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Adenosine diphosphate glucose pyrophosphorylase (AGPase) is the rate limiting enzyme of starch biosynthesis that directly affects the wheat productivity. AGPase and grain growth rate (GGR) discerned to be following strict temperature regimen in wheat disomic chromosome substitution (DCS) lines. The first half of grain filling period had chromosome 1B and 2D as prominent players, whereas second half was mainly controlled by chromosomes 6A and 5B. Chromosome 2D had major contribution towards yield in a specific temperature range of 23 ± 1.5 °C during initial stages of grain filling which can serve as an effective early screening tool for terminal heat tolerance in wheat. Chromosome 2D with highest amylose content can also be utilized to produce low digestibility flour. Grain yield was found to be significantly associated with spikes/plant, grains/spike, grain weight/spike and plant biomass. Further, path analysis indicated that though grains/spike had less direct effect on grain yield but its indirect impact on grain yield via AGPase-21 activity was high. [ABSTRACT FROM AUTHOR]

Lasso peptides, biologically active molecules with a distinct structurally constrained knotted fold, are natural products belonging to the class of ribosomally-synthesized and posttranslationally modified peptides (RiPPs). Lasso peptides act upon several bacterial targets, but none have been reported to inhibit the ribosome, one of the main antibiotic targets in the bacterial cell. Here, we report the identification and characterization of the lasso peptide antibiotic, lariocidin (LAR), and its internally cyclized derivative, lariocidin B (LAR-B), produced by Paenabacillussp . M2, with broad-spectrum activity against many bacterial pathogens. We show that lariocidins inhibit bacterial growth by binding to the ribosome and interfering with protein synthesis. Structural, genetic, and biochemical data show that lariocidins bind at a unique site in the small ribosomal subunit, where they interact with the 16S rRNA and aminoacyl-tRNA, inhibiting translocation and inducing miscoding. LAR is unaffected by common resistance mechanisms, has a low propensity for generating spontaneous resistance, shows no human cell toxicity, and has potent in vivo activity in a mouse model of Acinetobacter baumannii infection. Our finding of the first ribosome-targeting lasso peptides uncovers new routes toward discovering alternative protein synthesis inhibitors and offers a new chemical scaffold for developing much-needed antibacterial drugs., Competing Interests: COMPETING INTERESTS STATEMENT The authors declare no competing interests.

Inclusion of a phase change material such as germanium-antimony-telluride (Ge 2 Sb 2 Te 5 or GST) enhances the performance of plasmonic metasurface absorbers (PMAs). One-dimensional (1-D) plasmonic metasurfaces (PMs) support the excitation of surface plasmon modes for the normal incidence of transverse magnetically (TM) polarized light. The 1-D PMAs absorb incident light because of their confinement in the groove region, which is possible because of the surface plasmon modes excited at the metal-dielectric interface. A thin layer of the phase change material enhances the absorption of incident light because of the increasing strength of the confined electromagnetic field in the vicinity of the PMA. We developed a GST loaded, low cost, 1-D PMA for the absorption of near-infrared (NIR) light (740-920 nm). The PMA was fabricated using an Ag coated 1-D patterned polycarbonate, which was obtained from a commercial digital versatile disk (DVD). A 1-D PMA of 1 cm 2 in size obtained from a DVD was coated with a GST layer of 8 nm in thickness to achieve the maximum absorption of 99.56% for the hexagonal closed packed (h.c.p.) crystalline state of the GST loaded layer. Control experiments were performed for different temperatures and different thicknesses of the GST layer for achieving an optimal performance nearing perfect absorption. Electric and magnetic field profiles were simulated for the normal incidence of TM-polarized light to understand the underlying physics of the light-matter interaction with the PMA. Such a PMA can be used to develop various cost-effective optical devices, such as optical sensors, optical filters, photodetectors, and heat absorbing photonic windows in the NIR wavelength regime.

