Exploring Anisotropic Carrier Transport in WSe2-WTe2 Superlattices: A Computational Study.

Superlattice structures offer distinct benefits in modern semiconductor technology, enabling the development of a deeper understanding of their sublayer arising from the interfaces. However, the advancement of large-scale applications encounters additional concerns, such as the stability and performance of the superlattice. In this study, we employ density functional theory calculations combined with the Boltzmann transport theory to comprehensively analyze the electronic structural and transport properties of the hexagonal phase of WSe2 and the WSe2-WTe2 superlattice for their applications in carrier transport fields. Previous studies showed that longitudinal acoustics phonon limited carrier mobility determined by deformation potential theory (DPT) often compromises the accuracy and overestimates the relaxation time by 2 orders. Herein, we conduct an in-depth analysis of band structural and transport properties, addressing the aforementioned inconsistency by exclusively incorporating scattering from longitudinal optical phonons to accurately compute mobility using the Fröhlich interaction. Our findings reveal a significant enhancement in mobility for both electrons and holes in the WSe2-WTe2 superlattice, reaching 545 and 476 cm2 V-1 s-1, respectively, compared to 104 and 132 cm2 V-1 s-1 for WSe2, which suggests that this superlattice is a promising material for electronics and transport applications.

Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3; a rare example of using a S···O binding interaction for drug design.

As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.

Computational approach to enhance thermoelectric performance of Ag2Se by S and Te substitutions.

Designing an n-type thermoelectric material with a high thermoelectric figure of merit at near room temperature is extremely challenging. Generally, pristine Ag2Se reveals unusually low thermal conductivity along with a high electrical conductivity and Seebeck coefficient, which leads to high thermoelectric performance (n-type) at room temperature. Herein, we report a pseudo-ternary phase (Ag2Se0.5Te0.25S0.25) that exhibits significantly high thermoelectric performance (zT ∼ 2.1) even at 400 K. First-principles calculation reveals that the Rashba type of spin-dependent band spitting, which originates due to sulfur and tellurium substitution, helps to improve the thermopower magnitude. We also show that the intrinsic carrier mobility is not only controlled by the carrier effective mass but is substantially limited by longitudinal acoustic and optical phonon modes, which is an extension of the deformation potential theory. Locally off-center sulfur atoms, together with the increase in configurational entropy via substitution of Te and S atoms in Ag2Se, lead to a drastic reduction in the lattice thermal conductivity (klat ∼ 0.34 W m-1 K-1 at 400 K). The Rashba effect coupled with the configurational entropy synergistically results in a high thermoelectric figure of merit in the n-type thermoelectric material working in the near-room-temperature regime.

Boosting algorithms for projecting streamflow in the Lower Godavari Basin for different climate change scenarios.

The present study investigates the ability of five boosting algorithms, namely Adaptive Boosting (AdaBoost), Categorical Boosting (CatBoost), Light Gradient Boosting (LGBoost), Natural Gradient Boosting (NGBoost), and eXtreme Gradient Boosting (XGBoost) for simulating streamflow in the Lower Godavari Basin, India. Monthly rainfall, temperatures, and streamflow from 1982 to 2020 were used for training and testing. Kling Gupta Efficiency (KGE) was deployed to assess the ability of the boosting algorithms. It was observed that all the boosting algorithms had shown good simulating ability, having KGE values of AdaBoost (0.87, 0.85), CatBoost (0.90, 0.78), LGBoost (0.95, 0.93), NGBoost (0.95, 0.95), and XGBoost (0.91, 0.90), respectively, in training and testing. Thus, all the algorithms were used for projecting streamflow in a climate change perspective for the short-term projections (2025-2050) and long-term projections (2051-2075) for four Shared Socioeconomic Pathways (SSPs). The highest streamflow for all four SSPs in the case of NGBoost is more than the historical scenario (9382 m3/s), whereas vice-versa for the remaining four. The effect of ensembling the outputs of five algorithms is also studied and compared with that of individual algorithms.

Improving blast resistance of maintainer line DRR 9B by transferring broad spectrum resistance gene Pi2 by marker assisted selection in rice.

