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Visceral leishmaniasis (VL) control in the Indian subcontinent is currently based on case detection and treatment, and on vector control using indoor residual spraying (IRS). The use of long-lasting insecticidal nets (LN) has been postulated as an alternative or complement to IRS. Here we tested the impact of comprehensive distribution of LN on the density of Phlebotomus argentipes in VL-endemic villages.A cluster-randomized controlled trial with household P. argentipes density as outcome was designed. Twelve clusters from an ongoing LN clinical trial--three intervention and three control clusters in both India and Nepal--were selected on the basis of accessibility and VL incidence. Ten houses per cluster selected on the basis of high pre-intervention P. argentipes density were monitored monthly for 12 months after distribution of LN using CDC light traps (LT) and mouth aspiration methods. Ten cattle sheds per cluster were also monitored by aspiration.A random effect linear regression model showed that the cluster-wide distribution of LNs significantly reduced the P. argentipes density/house by 24.9% (95% CI 1.80%-42.5%) as measured by means of LTs.The ongoing clinical trial, designed to measure the impact of LNs on VL incidence, will confirm whether LNs should be adopted as a control strategy in the regional VL elimination programs. The entomological evidence described here provides some evidence that LNs could be usefully deployed as part of the VL control program.ClinicalTrials.gov CT-2005-015374.

Abstract The PepTSo transporter mediates the transport of peptides across biological membranes. Despite advancements in structural biology, including cryogenic electron microscopy structures resolving PepTSo in different states, the molecular basis of peptide recognition and transport by PepTSo is not fully elucidated. In this study, we used molecular dynamics simulations, Markov State Models (MSMs), and Transition Path Theory (TPT) to investigate the transport mechanism of an alanine-alanine peptide (Ala-Ala) through the PepTSo transporter. Our simulations revealed conformational changes and key intermediate states involved in peptide translocation. We observed that the presence of the Ala-Ala peptide substrate lowers the free energy barriers associated with transition to the inward-facing state. We also show a proton transport model and analyzed the pharmacophore features of intermediate states, providing insights for rational drug design. These findings highlight the significance of substrate binding in modulating the conformational dynamics of PepTSo and identify critical residues that facilitate transport.

Abstract Cyclopamine, a natural alkaloid, can act as an agonist when it binds to the Cysteine-Rich Domain (CRD) of Smoothened receptor and as an antagonist when it binds to the Transmembrane Domain (TMD). To study the effect of cyclopamine binding to each site experimentally, mutations in the other site are required. Hence, simulations are critical for understanding the WT activity due to binding at different sites. Using multi-milliseconds long aggregate MD simulations combined with Markov state models and machine learning, we explore the dynamic behavior of cyclopamine’s interactions with different domains of WT SMO. A higher population of the active state at equilibrium, a lower free energy barrier of ~2 kcal/mol, and expansion of hydrophobic tunnel to facilitate cholesterol transport agrees with cyclopamine’s agonistic behavior when bound to CRD. A higher population of the inactive state at equilibrium, a higher free energy barrier of ~4 kcal/mol and restricted hydrophobic tunnel shows cyclopamine’s antagonistic behavior when bound to TMD. With cyclopamine bound to both sites, there is a slightly larger inactive population at equilibrium and an increased free energy barrier (~3.5 kcal/mol) exhibiting an overall weak antagonistic effect. These findings show cyclopamine’s domain-specific modulation of SMO regulates Hedgehog signaling and cholesterol transport.

Metabolic dysfunction‐associated steatohepatitis‐driven hepatocellular carcinoma (MASH‐HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor‐alpha (TNF‐α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF‐α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF‐mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH‐HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 μL·g−1, weekly) for 24 weeks. TACE activity, TNF‐α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF‐α, which upregulated AATF, a key molecular driver of MASH‐HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF‐mediated inflammation, fibrosis, and oncogenesis in MASH‐HCC, offering a potential target for therapeutic intervention.