Dermoid cysts in the floor of the mouth are a relatively rare and unusual site of location anomalies presumed to be caused by entrapment of germinal epithelium along the lines of embryonic fusion. It presents as soft, non-painful, and slowly growing swelling along the lines of fusion during the closure of mandibular and hyoid branch arches. These cysts are developmental and histopathologically classified into three types: epidermoid, dermoid, and teratoid. We are reporting a rare case of a 32-year-old female who presented in the outpatient department with complaints of painless swelling over the floor of the mouth for two years, suggesting a benign sublingual mass. This case report underscores the importance of clinical presentation, diagnostic workup, and surgical approach in achieving successful outcomes for sublingual mass., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, . et al.)

The regular monitoring and accurate diagnosis of arrhythmia are critically important, leading to a reduction in mortality rate due to cardiovascular diseases (CVD) such as heart stroke or cardiac arrest. This paper proposes a novel convolutional neural network (CNN) model for arrhythmia classification. The proposed model offers the following improvements compared with traditional CNN models. Firstly, the multi-channel model can concatenate spectral and spatial feature maps. Secondly, the structural unit is composed of a depthwise separable convolution layer followed by activation and batch normalization layers. The structural unit offers effective utilization of network parameters. Also, the optimization of hyperparameters is done using Hyperopt library, based on Sequential Model-Based Global Optimization algorithm (SMBO). These improvements make the network more efficient and accurate for arrhythmia classification. The proposed model is evaluated using tenfold cross-validation following both subject-oriented inter-patient and class-oriented intra-patient evaluation protocols. Our model achieved 99.48% and 99.46% accuracy in VEB (ventricular ectopic beat) and SVEB (supraventricular ectopic beat) class classification, respectively. The model is compared with state-of-the-art models and has shown significant performance improvement., Competing Interests: Conflict of interestThe authors declare no conflict of interest to disclose., (© The Author(s) 2021.)

Salinity is a major abiotic stress, limiting plant growth and agriculture productivity worldwide. Salicylic acid is known to alleviate the negative effects of salinity. The present study demonstrated the impact of SA on sorghum, a moderately salt-tolerant crop, grown for food, fodder, fiber, and fuel. A screen house experiment was conducted using sorghum genotypes Haryana Jowar HJ 513 and HJ 541 under 4 salt levels (0, 5.0, 7.5, and 10.0 dS m -1 NaCl) and 3 SA (0, 25, and 50 mg dm -3 ) levels with 12 combinations. The leaves were assayed for electrolyte leakage percentage (ELP), i.e., 88.7 % in HJ 541 and 87.2 % in HJ 513, and osmolyte content. Proline content, total soluble carbohydrate content, and glycine betaine content increased considerably. Photosynthetic rate, transpiration rate, and stomatal conductance declined at higher salt levels. The specific enzymatic activities of SOD, CAT, and POX increased 41.1 %, 122.0 %, and 72.8 %, respectively, in HJ 513 under salt stress. Combinations of salt treatment and SA decreased ELP and enhanced osmolyte concentration, rates of gaseous exchange attributes, and also the antioxidant enzymatic activity in salt-stressed leaves. The study established that the specific activity of antioxidative enzymes is enhanced further by addition of SA which may protect the cells from oxidative damage under salt stress, thus mitigating salt stress and enhancing the yield of sorghum. SA can ameliorate the salt stress in plants by affecting the metabolic or physiological frameworks. SA application is an effective management strategy towards mitigating salt stress in order to meet agricultural production and sustainability., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The use of efflux pump inhibitors (EPIs) as potentiators along with the traditional antibiotics assists in the warfare against antibiotic-resistant superbugs. Efflux pumps of the resistance-nodulation-cell division (RND) family play crucial roles in multidrug resistance in Escherichia coli and Pseudomonas aeruginosa . Despite several efforts, clinically useful inhibitors are not available at present. This study describes ethyl 4-bromopyrrole-2-carboxylate (RP1) isolation, an inhibitor of RND transporters from the library of 4000 microbial exudates. RP1 acts synergistically with antibiotics by reducing their minimum inhibitory concentration in strains overexpressing archetype RND transporters (AcrAB-TolC and MexAB-OprM). It also improves the accumulation of Hoechst 33342 and inhibits its efflux (a hallmark of EPI functionality). The antibiotic-RP1 combinations prolong the postantibiotic effects and reduce the mutation prevention concentration of antibiotics. Additionally, from Biolayer Interferometry spectra, it appears that RP1 is bound to AcrB. RP1 displays low mammalian cytotoxicity, no Ca 2+ channel inhibitory effects, and reduces the intracellular invasion of E. coli and P. aeruginosa in macrophages. Furthermore, the RP1-levofloxacin combination is nontoxic, well-tolerated, and notably effective in a murine lung infection model. In sum, RP1 is a potent EPI and worthy of further consideration as a potentiator to improve the effectiveness of existing antibiotics.