Hybrid rice technology offers great promise to further enhance rice production and productivity for global food security. Improving hybrid rice parental lines is the first step in developing heterotic rice hybrids. To improve resistance against blast disease, a maintainer line DRR 9B was fortified with a major broad-spectrum blast resistance gene Pi2 through marker-assisted selection. The rice blast caused by Magnaporthe oryzae is a major disease and can cause severe yield losses upto 100%. The NILs of Samba Mahsuri namely BA-23-11-89-12-168 possessing Pi2 was utilized as a donor parent. The PCR-based molecular marker tightly linked to Pi2 gene was used for the foreground selection at BC1F1 generation. The molecular marker tightly linked to the major fertility restorer gene Rf4 was used for negative selection (i.e., selection of plants possessing non fertility restoring alleles) at BC1F1 generation to identify maintainer lines. The positive plants with Rf4 gene were added to the restorer pool for restorer line development. At each stage, MAS for Pi2 coupled with stringent phenotypic selection for agro-morphological and grain quality traits were exercised. At BC1F3 generation, one hundred families were screened against blast disease at uniform blast nursery (UBN) and selected resistant lines were advanced to next generations. In the BC1F5 generation plants were subjected to agro-morphological evaluation for yield and yield-contributing traits. The selected plants at BC1F5 generation were crossed with DRR 9A to assess the maintainer ability of blast resistance lines and for further CMS line conversion for hybrid rice breeding for developing blast resistance rice hybrids.

Measuring the quality of antenatal care in a context of high utilisation: evidence from Telangana, India.

BACKGROUND: Antenatal care coverage has dramatically increased in many low-and middle-income settings, including in the state of Telangana, India. However, there is increasing evidence of shortfalls in the quality of care women receive during their pregnancies. This study aims to examine dimensions of antenatal care quality in Telangana, India using four primary and secondary data sources. METHODS: Data from two secondary statewide data sources (National Family Health Survey (NFHS-5), 2019-21; Health Management Information System (HMIS), 2019-20) and two primary data sources (a facility survey in 19 primary health centres and sub-centres in selected districts of Telangana; and observations of 36 antenatal care consultations at these facilities) were descriptively analysed. RESULTS: NFHS-5 data showed about 73% of women in Telangana received all six assessed antenatal care components during pregnancy. HMIS data showed high coverage of antenatal care visits but differences in levels of screening, with high coverage of haemoglobin tests for anaemia but low coverage of testing for gestational diabetes and syphilis. The facility survey found missing equipment for several key antenatal care services. Antenatal care observations found blood pressure measurement and physical examinations had high coverage and were generally performed correctly. There were substantial deficiencies in symptom checking and communication between the woman and provider. Women were asked if they had any questions in 22% of consultations. Only one woman was asked about her mental health. Counselling of women on at least one of the ten items relating to birth preparedness and on at least one of six danger signs occurred in 58% and 36% of consultations, respectively. CONCLUSION: Despite high coverage of antenatal care services and some essential maternal and foetal assessments, substantial quality gaps remained, particularly in communication between healthcare providers and pregnant women and in availability of key services. Progress towards achieving high quality in both content and experience of antenatal care requires addressing service gaps and developing better measures to capture and improve women's experiences of care.

Effect of over dilution of semen with tris extender on motion and functional attributes of bull spermatozoa during cryopreservation.

The present study was aimed to evaluate the effect of over dilution of semen with tris extender on motion and functional attributes of bull sperm post-thaw. Ejaculates (n = 24; mass motility ≥3+) were collected from bulls (n = 4) using artificial vagina, diluted to 20, 15, 10 and 5 million spermatozoa/0.25 ml, and cryopreserved. The results revealed that total motility (%), progressive motility (%) and rapid motility (%), straight linear velocity (µm/s), straightness (%) reduced significantly (p < 0.05) when semen was diluted to 5 million sperm concentration. Among the various sperm function attributes, proportions of live spermatozoa, acrosome intact spermatozoa, hypo-osmotic swelling responsive spermatozoa and non-capacitated spermatozoa reduced (p < 0.05) in 5 million spermatozoa, and the proportions of moribund spermatozoa, dead spermatozoa, live acrosome reacted spermatozoa, dead acrosome intact spermatozoa, capacitated spermatozoa and spermatozoa with lipid peroxidation increased significantly (p < 0.05) when semen was diluted from 20 to 5 million. However, the over-dilution of semen did not affect slow motility, dead acrosome reacted spermatozoa, sperm protamine deficiency and spermatozoa with lipid peroxidation. In conclusion, the over dilution of semen affected sperm motion and functional attributes of frozen-thawed bull semen.

