.001)) for influenza A (H1N1)pdm09 infection. Conclusion The current study identified the risk factors of influenza A (H1N1)pdm09 infection among TB patients with ILI.

The enteric system residing notorious Salmonella typhimurium (S. typhi) is an intracellular, food-borne, and zoonotic pathogen causing typhoid fever. Typhoid fever is one of the leading causes of mortality and morbidity in developing and underdeveloped countries. It also increased the prevalence of multidrug resistance globally. Currently, available anti-bacterial modalities are unable to penetrate into the intracellular compartments effectively for eradicating S. typhi infection. Therefore, in this study, we developed nanostructured lipid-based carriers in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for targeted delivery of ciprofloxacin (CIP) into the S. typhi intracellular reservoirs. Capryol 90, Tween 80, and Span 20 were finalized as suitable oil, surfactant, and co-surfactant, respectively, according to the pseudoternary phase diagram emulsifying region. Targeting capability and mucopenetration of the SNEDDS was attributed to the inclusion of amidated pluronic (NH2-F127). Developed NH2-F127 SNEDDS were characterized via physicochemical, in vitro, ex vivo, and in vivo evaluation parameters. The size of the SNEDDS was found to be 250 nm, having positively charged zeta potential. In vitro dissolution of SNEDDS showed 80% sustained release of CIP in 72 h with maximum entrapment efficiency up to 90% as well as good hemocompatibility by showing less than 0.2% hemolysis and 90% biocompatibility. The survival rate of S. typhi in macrophages (RAW 264.7) was minimal, i.e., only 2% in the case of NH2-F127 SNEDDS. Macrophage uptake assay via nanostructures confirmed the maximum cellular uptake as evidenced by the highest fluorescence. Biofilm dispersion assay showed rapid eradication of developed resistant biofilms on the gall bladder. In vivo pharmacokinetics showed improved bioavailability by showing an increased area under the curve (AUC) value. Taken together, NH2-F127-SNEDDS can be utilized as an alternative and efficient delivery system for the sustained release of therapeutic amounts of CIP for the treatment of S. typhi.

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h -NTPDase1 having IC 50 values in lower micromolar range, these include compounds 8b (IC 50 = 0.29 ± 0.02 µM), 8e (IC 50 = 0.15 ± 0.009 µM), 8f (IC 50 = 0.24 ± 0.01 µM) and 8l (IC 50 = 0.30 ± 0.03 µM). Similarly, compound 8k (IC 50 = 0.16 ± 0.01 µM) was found to be a selective h -NTPDase2 inhibitor. In case of h -NTPDase3, most potent inhibitors were compounds 8c (IC 50 = 0.19 ± 0.02 µM) and 8m (IC 50 = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion.

Lithium (Li) plays a significant role in human physiology and psychology; however, it is non-essential for plants. The extensive use of Li in industrial processes and battery-powered devices poses a potential global threat to living organisms. This study assessed the impact of varying soil Li concentrations (0, 20, 40, 60, and 80 mg/kg) on carrot (Daucus carota L.) plants. Results revealed that Li concentrations exceeding 40 mg/kg soil had detrimental effects on carrot growth. Compared to 0 mg/kg soil, Li concentrations of 60 and 80 mg/kg reduced shoot fresh biomass by 51% and 82%, respectively, and root fresh biomass by 68% and 89%, respectively. Elevated Li levels in the soil also increased hydrogen peroxide (H2O2) content in shoots and triggered enhanced activity of antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT). Additionally, soil Li disrupted the uptake and translocation of essential nutrients such as potassium (K) and calcium (Ca) from roots to shoots. This study concludes that while low Li levels may elicit a positive response in plants, higher concentrations significantly impair growth and could contribute to the accumulation of Li in the food chain.