Extensive usage of antibiotics has led to the emergence of drug-resistant strains of pathogens and hence, there is an urgent need for alternative antimicrobial agents. Antimicrobial Peptides (AMPs) of bacterial origin have shown the potential to replace some conventional antibiotics. In the present study, an AMP was isolated from Bacillus subtilis subsp. spizizenii strain Ba49 present on the Allium cepa, the common onion and named as peptide-Ba49. The isolated AMP was purified and characterized. The purified peptide-Ba49, having a molecular weight of ~ 3.3 kDa as determined using mass spectroscopy, was stable up to 121 °C and in the pH range of 5-10. Its interaction with protein degrading enzymes confirmed the peptide nature of the molecule. The peptide exhibited low minimum inhibitory concentration (MIC) against Staphylococcus aureus and its (Methicillin-resistant Staphylococcus aureus) MRSA strains (MIC, 2-16 µM/mL). Further, time kill kinetic assay was performed and analysis of the results of membrane depolarization and permeabilization assays (TEM, DiBAC 4 (3) and PI) suggested peptide-Ba49 to be acting through the change in membrane potential leading to disruption of S. aureus membrane. Additionally, cytotoxicity studies of peptide-Ba49, carried out using three mammalian cell lines viz. HEK 293T, RAW 264.7, and L929, showed limited cytotoxicity on these cell lines at a concentration much higher than its MIC values. All these studies suggested that the AMP isolated from strain Ba49 (peptide-Ba49) has the potential to be an alternative to antibiotics in terms of eradicating the pathogenic as well as drug-resistant microorganisms.

Conjugates between pharmaceuticals and small molecules enable access to a vast chemical space required for the discovery of new lead molecules with modified therapeutic potential. However, the dearth of specific chemical reactions that are capable of functionalizing drugs and bioactive natural products presents a formidable challenge for preparing their conjugates. Here, we report a support-free CuI-nanoparticle-catalyzed strategy for conjugating electron-deficient and electron-rich terminal alkynes with a ciprofloxacin methyl ester. Our conjugation technique exploits the late-stage functionalization of bioactive natural products such as tocopherol, vasicinone, amino acids, and pharmaceuticals such as aspirin and paracetamol to provide conjugates in excellent yields under mild and green conditions. This protocol also enabled the synthesis of (hetero)arene-ciprofloxacin 1,4-disubstituted 1,2,3-triazoles in good yields and high regioselectivities. These synthesized ciprofloxacin conjugates were evaluated in vitro for their antibacterial activity against a panel of relevant bacteria. A significant number of conjugates showed comparable activity against Gram-positive and Gram-negative bacteria. Moreover, some conjugates exhibited less toxicity than ciprofloxacin against two mammalian cell lines, suggesting the utility for the future investigation of these compounds for in vivo efficacy and pharmacokinetic studies.

Background: Giardia duodenalis is a common cause of chronic diarrhea especially in tropical countries. Diagnosis is based on microscopy (three stool samples) for trophozoites/cysts. Role of stool or duodenal biopsy PCR as a diagnostic method needs to be defined. We conducted a prospective study to determine the diagnostic characteristics of G. duodenalis stool and duodenal biopsy PCR in comparison to stool microscopy (reference standard). Later, we compared other techniques with stool PCR, considering it as new reference standard and characterized the type of Giardia assemblage., Methods: G. duodenalis stool nested PCR was first evaluated using 40 positive controls and 50 negative controls considering stool microscopy as reference standard. Patients with chronic diarrhea (n = 100) were evaluated by stool microscopy and nested PCR. In 30 patients in whom upper gastrointestinal endoscopy was performed, duodenal biopsy samples were obtained and evaluated by histopathology, imprint cytology, and nested PCR. The type of Giardia assemblage was detected by assemblage-specific PCR., Results: Stool nested PCR was found to have sensitivity and specificity of 100% and 94%, respectively, compared to stool microscopy. In patients with chronic diarrhea, 48% had evidence of Giardia infection. Stool microscopy detected 65%, stool PCR detected an additional 27%, and duodenal biopsy PCR detected an additional 8% of cases. The commonest assemblage found was assemblage B. Clinical and demographic characteristics were similar in patients harboring either assemblage A or B., Conclusion: Stool PCR is more sensitive than stool microscopy. By utilizing stool microscopy, stool nested PCR, and duodenal biopsy PCR in sequential manner, diagnostic yield can be increased.