Advances in Diagnosis and Risk Stratification of Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Advances in high-throughput DNA sequencing technology in the past decade have made a tremendous impact on basic science and clinical practice. Methods using the latest next generation sequencing technology can sequence an entire human genome within a few hours. Diagnosis and prognostication of hematologic neoplasms have moved from traditional histology and immunophenotyping to integration of cytogenetic and genomic alterations. Using illustrative cases, this chapter provides an overview of the utility of using genomic data for prognostication as well as treatment decision-making for patients with bone marrow neoplasms.

Genetics and Diagnostic Approach to Lymphoblastic Leukemia/Lymphoma.

Our understanding of the genetics and biology of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia, ALL) has advanced rapidly in the past decade with advances in sequencing and other molecular techniques. Besides recurrent chromosomal abnormalities detected by karyotyping or fluorescence in situ hybridization, these leukemias/lymphomas are characterized by a variety of mutations, gene rearrangements as well as copy number alterations. This is particularly true in the case of Philadelphia-like (Ph-like) ALL, a major subset which has the same gene expression signature as Philadelphia chromosome-positive ALL but lacks BCR-ABL1 translocation. Ph-like ALL is associated with a worse prognosis and hence its detection is critical. However, techniques to detect this entity are complex and are not widely available. This chapter discusses various subsets of ALL and describes our approach to the accurate classification and prognostication of these cases.

Prognostic Significance of ALDH1, Bmi1, and OCT4 Expression in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

BACKGROUND: Increasing evidence suggests the involvement of cancer stem cells (CSCs) in both oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Among the various CSC markers, aldehyde dehydrogenase (ALDH) 1, B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1), and octamer-binding protein 4 (OCT4) have been noted to increase in OSCC. The aim of the study was to analyze ALDH1, Bmi1, and OCT4 expression in OED and OSCC with clinicopathologic correlation and survival analysis. METHODS: A total of 40 cases each of OED and OSCC were retrieved from departmental archives. Expression of ALDH1, Bmi1, and OCT4 was analyzed using immunohistochemistry and was correlated with clinicopathological parameters. A follow-up ranging from 6 to 52 months was considered for Kaplan-Meier survival analysis. The log-rank test was performed to analyze significant difference in survival rates. RESULTS: The expression levels of ALDH1, Bmi1, and OCT4 increased significantly from OED through OSCC (P < .05). The expression of ALDH1 and OCT4 showed a significant correlation with lymph node metastasis. Positive cases of ALDH1 showed a significantly reduced survival rate compared to cases showing negative expression. Kaplan-Meier survival analysis showed a significant reduction of survival rate (P = .00) in patients showing a positive expression for all the 3 markers. CONCLUSION: ALDH1 and OCT4 could be used as individual prognostic markers for assessing prognosis. ALDH1, Bmi1, and OCT4 could be used as a collective panel of markers to enable surgeons in predicting the prognosis of patients and thereby carry out prompt follow-up for such cases.

Medical Student Exposure to Radiation Oncology Through the Pre-clerkship Residency Exploration Program (PREP): Effect on Career Interest and Understanding of Radiation Oncology.

Medical students receive little exposure to Radiation Oncology (RO) during pre-clinical training and clerkship. Pre-clerkship Residency Exploration Program (PREP) was developed by medical students at our institution to provide students with exposure to disciplines like RO with which they may not have had previous exposure, with the goal of helping with career decision making. The purpose of this study was to review how PREP affected self-reported interest in RO. PREP is a 2-week intensive elective developed by students at Dalhousie University that provides exposure to 12 specialties, including RO. PREP includes five components: half day clinical rotations, skills sessions, simulations, specialty-specific workshops, and lunchtime panel discussions. PREP participants completed questionnaires pre- and post-participation to assess career interest and understanding of Radiation Oncology. Forty participants took part in PREP. Thirty-six responded to pre-PREP questionnaires and 37 to the post-PREP questionnaire. Participants reported increasing interest in RO (24 students, 64.8%) and an increase in the understanding of the role and responsibilities of a radiation oncologist such that they felt comfortable making a career decision about RO. In pre-PREP, five (13.8%) participants listed RO as a top 3 career choice. Post-program, this number increased to nine (25.0%) of the same surveyed participants. PREP has demonstrated early exposure to RO can increase interest in RO as a career choice. Early clinical exposure experiences like we describe here may be useful for specialties such as RO, which is having difficulty filling residency positions in Canada despite an optimistic job forecast for trainees.

