Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis.

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of - 5.5, - 6.1, - 4.5, and - 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein-ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.

Outbreak investigation of NDM-producing Burkholderia cepacia causing neonatal sepsis in Pakistan.

Aim: To investigate the outbreak of Burkholderia cepacia complex (BCC), mortality, antimicrobial resistance and associated risk factors in the neonatal intensive care unit. Method: Eighteen blood culture samples from neonates and twenty swab samples from different neonatal intensive care unit surfaces were collected. The VITEK 2 was used to confirm the isolates and generate the antibiogram. PCR was used to identify blaNDM. Results: Eighteen samples tested positive for BCC, and 10/18 (55.5%) of the neonates died. 13/18 (72%) of the neonates had late-onset neonatal sepsis, and 10/18 (55%) had low birth weight. Resistance to minocycline and chloramphenicol was 100%, 72.2% to meropenem; 72.2% NDM gene was found in neonates and was 20% from the environment. Conclusion: Outbreak of NDM-producing BCC resulting in high neonatal mortality in NICU.

Neonatal septicemia, or blood poisoning, is a dangerous illness in newborns. It is caused by bacteria or other infections entering the blood and spreading. Pregnancy, labor, delivery and exposure after birth can result in infection of the newborn. Neonatal septicemia kills 700,000 babies worldwide, mostly in low- and middle-income countries. Burkholderia cepacia complex bacteria can cause infections in people with weaker immune systems or other disorders. They are particularly dangerous in hospitals, as they can cause chronic lung problems. This study collected blood samples from newborns with blood poisoning. Most samples that contained Burkholderia cepacia complex were not susceptible to drugs. Four of the newborns carried the same bacteria, indicating that hospital staff should practice hand washing and equipment and environmental cleaning to prevent the spread of the bacteria.

The molecular basis of extensively drug-resistant Salmonella Typhi isolates from pediatric septicemia patients.

Sepsis is a syndromic response to infections and is becoming an emerging threat to the public health sector, particularly in developing countries. Salmonella Typhi (S. Typhi), the cause of typhoid fever, is one primary cause of pediatric sepsis in typhoid endemic areas. Extensively drug-resistant (XDR) S. Typhi is more common among pediatric patients, which is responsible for over 90% of the reported XDR typhoid cases, but the majority of antibiotic resistance studies available have been carried out using S. Typhi isolates from adult patients. Here, we characterized antibiotic-resistance profiles of XDR S. Typhi isolates from a medium size cohort of pediatric typhoid patients (n = 45, 68.89% male and 31.11% female) and determined antibiotic-resistance-related gene signatures associated with common treatment options to typhoid fever patients of 18 XDR S. Typhi representing all 45 isolates. Their ages were 1-13 years old: toddlers aging 1-2 years old (n = 9, 20%), pre-schoolers aging 3-5 years old (n = 17, 37.78%), school-age children aging 6-12 years old (n = 17, 37.78%), and adolescents aging 13-18 years old (n = 2, 4.44%). Through analyzing blaTEM1, dhfR7, sul1, and catA1genes for multidrug-resistance, qnrS, gyrA, gyrB, parC, and parE for fluoroquinolone-resistance, blaCTX-M-15 for XDR, and macAB and acrAB efflux pump system-associated genes, we showed the phenotype of the XDR S. Typhi isolates matches with their genotypes featured by the acquisitions of the genes blaTEM1, dhfR7, sul1, catA1, qnrS, and blaCTX-M-15 and a point mutation on gyrA. This study informs the molecular basis of antibiotic-resistance among recent S. Typhi isolates from pediatric septicemia patients, therefore providing insights into the development of molecular detection methods and treatment strategies for XDR S. Typhi.

Molecular detection of extensively drug-resistant Salmonella Typhi and carbapenem-resistant pathogens in pediatric septicemia patients in Pakistan - a public health concern.