The rapid emergence of antimicrobial resistance in Acinetobacter baumannii coupled with the dried pipeline of novel treatments has driven the search for new therapeutic modalities. Gram-negative bacteria have an extra outer membrane that serves as a permeability barrier for various hydrophobic and/or large compounds. One of the popular approaches to tackle this penetration barrier is use of potentiators or adjuvants in combination with traditional antibiotics. This study reports the in vitro potential of an antimicrobial peptide tridecaptin M in combination with other antibiotics against different strains of A. baumannii . Tridecaptin M sensitized the bacteria to rifampicin, vancomycin, and ceftazidime. Further, we observed that a tridecaptin M and rifampicin combination killed the bacteria completely in 4 h in an ex vivo blood infection model and was superior to rifampicin monotherapy. The study also found that concomitant administration of both compounds is not necessary to achieve the antimicrobial effect. Bacteria pre-treated with tridecaptin M (for 2-4 h) followed by exposure to rifampicin showed similar killing as obtained for combined treatment. Additionally, this combination hampered the survival of persister development in comparison to rifampicin alone. These findings encourage the future investigation of this combination to treat severe infections caused by extremely drug-resistant A. baumannii .

The flexibility of the adenylation domains of non-ribosomal peptide synthetases (NRPSs) to different substrates creates a diversity of structurally similar peptides. In the present study, we investigated the antimicrobial activity of different natural variants synthesized by tridecaptin M gene cluster and performed the in vitro drug kinetics on this class. The natural variants were isolated and characterized using MALDI-MS and tandem mass spectrometry. All the peptides were studied for their antimicrobial activity in different pathogens, including colistin-resistant bacteria, and for haemolytic activity. Furthermore, in vitro drug kinetics was performed with tridecaptin M (or M 1 , the major product of the gene cluster). The natural variants displayed a varying degree of bioactivity with M 11 showing the most potent antibacterial activity (MIC, 1-8 µg/ml), even against A. baumannii and P. aeruginosa strains. The in vitro kinetic studies revealed that tridecaptin M at a concentration of 16 µg/ml eradicated the bacteria completely in high-density culture. The compound demonstrated desirable post-antibiotic effect after two-hour exposure at MIC concentration. We also observed the reversal of resistance to this class of antibiotics in the presence of carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Altogether, the study demonstrated that tridecaptins are an excellent drug candidate against drug-resistant Gram-negative bacteria. Future studies are required to design a superior tridecaptin by investigating the interactions of different natural variants with the target.

Nosocomial infections caused by Klebsiella pneumoniae are primarily characterized by a high prevalence of extended-spectrum β-lactamases (ESBL's) and a soaring pace of carbapenemase dissemination. Availability of limited antimicrobial agents as a therapeutic option for multidrug-resistant bacteria raises an alarming concern. This study aimed at the molecular characterization of multidrug-resistant K. pneumoniae clinical isolates and studied the role of efflux pumps in β-lactam resistance. Thirty-three isolates confirmed as ESBL-positive K. pneumoniae that harbored resistance genes to major classes of antibiotics. The results showed that CTX-M15 was the preeminent β-lactamase along with carbapenemases in ESBL-positive isolates. However, the efficacy of different antibiotics varied in the presence of lactamase inhibitors and efflux pump inhibitors (EPIs). Those showing increased efficacy of antibiotics with EPI were further explored for the expression of efflux pump genes and expressed a significantly different level of efflux pumps. We found that an isolate had higher expression of kpnF (SMR family) and kdeA (MATE family) pump genes relative to RND family pump genes. No mutations were observed in the genes for porins. Together, the findings suggest that β-lactamases are not the only single factor responsible for providing resistance against the existing β-lactam drugs. Resistance may increase many folds by simultaneous expression of RND family (the most prominent family in Gram-negative bacteria) and other efflux pump family.