Addition of overland runoff and flow routing methods to SWMM-model application to Hyderabad, India.

Hydrological models apply different methods to estimate runoff and route flows. Suitability of these methods is not unique, but varies with catchment conditions. This study aims to find the suitable overland runoff and flow routing methods for a catchment in Hyderabad, India, using customised Storm Water Management Model (SWMM-C). Currently, SWMM adapts only non-linear reservoir (NLR) method to estimate overland runoff. Linear reservoir (LR) and kinematic wave overland flow (KWO) have been incorporated as additional overland runoff methods. For flow routing, SWMM currently has kinematic wave (KW) and dynamic wave (DW) methods. Muskingum, Muskingum Cunge (MC) and lag methods have been included as additional methods in this customised version. SWMM-C was calibrated with four event rainfalls and tested with six event rainfalls using all possible combinations of overland runoff and flow routing methods. Efficiency of SWMM-C in simulating runoff was evaluated using performance indices. Results showed that for low magnitude event rainfalls, NLR, LR and KWO simulated runoff with a maximum deviation of 50%, 60% and 40% from observed runoff, respectively. In high magnitude event rainfalls, NLR, LR and KWO simulated runoff with maximum deviations of 20%, 40% and 20%, respectively, from the observed runoff. It was inferred from model outputs that NLR method could simulate runoff reasonably well for rainfalls that have duration greater than the time of concentration of catchment. LR method could simulate peak runoff better. KWO method was found to be suitable for chosen catchment for all rainfall durations. Flow routing methods KW, DW and MC are found to have minor influences on the runoff.

Glutathione S-Transferase P1 313 (A > G) Ile105Val Polymorphism Contributes to Cancer Susceptibility in Indian Population: A Meta-analysis of 39 Case-Control Studies.

GSTP1 involved in the metabolism of carcinogens and toxins, reduces damage of DNA and act as a suppressor of carcinogenesis. Many studies have reported that 313 A > G polymorphism is associated with different cancer in Indian population, but the results remain conflicting rather than conclusive. Therefore, we have performed meta-analysis to clarify the more precise association of GSPT1 313 A > G polymorphism with cancer risk in Indian population. We retrieved all relevant published literature from PubMed (Medline) and Google scholar web database and included those study only based on the established inclusion criteria. Pooled ORs and 95% CIs were used to appraise the strength of association. Publication bias and sensitivity analysis was also evaluated. A total of 6581 confirmed cancer cases and 8218 controls were included from eligible thirty nine case-controls studies. Pooled analysis suggested that the variant genotypes significantly increased the risk of cancer in allele (G vs. A: OR 1.266, 95% CI 1.129-1.418, p = 0.001), heterozygous (AG vs. AA: OR 1.191, 95% CI 1.047-1.355, p = 0.008), homozygous (GG vs. AA: OR 1.811, 95% CI 1.428-2.297, p = 0.001), dominant (GG + AG vs. AA: OR 1.276, 95% CI 1.110-1.466, p = 0.001) and recessive (GG vs. AG + AA: OR 1.638, 95% CI 1.340-2.002, p = 0.001) genetic models. The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias. This meta-analysis suggests that the GSTP1 313 A > G polymorphism may contribute to genetic susceptibility to cancer in Indian population. However, larger studies and randomized clinical trial will be required to elucidate the biological and molecular mechanism of GSTP1 gene in cancer.

Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus-associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial.

Background: We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods: Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results: Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions: Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration: ISRCTN 10248064.

Niacin deficiency modulates genes involved in cancer: Are smokers at higher risk?