Abstract Transporters are targeted by endogenous metabolites and exogenous molecules to reach cellular destinations, but it is generally not understood how different substrate classes exploit the same transporter’s mechanism. Any disclosure of plasticity in transporter mechanism when treated with different substrates becomes critical for developing general selectivity principles in membrane transport catalysis. Using extensive molecular dynamics simulations with an enhanced sampling approach, we select the Arabidopsis sugar transporter AtSWEET13 as a model system to identify the basis for glucose versus sucrose molecular recognition and transport. Here we find that AtSWEET13 chemical selectivity originates from a conserved substrate facial selectivity demonstrated when committing alternate access, despite mono-/di-saccharides experiencing differing degrees of conformational and positional freedom throughout other stages of transport. However, substrate interactions with structural hallmarks associated with known functional annotations can help reinforce selective preferences in molecular transport.

Abstract With the diversity of lipid-protein interactions, any observed membrane protein dynamics or functions directly depend on the lipid bilayer selection. However, the implications of lipid bilayer choice are seldom considered unless characteristic lipid-protein interactions have been previously reported. Using molecular dynamics simulation, we characterize the effects of membrane embedding on plant aquaporin SoPIP2;1, which has no reported high-affinity lipid interactions. The regulatory impacts of a realistic lipid bilayer, and nine different homogeneous bilayers, on varying SoPIP2;1 dynamics are examined. We demonstrate that SoPIP2;1’s structure, thermodynamics, kinetics, and water transport are altered as a function of each membrane construct’s ensemble properties. Notably, the realistic bilayer provides stabilization of non-functional SoPIP2;1 metastable states. Hydrophobic mismatch and lipid order parameter calculations further explain how lipid ensemble properties manipulate SoPIP2;1 behavior. Our results illustrate the importance of careful bilayer selection when studying membrane proteins. To this end, we advise cautionary measures when performing membrane protein molecular dynamics simulations.

One of the work items in fifth generation (5G) radio layer 1 (RAN1) in the Release-18 third-generation partnership project (3GPP) standardization activity concerns sounding reference signal (SRS) enhancements to deal with interference management in time-division duplex (TDD) coherent joint transmission (CJT) for multiple transmission reception points (multiple TRPs or mTRP). The work item proposed to study two approaches: 1) interference randomization techniques (IRT) and 2) capacity enhancements (CE) of SRS. This paper discusses this work item in detail along with the authors’ contributions to it. This paper can be broadly divided into three parts. In the first part, we provide an overview of the various techniques discussed by different companies in the standards. In the second part, we present our contribution of a novel SRS receiver with enhanced SRS capacity. We show how our improved SRS receiver allows the transmission of six SRSs over 12 subcarriers, which results in better performance (greater than 5 dB gain) than a conventional SRS receiver that supports only four SRSs over 12 subcarriers, as per the existing 3GPP standard. Capacity improvement is achieved by enabling closer placement of the SRS in the cyclic shift (CS) domain, which depends on leakage. Conventional SRS receivers are based on discrete Fourier transform (DFT), which have more leakages than the proposed Slepian-based SRS receiver, which has fewer leakages. We analysed in detail the effects of both DFT and Slepian on leakages in the CS domain. This capacity and/or performance improvement allows more user equipments (UEs) to simultaneously transmit SRS, allowing lower uplink transmission power to attain the same performance as conventional SRS receivers, thereby improving coverage. We investigate the changes that need to be implemented in existing standards to support such receivers, which can achieve an enhanced SRS capacity. In the third part, we present three novel enhancement techniques, that we proposed, namely, per-port cyclic shift (PP-CS) allocation scheme, CS hopping in a subset and muting of SRS transmission. CS hopping in a subset was accepted in 5G RAN1 Release-18 3GPP standardization activity as a means of reducing interference in TDD CJT for mTRP. In the section on simulation results in this paper, we show that there is a distinct improvement in performance (compared to existing legacy systems) when CS hopping is employed. This is because, in the CS domain, as the CS associated with a user hops across orthogonal frequency-division multiplexing (OFDM) symbols, it has different neighbouring users in different symbols and leakages due to these neighbours get reduced as the channel estimates are averaged over different OFDM symbols. We demonstrate that it is possible to mitigate almost all interference and reach the zero-interference lower bound of a single TRP (sTRP) case with a combination of PP-CS, CS hopping in a subset, and muting of SRS transmission. The key idea is to recognize that the extra propagation distance (EPD) of UEs from other TRPs results in higher frequency selectivity in the channel. To address this, we designed efficient SRS CS resource-allocation strategies.

