HAT and HDAC: Enzyme with Contradictory Action in Neurodegenerative Diseases.

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors.

Out-of-pocket expenditures and catastrophic expenditures on inpatient care among households of an urban village in Delhi.

Background: Out-of-pocket expenditure (OOPE) for inpatient care has been known to cause maximum impoverishment. It can have debilitating consequences for urban poor households. It is necessary to study inpatient care costs and the related factors among the households of an urban village to determine their vulnerability to catastrophic expenditure and to protect them from it. Objective: The study aimed to calculate the mean OOPE on inpatient care, and catastrophic health expenditure among households of an urban village in Delhi. Design: This was a cross-sectional study conducted over 18 months among urban village households of Delhi who have been residing for the last 1 year. Methods: A sample size of 188 was calculated based on another study, and households were selected using systematic random sampling. A pre-designed, pre-tested, semi-structured, and interviewer-administered questionnaire in Hindi was used to elicit and record relevant information. Data were recorded and coded, and analysis was done using licensed SPSS v.26 software. Tables were generated for relevant data, and cross-tables were used to assess statistical association with chi-square or Fisher exact tests, as required. A p-value of 0.05 was considered statistically significant. Results: The mean annual OOPE borne by a household on inpatient care was INR 6870.3 (SD ± 30,580.6), where 93.3% of OOPE was incurred while seeking treatment from public facilities. The OOPE on inpatient care had a statistically significant association with households having joint family, members from vulnerable population, and belonging to Delhi. Conclusion: The households of an urban village of Aliganj, Delhi, have high OOPE on inpatient care (60.6%) and catastrophic health expenditure (75.6%).

A Sustainability-Based Expert System for Additive Manufacturing and CNC Machining.

The objective of this research study is to develop a set of expert systems that can aid metal manufacturing facilities in selecting binder jetting, direct metal laser sintering, or CNC machining based on viable products, processes, system parameters, and inherent sustainability aspects. For the purposes of this study, cost-effectiveness, energy, and auxiliary material usage efficiency were considered the key indicators of manufacturing process sustainability. The expert systems were developed using the knowledge automation software Exsys Corvid®V6.1.3. The programs were verified by analyzing and comparing the sustainability impacts of binder jetting and CNC machining during the fabrication of a stainless steel 316L component. According to the results of this study, binder jetting is deemed to be characterized by more favorable indicators of sustainability in comparison to CNC machining, considering the fabrication of components feasible for each technology.

Fullerene C70 as Photoredox Catalyst for the Synthesis of Pyrrolo[2,1-a]isoquinolines by 1,3-Dipolar Cycloaddition-Aromatization Sequence.

Herein, fullerene (C70 ) is introduced as an effective photoredox catalyst for the construction of a highly functionalised pyrrolo[2,1-a]isoquinoline framework by 1,3-dipolar cycloaddition-aromatisation reaction sequence. The ability of C70 to efficiently harvest visible light, its long-triplet state lifetime, good photostability, and strong singlet oxygen generation potential (Φ▵ ≈1), make it an efficient photoredox catalyst. Upon photoirradiation, C70 promotes the formation of singlet oxygen and superoxide radical by energy transfer (EnT) and single electron transfer (SET) mechanism. The superoxide radical acts as a potential oxidant in the formation of azomethine ylide through the oxidation-deprotonation tandem process. Azomethine ylide further participates in [3+2]-cycloaddition reaction protocol with alkene/alkyne to give the corresponding pyrrolo[2,1-a]isoquinolines. Interestingly, this protocol allows the activation of a wide range of substrates giving access to a diverse library of 48 well-decorated pyrrolo[2,1-a]isoquinolines with good functional group tolerance.

Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection.

Objectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals.

Aza-dipyrrinato ruthenium sensitizers for enhancement of Light-Harvesting ability of Dye-Sensitized solar cells.

Three new aza-dipyrrinato ruthenium sensitizers AZA-BPY, AZA-BPY-NCS, and AZA-TER, have been designed and successfully synthesized. We have studied the effect of aza-dipyrrinato ligands on the photo-physical and electrochemical properties. The aza-dipyrrinato ancillary ligand exhibited enhancement in the light-harvesting capability compared to the traditional dipyrrinato ligand by coordinating ruthenium metal. The strong σ-donor characteristic of the aza-dipyrrinato ligand showed more adequate properties: red-shift in the absorption extended into the NIR region ( ≈ 1000 nm), and redox potentials compared to our earlier reported dipyrrinato sensitizer (GS3), which are confirmed by the UV-Vis absorption spectroscopy and cyclic voltammetry. All the characteristics features shows that these dyes are a good sensitizer candidate for DSSCs.

Indian Society of Hematology and Blood Transfusion (ISHBT) Consensus Document on Hematological Practice During COVID-19 Pandemic.