The role of niacin's metabolite, nicotinamide adenine dinucleotide (NAD), in DNA repair via base-excision repair pathway is well documented. We evaluated if niacin deficiency results in genetic instability in normal human fetal lung fibroblasts (MRC-5), and further, does it leads to enhanced accumulation of cigarette smoke-induced genetic damage? MRC-5 cells were grown discretely in niacin-proficient/deficient media, and exposed to nicotine-derived nitrosamine ketone (NNK, a cigarette smoke carcinogen). Niacin deficiency abated the NAD polymerization, augmented the spontaneous induction of micronuclei (MN) and chromosomal aberrations (CA) and raised the expression of 10 genes and suppressed 12 genes involved in different biological functions. NNK exposure resulted in genetic damage as measured by the induction of MN and CA in cells grown in niacin-proficient medium, but the damage became practically marked when niacin-deficient cells were exposed to NNK. NNK exposure raised the expression of 16 genes and suppressed the expression of 56 genes in cells grown in niacin-proficient medium. NNK exposure to niacin-deficient cells raised the expression of eight genes including genes crucial in promoting cancer such as FGFR3 and DUSP1 and suppressed the expression of 33 genes, including genes crucial in preventing the onset and progression of cancer like RASSF2, JUP, and IL24, in comparison with the cells grown in niacin-proficient medium. Overall, niacin deficiency interferes with the DNA damage repair process induced by chemical carcinogens like NNK, and niacin-deficient population are at the higher risk of genetic instability caused by cigarette smoke carcinogen NNK.

AA genotype of cyclin D1 G870A polymorphism increases breast cancer risk: Findings of a case-control study and meta-analysis.

BACKGROUND: Cyclin D1 (CCND1) polymorphisms, a regulator of the cell cycle progress from G1 to the S phase, may lead to uncontrolled cell proliferation and lack of apoptosis. G870A, a common single-nucleotide polymorphism in CCND1 influences breast cancer risk. However, the association between G870A polymorphism and breast cancer risk is ambiguous so far. MATERIALS AND METHODS: In this case-control study, we analyzed the role of G870A polymorphism with breast cancer risk in Indian women. A meta-analysis of 18 studies was also performed to elucidate this association by increasing statistical power. RESULTS: In our case-control study, significant risk association of the CCND1 G870A AA genotype with breast cancer in total cohort (odds ratio [OR], 2.98; 95% confidence interval [CI], 1.64-5.42; P value, 4.96e-04) and premenopausal women (OR, 3.31; 95% CI, 1.54-7.08; P value, .003) was found. The results of the meta-analysis showed that AA genotype of the CCND1 G870A polymorphism significantly increases breast cancer risk in total pooled data (AA vs GG+GA: OR = 1.20; 95% CI = 1.03 to 1.39; P value, 0.016*) and Caucasian (AA vs GG+GA: OR = 1.22; 95% CI = 0.99 to 1.51; P value, .056*) but not in Asian population. Further, a significant protective association with breast cancer was also found in the GA vs AA comparison model in pooled data (OR = 0.73; 95% CI = 0.58 to 0.92; P value, .007*) as well as in Caucasian subgroup (OR = 0.62; 95% CI = 0.49 to 0.94; P value, .022*). CONCLUSION: CCND1 G870A AA genotype was found associated with breast cancer risk. Future association studies considering the environmental impact on gene expression are required to validate/explore this association.

A trial sequential meta-analysis of IFN-γ +874 A>T (rs2430561) gene polymorphism and extrapulmonary tuberculosis risk.

Interferon-γ (IFN-γ) plays a crucial role in immunological responses against Mycobacterium tuberculosis (M.tb) infection. The polymorphism at +874 A > T (rs2430561) influences the levels of IFN-γ, which may further influence the susceptibility to extrapulmonary tuberculosis (EPTB). This polymorphism has been investigated with respect to EPTB occurrence in different populations and provided contradictory and conflicting results. This study was performed to meta-statistically analyze the data and draw a more accurate conclusion regarding the association of IFN-γ +874 A > T gene polymorphism and EPTB susceptibility. A quantitative synthesis was executed for the pertinent studies retrieved from online web-databases viz. Google Scholar, PubMed/Medline and EMBASE. The pooled odds ratios (ORs) and confidence intervals (95% CIs) were estimated for all the genetic models by meta-analysis. A total of eight studies were retrieved which included 762 confirmed EPTB cases and 1341 controls. The meta-analysis results revealed reduced association of EPTB in allelic contrast (T vs. A: p = 0.001; OR = 0.668, 95% CI = 0.524 to 0.850), homozygous (TT vs. AA: p = 0.017; OR = 0.450, 95% CI = 0.234 to 0.868), heterozygous (AT vs. AA: p = 0.004; OR = 0.574, 95% CI = 0.395 to 0.835), dominant (TT + AT vs. AA: p = 0.003; OR = 0.536, 95% CI = 0.354 to 0.810) and recessive (TT vs. AA + AT: p = 0.039; OR = 0.662, 95% CI = 0.448 to 0.980) genetic models. Furthermore, re-sampling statistics also revealed reduced risk of EPTB in overall population and Asian subgroup. This meta-analysis concluded that IFN-γ +874 A > T gene polymorphism is meaningfully related with the reduced EPTB risk in overall and Asian population, and further necessitates larger studies to be conducted on this topic in other races.