Aim: To determine the prevalence of multidrug (MDR) and extensively drug-resistant (XDR) pathogens from pediatric blood samples Methods: In total, 4543 children's blood samples were processed in the BacT/ALERT system. Confirmation of the isolates and MIC was determined in VITEK® 2 system. Molecular identification of blaIMP, blaVIM and blaOXA-48 was done by PCR. Results: Of 4543 blood cultures, 458 (10%) were positive for bacterial growth and Salmonella Typhi (415; 90%) remained the primary pathogens. Antibiogram revealed 208 (50.1%) and 137 (33%) were MDR and XDR S. Typhi, respectively. Klebsiella pneumoniae displayed 46% resistance to imipenem. One hundred twelve (81.7%) XDR Typhi were positive for blaCTXM, whereas 14 (66.6%) blaVIM were found in carbapenem-resistant bacteria. Conclusion: A high prevalence of MDR and XDR pathogens was found in peads blood culture.

Regulation of blood-testis barrier assembly in vivo by germ cells.

The assembly of the blood-testis barrier (BTB) during postnatal development is crucial to support meiosis. However, the role of germ cells in BTB assembly remains unclear. Herein, KitW/KitWV mice were used as a study model. These mice were infertile, failing to establish a functional BTB to support meiosis due to c-Kit mutation. Transplantation of undifferentiated spermatogonia derived from normal mice into the testis of KitW/KitWV mice triggered functional BTB assembly, displaying cyclic remodeling during the epithelial cycle. Also, transplanted germ cells were capable of inducing Leydig cell testosterone production, which could enhance the expression of integral membrane protein claudin 3 in Sertoli cells. Early spermatocytes were shown to play a vital role in directing BTB assembly by expressing claudin 3, which likely created a transient adhesion structure to mediate BTB and cytoskeleton assembly in adjacent Sertoli cells. In summary, the positive modulation of germ cells on somatic cell function provides useful information regarding somatic-germ cell interactions.-Li, X.-Y., Zhang, Y., Wang, X.-X., Jin, C., Wang, Y.-Q., Sun, T.-C., Li, J., Tang, J.-X., Batool, A., Deng, S.-L., Chen, S.-R., Cheng, C. Y., Liu, Y.-X. Regulation of blood-testis barrier assembly in vivo by germ cells.

PROPOLIS AS AN ANTIBACTERIAL AGENT AGAINST CLINICAL ISOLATES OF MDR-ACINETOBACTER BAUMANNII.

BACKGROUND: Multidrug resistant (MDR) Acinetobacter baumannii has emerged as an important health care problem. The organism is now identified as an important nosocomial pathogen particularly in the intensive care settings. The therapeutic options to treat this pathogen are limited; thus it needs testing for alternatives, like those of plant origin or natural products. Propolis is one of such products which have been tested against this organism. METHODS: A. baumannii (n=32) were collected from Fatima Memorial Hospital, Lahore. The isolates were identified on the basis of their morphology, cultural characteristics and biochemical profile. The susceptibility of the isolates to various antimicrobials was evaluated as per Kirby-Bauer disc diffusion method according to (CLSI 2010). An ethanolic extract of propolis was prepared by the ultrasonic extraction method and its antibacterial activity was evaluated by the agar well diffusion technique. Minimum inhibitory concentration (MIC) was also determined by the agar dilution technique. RESULTS: The isolates were found to be resistant to most of the commonly used anti-acinetobacter antimicrobials; doxycycline however was the exception. Propolis from Sargodha (EPS) and Lahore (EPL) showed zones of inhibition of 21.8 +/- .29 mm and 15.66 +/- 2.18 mm respectively. MIC ranges of EPS and EPL similarly was from 1.5-2.0 mg/ml and 4.0-4.5 mg/ml respectively. CONCLUSION: It is clear that EPS has potential edge of activity as compared to EPL. Nevertheless the potential efficacy of propolis must be subjected to pharmaceutical kinetics and dynamics to precisely determine its potential antimicrobial usefulness.