The SARS-CoV-2 (COVID-19) pandemic is a worldwide public health emergency with widespread impact on health care delivery. Unforeseen challenges have been noted during administration of usual haematology care in these unusual COVID-19 times. Medical services have been overstretched and frontline health workers have borne the brunt of COVID-19 pandemic. Movement restrictions during lockdown prevented large sections of population from accessing health care, blood banks from holding blood drives, and disrupted delivery of diagnostic hematology services. The disruption in hematology care due to COVID-19 pandemic in India has been disproportionately higher compared to other subspecialities as hematology practice in India remains restricted to major cities. In this review we chronicle the challenges encountered in caring for hematology patients during the COVID-19 pandemic in India and put forth recommendations for minimizing their impact on provision of hematology care with special emphasis on hematology practice in lower and middle income countries (LMICs).

Genomic Landscape and Targeted Treatment of Gallbladder Cancer: Results of a First Ongoing Prospective Study.

Background Prognosis of gallbladder cancer (GBC) has not changed in the past 20 years. Comprehensive genomic profiling (CGP) carries potential to determine the actionability for multiple targets, including ERBB2 , ERBB3 , MET , ROSI , FGFR , and PIK3 . This study evaluates the role of CGP and targeted therapies. Methods This is a multicenter, prospective, single-arm study. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture-based CGP was performed by Foundation Medicine CDx. All patients received first-line chemotherapy with gemcitabine-cisplatin regimen. Patients with ERBB2/3 amplification received trastuzumab with capecitabine or nab-paclitaxel, and patients with MET amplification were treated with crizotinib. For ERBB2/3 mutations, lapatinib plus capecitabine regimen was used. Results Fifty patients were studied with a median age of 56 years (range 26-83) and a male-to-female ratio of 1:1.6. ERBB2 and ERBB3 amplification was seen in 9 (18%) and 2 (4%) patients, respectively. Four patients with ERBB2 amplification received trastuzumab and/or lapatinib, showed partial response, and maintained response beyond 12 weeks. One patient had mixed response, whereas two patients progressed on trastuzumab and lapatinib. Three patients with ERBB3 mutations showed response to lapatinib-capecitabine. One patient with MET amplification responded to crizotinib for 4 weeks. PIK3 mutations were present in 14% of cases and were independent of ERBB aberrations. Conclusion GBC is enriched in 28% of patients with ERBB2 and ERBB3 amplifications and/or mutations. Responses are seen with lapatinib in concurrent ERBB2 mutation and amplification. ERBB3 mutation showed response to lapatinib. MET and PIK3 are new findings in GBC, which may be targeted.

Fabrication of deoxycholic acid tethered α-cyanostilbenes as smart low molecular weight gelators and AIEE probes for bio-imaging.

Four novel deoxycholic acid tethered α-cyanostilbenes were designed, synthesized and characterized using detailed spectroscopic analysis. The synthesized deoxycholic acid tethered α-cyanostilbene derivatives formed stable gels with a variety of solvents, such as xylene, toluene, mesitylene, decane, dodecane etc. The stable gels showed lamellar sheet type structures stacked over each other, consisting of entangled fibres as evident from SEM, TEM and Fluorescence Microscopy images; The synthesized compounds exhibited AIEE behaviour in H2O/THF mixture, with the maximum emission observed in 70% H2O/THF fraction along with a bathochromic shift. A solvent thickening experiment was perform to establish the mechanism of AIEE and the AIEE property was explored for bacterial bio-imaging. The synthesized derivatized steroids proved their potential as multifunctional organic materials.

A Randomized Controlled Trial to Compare the Efficacy, Safety and Tolerability of Asenapine versus Olanzapine in Management of Schizophrenia

Objective@#Schizophrenia is a serious disease characterized by impairment in the perception or expression of reality, leading to occupational and social dysfunction. The use of antipsychotic medication is now universal in the first-line treatment of schizophrenia. This study was undertaken to compare the efficacy of asenapine with a standard atypical antipsychotic, olanzapine in treating this disease. @*Methods@#It was designed as a single blind, randomized, controlled, parallel group, single centre Phase IV trial of a newer atypical antipsychotic, asenapine versus existing standard atypical antipsychotic, olanzapine. Total 80 subjects were enrolled as per eligibility criteria.Each recruited subject received daily treatment with the trial medication (Olanzapine 10 mg or Asenapine 10 mg daily) for duration of 12 weeks. BPRS, CGI-S, CGI-I, Laboratory parameters and compliance was assessed and analyzed. Continuous variables were compared by t test and non-parametric data was analyzed by Mann−Whitney U test and Wilcoxon signed rank test. Likely categorical variables were analyzed by chi-square test or Fisher’s exact test, as appropriate. @*Results@#The duration of schizophrenia at presentation was comparable in both the treatment groups. There was significant reduction of BPRS score between any two visits of each treatment groups. The decline in CGI-S and CGI-I scores was statistically significant (p ＜ 0.001) when compared between visits of any of the both treatment arms.Adherence to treatment was excellent for all patients. @*Conclusion@#Newer atypical antipsychotic asenapine is more effective than standard olanzapine in reducing the symptoms of schizophrenia in this study and further larger studies are to be done.