Efflux pumps are always at the forefront of bacterial multidrug resistance and account for the failure of antibiotics. The present study explored the potential of 2-(2-Aminophenyl) indole (RP2), an efflux pump inhibitor (EPI) isolated from the soil bacterium, to overcome the efflux-mediated resistance in Staphylococcus aureus . The RP2/antibiotic combination was tested against efflux pump over-expressed S. aureus strains. The compound was further examined for the ethidium bromide (EtBr) uptake and efflux inhibition assay (a hallmark of EPI functionality) and cytoplasmic membrane depolarization. The safety profile of RP2 was investigated using in vitro cytotoxicity assay and Ca 2+ channel inhibitory effect. The in vivo efficacy of RP2 was studied in an animal model in combination with ciprofloxacin. RP2 exhibited the synergistic activity with several antibiotics in efflux pump over-expressed strains of S. aureus . In the mechanistic experiments, RP2 increased the accumulation of EtBr, and demonstrated the inhibition of its efflux. The antibiotic-EPI combinations resulted in extended post antibiotic effects as well as a decrease in mutation prevention concentration of antibiotics. Additionally, the in silico docking studies suggested the binding of RP2 to the active site of modeled structure of NorA efflux pump. The compound displayed low mammalian cytotoxicity and had no Ca 2+ channel inhibitory effect. In ex vivo experiments, RP2 reduced the intracellular invasion of S. aureus in macrophages. Furthermore, the RP2/ciprofloxacin combination demonstrated remarkable efficacy in a murine thigh infection model. In conclusion, RP2 represents a promising candidate as bacterial EPI, which can be used in the form of a novel therapeutic regimen along with existing and upcoming antibiotics, for the eradication of S. aureus infections., (Copyright © 2019 Tambat, Jangra, Mahey, Chandal, Kaur, Chaudhary, Verma, Thakur, Raje, Jachak, Khatri and Nandanwar.)

Antibiotic-resistance is ever growing burden on our society for the past many years. Many synthetic chemistry approaches and rational drug-design have been unable to pace up and tackle this problem. Natural resources, more specifically, the microbial diversity, on the other hand, make a traditional and still the best platform to search for new chemical scaffolds and compounds. Here, we report the antimicrobial characteristics of novel bacterial isolate from a salt lake in India. We screened the bacterial isolates for their inhibitory activity against indicator bacteria and found that four novel species were able to prevent the growth of test strains studied in vitro. Further, we characterized one novel species (SMB1 T  = SL4-2) using polyphasic taxonomic approaches and also purified the active ingredient from this bacterium. We successfully characterized the antimicrobial compound using mass spectroscopy and amino acid analysis. We also allocated two novel biosynthetic gene clusters for putative bacteriocins and one novel non-ribosomal peptide gene cluster in its whole genome. We concluded that the strain SMB1 T belonged to the genus Paenibacilllus with the pairwise sequence similarity of 98.67% with Paenibacillus tarimensis DSM 19409 T and we proposed the name Paenibacillus sambharensis sp. nov. The type strain is SMB1 T (=MTCC 12884 = KCTC 33895 T ).