ABSTRACT: This study aims to investigate the role of the indigenous construct lokasamgraha in the context of social entrepreneurship. We identified lokasamgraha through content analysis of the Bhagavad Gita, employing the methodological approaches proposed by Bhawuk (2010). Using the lens of paradox theory, we investigated commonly accepted tensions in social enterprises. We developed a framework to explain how lokasamgraha can assist social enterprises in managing tensions and achieving the triple bottom-line. Furthermore, we validated this framework by citing a lokasamgraha-based social enterprise in India. Finally, before concluding, we discussed the implications and future research directions.

Complex craniovertebral junction (CVJ) defects account for a considerable proportion of CVJ diseases. Given the heavily assimilated C1, an unfavorable C1–C2 joint orientation, an overriding C2 superior facet, a low-hanging occiput, and an abnormal vertebral artery course with a high-riding vertebral artery, placement of C1 lateral mass screws might be difficult. To address this, a novel technique for placing C1 lateral mass screws that avoid vertebral artery injury, low-hanging occiput, and overriding C2 superior facet was developed in this study. This approach enables firm fixation of C1–C2 even in difficult situations where the placement of the C1 lateral mass is challenging.

A dominating set D ⊆ V is a co-independent dominating (CID)-set a graph G = (V, E) if Δ((V - D)) = 0. The co-independent domination number γci(G) is the minimum cardinality of a co-independent dominating set and γci-set is a minimum co-independent dominating set of G. In this paper, we obtain the total number of γci-sets in certain class of circulant graphs apart from strongly regular graphs which are the blocks of Partially Balanced Incomplete Block (PBIB) designs with m-association schemes for 1 ≤ m ≤ [p/2]. [ABSTRACT FROM AUTHOR]

Abstract Design of cannabinergic subtype selective ligands is challenging because of high sequence and structural similarities of cannabinoid receptors (CB1 and CB2). We hypothesize that the subtype selectivity of designed selective ligands can be explained by the ligand binding to the conformationally distinct states between cannabinoid receptors. Analysis of ~ 700 μs of unbiased simulations using Markov state models and VAMPnets identifies the similarities and distinctions between the activation mechanism of both receptors. Structural and dynamic comparisons of metastable intermediate states allow us to observe the distinction in the binding pocket volume change during CB1 and CB2 activation. Docking analysis reveals that only a few of the intermediate metastable states of CB1 show high affinity towards CB2 selective agonists. In contrast, all the CB2 metastable states show a similar affinity for these agonists. These results mechanistically explain the subtype selectivity of these agonists by deciphering the activation mechanism of cannabinoid receptors.

Background: Occlusal splints and anterior repositioning splints (ARSs) are widely accepted treatments for temporomandibular disorders (TMDs). However, there is uncertainty with regard to the most suitable amount of mandibular repositioning. The aim of this study is to evaluate the clinical and functional effects of the therapeutic position (ThP) established based on the Controlled Mandibular Repositioning (CMR) method. Methods: In this clinical trial, 20 subjects with 37 joints with disc displacement with reduction were recruited. The initial standard functional diagnostic protocol, MRI, and digital condylography were performed, and ThP was calculated with the CMR method. After a 6-month follow-up, the standard diagnostic protocol was repeated. The change in disc position was evaluated by means of MRI after 6 months of CMR therapy. Results: The MRI findings in the parasagittal plane demonstrated that out of the 37 joints presenting disc displacement, 36 discs were successfully repositioned; thus, the condyle–disc–fossa relationship was re-established. Therefore, the success rate of this pilot study was 97.3%. The mean position of the displaced discs was at 10:30 o’clock of the TMJ joint and at 12:00 o’clock after CMR therapy. Conclusions: The ThP determined using the CMR approach reduced all of the anteriorly displaced discs (except one). The CMR method allowed to define an optimum ThP of the mandible thus supporting patients’ effective adaptation to treatment position.