Introduction Low birth weight (LBW) is a well-known contributing factor to neonatal health, emphasizing the importance of maternal health and socio-economic conditions. The birth weight of a newborn is a major public health problem, which is more common in low-middle-income countries (LMICs). Objective The objective of this study is to assess the association of different socio-economic and maternal factors with LBW babies in Lahore. Methods This case-control study was carried out at the Obstetrics and Gynecological Department in Mayo Hospital, Lahore, Pakistan from September 25, 2023 to December 31, 2023. A total of 186 mothers who delivered in the maternity ward, categorized into two groups (93 cases and 93 controls), were included and data was collected with the help of a self-administered structured tool. A chi-square test was used to identify maternal risk factors significant for LBW babies. The strength of association between maternal risk factors and LBW babies was presented using the odds ratio (OR) with the respective 95% confidence interval (CI). Results The study revealed that maternal anemia [OR: 3.378, 95% CI: 1.568, 7.275] and inadequate nutritional status [OR: 1.031, 95% CI: 0.014, 0.071] were more likely to cause delivery of LBW babies. Regarding socio-demographic factors, household income < 25000 [OR: 5.185, 95% CI: 2.770, 9.707] and illiterate mothers [OR: 3.325, 95% CI: 1.820, 6.074] were associated with increased likelihood of LBW babies. Maternal age < 20 had a strong association [OR: 10.920, 95% CI: 2.455,48.575] with delivery of LBW children.  Conclusion The study concludes that multiple risk factors including anemia, inadequate nutritional status, household income < 25000, illiterate mother, and maternal age < 20 are strongly associated with LBW babies. It is apparent that a multimodal strategy is necessary to reduce the risk of LBW babies.

Soil salinity, drought, and increasing temperatures are serious environmental issues that drastically reduce crop productivity worldwide. Quinoa (Chenopodium quinoa Willd) is an important crop for food security under the changing climate. This study examined the physio-biochemical responses, plant growth, and grain yield of four quinoa genotypes (A7, Titicaca, Vikinga, and Puno) grown in pots containing normal (non-saline) or salt-affected soil exposed to drought and elevated-temperature treatments. Combinations of drought, salinity, and high-temperature stress decreased plant growth and yield more than the individual stresses. The combined drought, salinity, and heat stress treatment decreased the shoot biomass of A7, Puno, Titicaca, and Vikinga by 27, 36, 41, and 50%, respectively, compared to that of control plants. Similar trends were observed for grain yield, chlorophyll contents, and stomatal conductance. The combined application of these three stresses increased Na concentrations but decreased K concentrations in roots and shoots relative to control. Moreover, in the combined salinity, drought, and high-temperature treatment, A7, Puno, Titicaca, and Vikinga had 7.3-, 6.9-, 8-, and 12.6-fold higher hydrogen peroxide contents than control plants. All four quinoa genotypes increased antioxidant enzyme activities (CAT, SOD, and POD) to overcome oxidative stress. Despite A7 producing the highest biomass under stress, it did not translate into increased grain production. We conclude that Puno and Titicaca are more tolerant than Vikinga for cultivation in salt-affected soils prone to drought and heat stress.

Integration site profiling and clonality analysis of viral vector distribution in gene therapy is a key factor to monitor the fate of gene-corrected cells, assess the risk of malignant transformation, and establish vector biosafety. We developed the Genome Integration Site Analysis Pipeline (GENE-IS) for highly time-efficient and accurate detection of next-generation sequencing (NGS)-based viral vector integration sites (ISs) in gene therapy data. It is the first available tool with dual analysis mode that allows IS analysis both in data generated by PCR-based methods, such as linear amplification method PCR (LAM-PCR), and by rapidly evolving targeted sequencing (e.g., Agilent SureSelect) technologies. GENE-IS makes use of trimming strategies, customized reference genome, and soft-clipped information with sequential filtering steps to provide annotated IS with clonality information. It is a scalable, robust, precise, and reliable tool for large-scale pre-clinical and clinical data analysis that provides users complete flexibility and control over analysis with a broad range of configurable parameters. GENE-IS is available at https://github.com/G100DKFZ/gene-is.