Natural evolution in microbes exposed to antibiotics causes inevitable selection of resistant mutants. This turns out to be a vicious cycle which requires the continuous discovery of new and effective antibiotics. For the last six decades, we have been relying on semisynthetic derivatives of natural products discovered in "Golden Era" from microbes, especially Streptomyces sp. Low success rates of rational drug-design sparked a resurgence in the invention of novel natural products or scaffolds from untapped or uncommon microbial niches. Therefore, in this study, we examined the microbial diversity inhabiting the yak milk for their ability to produce antimicrobial compounds. We prepared the crude fermentation extracts of fifty isolates from yak milk and screened them against indicator strains for the inhibitory activity. Later, with the aid of gel filtration chromatography followed by reversed-phase HPLC, we isolated one antimicrobial compound Y5-P1 from the strain Y5 ( Pseudomonas koreensis ) which showed bioactivity against Gram-positive and Gram-negative bacteria. The compound was chemically characterized using HRMS, FTIR, and NMR spectroscopy and identified as 1-acetyl-9H-β-carboline-3-carboxylic acid. It showed minimum inhibitory activity (MIC) in the range of 62.5-250 μg /ml. The cytotoxicity results revealed that IC 50 against two mammalian cell lines i.e., HepG2 and HEK293T was 500 and 750 μg/ml, respectively. This is the first report on the production of this derivative of β-carboline by the microorganism. Also, the study enlightens the importance of microbes residing in uncommon environments or unexplored habitats in the discovery of a diverse array of natural products which could be designed further as drug candidates against highly resistant pathogens.

The alarming burden of antibiotic resistance in nosocomial pathogens warrants the discovery and development of new and effective antimicrobial compounds. Small cationic antimicrobial peptides seem to be a promising therapeutic alternative to fight multi-drug resistance. This study investigated the in-vitro potential of a previously reported lantibiotic, paenibacillin, from the clinical perspective. An antimicrobial peptide, M152-P4, was isolated, purified and characterized from a mud isolate, and its susceptibility was determined in clinical isolates of Staphylococcus aureus and Enterococcus spp. Time-kill kinetics, resistance, probable mode of action, haemolytic activity and mammalian cytotoxicity were investigated. M152-P4 was identified as paenibacillin based on mass spectroscopy data, amino acid analysis and biosynthetic gene cluster analysis. It had potent antibacterial activity against the Gram-positive pathogens tested, with minimum inhibitory concentrations from 0.1 to 1.56 µM. It appeared very challenging for S. aureus to develop resistance to this compound. Also, paenibacillin penetrated the outer layer of bacteria, and depolarized the membrane completely by creating pores in the plasma membrane with better potential than nisin. Paenibacillin showed no haemolysis up to 60 µM, and the half maximal inhibitory concentration on mammalian cell lines was >100 µM. These results highlight the excellent antibacterial properties of paenibacillin in clinically relevant pathogens. It is stable in the presence of serum, and non-haemolytic and non-cytotoxic even above the therapeutic concentration. Further research efforts regarding toxicity and in-vivo efficacy are necessary to develop paenibacillin as a next-generation therapeutic drug to overcome multi-drug resistance in Gram-positive pathogens., (Copyright © 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

The World Health Organization has categorized the Gram-negative superbugs, which are inherently impervious to many antibiotics, as critical priority pathogens due to the lack of effective treatments. The breach in our last-resort antibiotic (i.e., colistin) by extensively drug-resistant and pan-drug-resistant Enterobacteriaceae strains demands the immediate development of new therapies. In the present study, we report the discovery of tridecaptin M, a new addition to the family, and its potential against colistin-resistant Enterobacteriaceae in vitro and in vivo Also, we performed mode-of-action studies using various fluorescent probes and studied the hemolytic activity and mammalian cytotoxicity in two cell lines. Tridecaptin M displayed strong antibacterial activity (MICs of 2 to 8 μg ml -1 ) against clinical strains of Klebsiella pneumoniae (which were resistant to colistin, carbapenems, third- and fourth-generation cephalosporins, fluoroquinolones, fosfomycin, and other antibiotics) and mcr-1 -positive Escherichia coli strains. Unlike polymyxins, tridecaptin M did not permeabilize the outer membrane or cytoplasmic membrane. It blocked ATP synthesis in bacteria by dissipating the proton motive force. The compound exhibited negligible acquired resistance, low in vitro cytotoxicity and hemolytic activity, and no significant acute toxicity in mice. It also showed promising efficacy in a thigh infection model of colistin-resistant K. pneumoniae Altogether, these results demonstrate the future prospects of this class of antibiotics to address the unmet medical need to circumvent colistin resistance in extensively drug-resistant Enterobacteriaceae infections. The work also emphasizes the importance of natural products in our shrunken drug discovery pipeline., (Copyright © 2019 Jangra et al.)