ABSTRACT: This study evaluates the effectiveness of a typical clean-in-place (CIP) protocol against in vitro biofilms on whey reverse osmosis (RO) membranes developed under static condition. Bacterial isolates obtained from RO membrane biofilms were used to develop single and multispecies biofilms under laboratory conditions. A typical commercial CIP protocol was tested against the 24-h-old biofilms, and included 6 sequential treatment steps based on alkali, surfactant, acid, enzyme, a second surfactant, and a sanitizer treatment step. Experiments were conducted in 4 replicates and the data were statistically analyzed. The results revealed a variation in the resistance of mixed-species biofilms against the individual steps in the sequential CIP protocol. The overall 6 steps protocol, although resulted in a greater reduction, also resulted in the detection of survivors even after the final sanitizer step, reflect the ineffectiveness of the CIP protocol for complete removal of biofilms. Posttreatment counts of 0.71 log after the sequential CIP of mixed-species biofilm revealed the resistance of biofilm constitutive microbiota. Mixed-species biofilms, constituting different genera including Bacillus, Staphylococcus, and Streptococcus, were observed to be more resistant than most of the single-species biofilms. However, among the single-species biofilms, significantly different resistance pattern was observed for Bacillus isolates compared with the other bacterial isolates. All 5 isolates of Bacillus were found resistant with survivor counts of more than 1.0 log against the sequential CIP protocol tested. Thus, it can be concluded that the tested CIP protocol had a limited effectiveness to clean membrane biofilms formed on the whey RO membranes.

Background and aimsAngiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in hepatocellular carcinoma (HCC). In this study, we aim to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in HCC.MethodsHCC tissues were analyzed for AATF expression by qRT-PCR and immunohistochemistry. Stable clones of control and AATF knockdown (KD) were established in human HCC cells. The effect of AATF inhibition on the angiogenic processes was determined by proliferation, invasion, migration, chick chorioallantoic membrane (CAM) assay, zymography, and immunoblotting techniques.ResultsWe identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibiting AATF in QGY-7703 cells resulted in higher levels of pigment epithelium-derived factor (PEDF) than controls due to decreased matric metalloproteinase activity. Conditioned media from AATF KD cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Notably, PEDF inhibition effectively reversed the anti-angiogenic effect of AATF KD.ConclusionOur study reports the first evidence that the therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may serve as a promising approach for HCC treatment.

Due to Feit and Higman [12], the (thick) generalized n-gons exist only for n є {2, 3, 4, 6, 8} and are apparently quite rare for n = 6 or 8. By virtue of the above fact, in this article, we investigate the generalized polygons which are strongly regular graphs and pseudo geometric graphs. Also, we obtain the parameters of partial geometry and partially balanced incomplete block (PBIB) designs with association scheme arising from classical graph theoretic parameters (covering, independence, domination and neighborhood number) on generalized polygons. [ABSTRACT FROM AUTHOR]

Chiral assembly of achiral building blocks can engender properties without resorting to complex stereochemistry. Here, the authors reveal chiral emergence from achiral semiconducting polymers which pave the way to chiral (opto)electronics.

Here, the authors show that treatment with a monoclonal neutralizing antibody against the lung microbiota-derived proapoptotic peptide corisin ameliorates acute exacerbation of pulmonary fibrosis and severity of endotoxin-induced acute lung injury in mice.

Itaconic acid, also known as methylene succinic acid, is a colorless, crystalline substance that is found in nature. Due to its two functional carboxylic acid forms and - unsaturated bond, it can be used in a variety of sectors (plastics, super-absorbents, biopolymers, anti-scaling agents, etc.). Itaconic acid can be produced via thermally decarboxylating citric acid, catalysing the condensation of succinic acid derivatives with formaldehyde, decarboxylating aconitic acid, and fermentation utilizing Aspergillus terreus and other microbes. It is quite expensive and harmful to extract itaconic acid from the fermentation broth. In the present study, Iso-butanol, iso-octanol, groundnut, soybean, mustard, and rice bran oil were incorporated as solvents for separating itaconic acid from their solutions in distilled water. Liquid-liquid extraction experiments were conducted over the range of 0.08-0.533 mol.L-1 of itaconic acid. The results thus obtained were defined as the separation efficiency (E) and distribution coefficient (KD). Separation was observed at maximum efficiencies of 69.33%, 47.8%, 12.93%, 17.9%, 15.625% & 14.18% with iso-butanol, iso-octanol groundnut, soybean, mustard, and rice bran oil respectively. Since the solvents used in this study were natural and chemical, it can be helpful to make the process more eco-friendly and the efficiency of the process can be further increased with the help of reactive extractants.