B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors.

Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. We further demonstrated that injections (i.v.) of CpG-STAT3dODN inhibited growth of human OCI-Ly3 lymphoma in immunodeficient mice. Moreover, systemic CpG-STAT3dODN administration induced complete regression of the syngeneic A20 lymphoma, resulting in long-term survival of immunocompetent mice. Both TLR9 stimulation and concurrent STAT3 inhibition were critical for immune-mediated therapeutic effects, since neither CpG7909 alone nor CpG7909 co-injected with unconjugated STAT3dODN extended mouse survival. The CpG-STAT3dODN induced expression of genes critical to antigen-processing/presentation and Th1 cell activation while suppressing survival signaling. These effects resulted in the generation of lymphoma cell-specific CD8/CD4-dependent T cell immunity protecting mice from tumor rechallenge. Our results suggest that CpG-STAT3dODN as a systemic/local monotherapy or in combination with PD1 blockade can provide an opportunity for treating patients with B cell NHL.

Aspartate-ß-semialdeyhyde dehydrogenase as a potential therapeutic target of Mycobacterium tuberculosis H37Rv: Evidence from in silico elementary mode analysis of biological network model.

The emergence of multi-drug resistant strains and co-occurrence of tuberculosis with HIV creates a major burden to the human health globally. Failure of primary antibacterial therapy necessitates the identification of new mycobacterial drugs. In this study, a comprehensive analysis involving bottom-up systems biology approach was applied wherein we have identified potential therapeutic targets of Mycobacterium tuberculosis infections. Our study prioritized M. tuberculosis therapeutic targets (aspartate-ß-semialdeyhde dehydrogenase [ASD], dihydrodipicolinate reductase and diaminopimelate decarboxylase) based on flux and elementary mode analysis using direct mathematical modeling of the relevant metabolic pathways. Molecular docking and simulation studies of the priority target (ie, ASD) revealed the therapeutic potential of the selected natural products (Huperzine A, Rosmarinic acid, and Curcumin) based ASD inhibitors. The study highlights the crucial role of systems biology in conjunction with molecular interaction (docking) for probing novel leads against an increasingly resistant pathogen, M. tuberculousis.

Inhibition of C298S mutant of human aldose reductase for antidiabetic applications: Evidence from in silico elementary mode analysis of biological network model.

Human aldose reductase (hAR) is the key enzyme in sorbitol pathway of glucose utilization and is implicated in the etiology of secondary complications of diabetes, such as, cardiovascular complications, neuropathy, nephropathy, retinopathy, and cataract genesis. It reduces glucose to sorbitol in the presence of NADPH and the major cause of diabetes complications could be the change in the osmotic pressure due to the accumulation of sorbitol. An activated form of hAR (activated hAR or ahAR) poses a potential obstacle in the development of diabetes drugs as hAR-inhibitors are ineffective against ahAR. The therapeutic efficacy of such drugs is compromised when a large fraction of the enzyme (hAR) undergoes conversion to the activated ahAR form as has been observed in the diabetic tissues. In the present study, attempts have been made to employ systems biology strategies to identify the elementary nodes of human polyol metabolic pathway, responsible for normal metabolic states, followed by the identification of natural potent inhibitors of the activated form of hAR represented by the mutant C298S for possible antidiabetic applications. Quantum Mechanical Molecular Mechanical docking strategy was used to determine the probable inhibitors of ahAR. Rosmarinic acid was found as the most potent natural ahAR inhibitor and warrants for experimental validation in the near future.