Nosocomial infections caused by antibiotic-resistant Gram-negative pathogens are of grave concern today. Polymyxins are considered as the last resorts of therapy to treat these multi-drug resistant (MDR) bacteria. But their associated nephrotoxicity and neurotoxicity calls for the development of safer polymyxin therapy until novel and less toxic antibiotics are discovered. No other polymyxin molecule except polymyxin B and E (colistin) is explored thoroughly in literature to demonstrate its clinical relevance. In the present study, we have isolated two antimicrobial compounds named P1 and P2 from the soil isolate Paenibacillus dendritiformis strain PV3-16, which we later identified as polymyxin A 2 and A 1 respectively. We tested their minimum inhibitory concentrations (MICs) against MDR clinical isolates, performed membrane permeabilization assays and determined their interaction with lipopolysaccharide (LPS). Finally, we studied their toxicity against human Leukemic monocyte cell line (THP-1) and embryonic kidney cell line (HEK 293). Both compounds displayed equal efficacy when compared with standard polymyxins. P1 was 2-4 fold more active in most of the clinical strains tested. Moreover, P1 showed higher affinity toward LPS. In cytotoxicity studies, P1 had IC 50 value (>1000 μg/ml) similar to colistin against HEK cells but immune cells, i.e., THP-1 cell lines were more sensitive to polymyxins. P1 showed less toxicity in THP-1 cell line than all other polymyxins checked. To sum up, P1 (polymyxin A 2 ) possessed better efficacy than polymyxin B and E and had least toxicity to immune cells. Since polymyxin A was not investigated thoroughly, we performed the comprehensive in vitro assessment of this molecule. Moreover, this is the first report of isolation and characterization of polymyxin A from P. dendritiformis . This compound should be further investigated for its in vivo efficacy and toxicity to develop it as a drug candidate.

Probiotic industries strive for new, efficient and promising probiotic strains that impart a positive impact on consumer health. Challenges are persisting in isolation, screening, and selection of the new indigenous probiotic strains. In the present research, we explored the probiotic potential of 17 lactic acid bacteria isolated from Yak milk in a series of in vitro tests. We also demonstrated their health benefits, i.e., cholesterol degradation, lactose digestion, antimicrobial activity, antioxidant, and anticancer activities. Principal component analysis revealed that more than 50% of the strains fulfilled the examined criteria, e.g., survival in acidic pH, bile concentrations, and adherent property. Approximately all the strains produced antimicrobial substances against the maximum number of tested strains including clinical strains. Most strains degraded cholesterol in comparison to the reference probiotic strain whereas strain Yc showed 1.5 times higher the degradation efficiency of the control strain. Lan4 strain exhibited remarkable anticancer activity and induced the maximum apoptosis (87%) in the Hela cells and was non-toxic to the non-cancerous HEK293 cells. Around ten strains showed positive lactose digestion. Overall, this can be concluded that selected lactic acid bacteria revealed excellent probiotic properties along with desirable health benefits. These strains need to be further investigated in details for their application in the development of novel probiotic preparations for the improvement of public health.

Life-saving medical implants like pacemakers and defibrillators face a big drawback that their batteries eventually run out and patients require frequent surgery to have these batteries replaced. With the advent of technology, alternatives can be provided for such surgeries. To power these devices, body energy harvesting techniques may be employed. Some of the power sources are patient's heartbeat, blood flow inside the vessels, movement of the body parts, and the body temperature (heat). Different types of sensors are employed, such as for sensing the energy from the heartbeat the piezoelectric and semiconducting coupled nanowires are used that convert the mechanical energy into electricity. Similarly, for sensing the blood flow energy, nanogenerators driven by ultrasonic waves are used that have the ability to directly convert the hydraulic energy in human body to electrical energy. Another consideration is to use body heat employing biothermal battery to generate electricity using multiple arrays of thermoelectric generators built into an implantable chip. These generators exploit the well-known thermocouple effect. For the biothermal device to work, it needs a 2°C temperature difference across it. But there are many parts of the body where a temperature difference of 5°C exists - typically in the few millimeters just below the skin, where it is planned to place this device. This study focuses on using body heat as an alternative energy source to recharge pacemaker batteries and other medical devices and prevent the possibility of life-risk during repeated surgery.