Background: Atlantoaxial Dislocation (AAD) is a complex disorder of craniovertebral junction (CVJ). Many techniques are available to treat AAD but there are some specific conditions where some techniques have advantage over the other. Technical Advantage: C2-3 transfacetal screw with standard C1 lateral mass fixation provides a stronger construct because of four cortices incorporation and divergent course of screws and is biomechanically comparable to other forms of C2 fixation techniques. It is a technically less demanding and time-consuming. It is also a good alternative in cases having significant osteopenia. Conclusion: C2-3 transfacetal screw with standard C1 lateral mass fixation is an effective alternative to routine C1 lateral mass and C2 pedicle/pars screw fixation in cases of atlantoaxial dislocation complicated with high riding or posteriorly placed vertebral artery and thin pedicle of C2 vertebra.

Atlantoaxial instability (AAI) is surgically a complex entity due to its proximity to vital neurovascular structures. C1-C2 fusion has been an established standard in its treatment for a considerable time now. Here, we have outlined the most common techniques for C2 screw fixation in practice at present such as C2 pedicle, C2 pars, C2 translaminar, C2 subfacetal, C2-C3 transfacetal, and C2 inferior facet screw. We have discussed in detail the technical as well as biomechanical aspects of each technique of C2 screw fixation in AAI and explored the intricacies of each technique.

Honey is a natural sweet substance produced by Apis sp. from floral nectar or other plant parts which are gathered, modified and stored in the honeycombs by honeybees. The current research was aimed to analyze the quality parameters of locally available honey. Honey samples of Apis laboriosa and Apis mellifera were collected during spring of 2019 & 2021 and autumn 2021 from the Bagmati province, Nepal. Samples were analyzed their physicochemical and phytochemical properties. The result shows that, the pH was ranged between [4.467 0.0306 - 5.05 0.02], rheological studies showed Newtonian flow and pseudo-plastic type of Non-Newtonian flow, specific optical rotation was ranged between [(+) 5.75 0.4684 - (-) 12.71 0.234], specific gravity was ranged between [1.35 0.00017 - 1.409 0.00022], moisture content was ranged between [19.2% - 25%]. Secondary Metabolite screening showed the honey samples possesses flavonoids, saponins, glycosides, tannins, amino acids, protein and reducing sugar. Total phenolic content was ranged between [1.0427 - 6.86288] gm GAE/Kg honey while total flavonoid content ranged between [0.016755 - 0.353132] gm QE/Kg Honey. IC50 obtained from DPPH assay ranged between [649.6465 - 9867.1617] ppm. Properties and qualities of honey are affected by seasonal factors and various floral sources. The samples were in positive correlation between flavanoid content, phenolic content and their respective anti-oxidant potency.

Background and Aims: Opioids have been favored as adjuvants to local anesthetics during spinal anesthesia. Nalbuphine, a µ-receptor antagonist and κ-receptor agonist, seems to be a suitable adjuvant to local anesthetics. The aim of this study was to compare postoperative analgesia and adverse effects of nalbuphine and fentanyl when used as an adjuvant to hyperbaric bupivacaine during spinal anesthesia. Materials and Methods: Sixty patients belonging to the American Society of Anesthesiologists Physical Status I and II were randomly allocated into two groups of thirty each. Patients in bupivacaine nalbuphine group (Group BN) received 0.8 mg (0.3 ml) of nalbuphine with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine diluted to 3 ml and bupivacaine-fentanyl group (Group BF) received 25 µg (0.5 ml) of fentanyl with 12.5 mg (2.5 ml) of 0.5% hyperbaric bupivacaine. Patients were assessed for hemodynamic changes, sensory and motor block, early postoperative analgesia, and adverse effects. Results: Onset, duration of sensory and motor block, and duration of effective analgesia were comparable between both groups. Postoperative visual analog scale score was 4.8 ± 1.12 in Group BN, and in Group BF, it was 3.86 ± 1.04 which was statistically highly significant (P = 0.0007). The number of patients demanding rescue analgesia in early postoperative period was 18 (60.0%) in Group BN and 7 (23.33%) in Group BF which was statistically significant (P = 0.004). Conclusion: Fentanyl was more efficient than nalbuphine in providing early postoperative analgesia when used as an adjuvant to hyperbaric bupivacaine. [ABSTRACT FROM AUTHOR]