Lentiviral Vpx induces alteration of mammalian cell nuclear envelope integrity.

Vpx, a virion-associated protein of Human Immunodeficiency Virus 2 (HIV-2) and Simian Immunodeficiency Virus (SIV) counteracts host restriction factor SAMDH1 for efficient viral DNA synthesis in the cytoplasm and mediates subsequent nuclear translocation of the viral genome. Vpx was found to be indispensable in the viral infection of terminally differentiated target cells and macaques infected with virions carrying truncated Vpx showed delayed pathogenesis, suggesting multiple roles of Vpx at different steps in the virus life cycle. The current study demonstrates a novel function of SIVsmPBj1.9 Vpx on the integrity of the nuclear envelope in HeLa cells. Results from the Super-Resolution Structured Illumination Microscopy (SR-SIM) analysis showed that Vpx puncta alter HeLa cell nuclear envelope assembly. Furthermore, three-dimensional (3D) SIM analysis of such regions suggests that Vpx is primed in a specific way to disrupt the nuclear envelope integrity. The nuclear incursion of cytoplasmic proteins through Vpx mediated ruptured nuclear envelope regions suggest that these events might play a critical role in the nuclear entry of otherwise cytoplasmically sequestered molecules and theirby may be assisting Vpx functions including the transport of viral genome into the nucleus, which is critical for the establishment of virus infection and pathogenesis.

Biological evaluation and structure activity relationship of 9-methyl-1-phenyl-9H-pyrido[3,4-b]indole derivatives as anti-leishmanial agents.

A series of piperazinyl-ß-carboline-3-carboxamide derivatives were designed through a molecular hybridization approach. Designed analogues were synthesized, characterized and evaluated for anti-leishmanial activity against Leishmania infantum and Leishmania donovani. In L. infantum inhibition assay, compounds 7d, 7g and 7c displayed potent inhibition of promastigotes (EC50 1.59, 1.47 and 3.73 µM respectively) and amastigotes (EC50 1.4, 1.9 and 2.6 µM respectively). SAR studies revealed that, para substitution of methoxy, chloro groups and methyl group on ortho position favored anti-leishmanial activity against L. infantum. Among these analogues 7d, 7h, 7n and 7g exhibited potent inhibition against L. donovani promastigotes (EC50 0.91, 4.0, 4.57 and 5.02 µM respectively), axenic amastigotes (EC50 0.9, 3.5, 2.2 and 3.8 µM respectively) and intracellular amastigotes (EC50 1.3, 7.8, 5.6 and 6.3 µM respectively). SAR studies suggested that, para substitution of methoxy group, para and meta substitution of chloro groups and benzyl replacement recommended for significant anti-leishmanial against L. donovani.

TP53 codon 72 polymorphism and the risk of glaucoma in a north Indian cohort: A genetic association study.

BACKGROUND: The TP53 codon 72 Proline-Arginine polymorphism (TP53 P72R) is the most widely studied candidate among those evaluated for a putative association between impaired apoptosis and glaucoma. Considering the earlier findings about enhanced apoptotic potential by the Arg variant of TP53 P72R and the conflicting results about its association with glaucoma, we initiated a hospital-based case-control association study in a north Indian cohort to investigate the association of TP53 P72R with glaucoma. MATERIALS AND METHODS: We examined the status of TP53 P72R in 139 cases of primary open angle glaucoma (POAG) and in 111 cases of primary angle closure glaucoma (PACG) with respect to 218 controls using the polymerase chain reaction-restriction fragment length polymorphism method. Logistic regression analysis including age and gender as covariates was carried out to test the association of the polymorphism with overall glaucoma, POAG, and PACG cases. RESULTS: We observed significant differences between the genotypic distributions of combined glaucoma cases and controls in the recessive model. POAG cases with respect to controls did not exhibit any significant differences in the genotypic distributions. In contrast, the genotypic distributions as per the additive and recessive models in PACG cases were significantly different from those in controls. The two models suggested an increased risk of PACG in the Arg homozygotes of the investigated cohort. CONCLUSIONS: Ours is the first study demonstrating the association of TP53 P72R with the risk of PACG. It emphasizes that apart from narrow anterior chamber angle, impaired apoptotic mechanisms could also be an important contributor toward PACG.

Spirulina platensis prevents high glucose-induced oxidative stress mitochondrial damage mediated apoptosis in cardiomyoblasts.

The current study was undertaken to study the effect of Spirulina platensis (Spirulina) extract on enhanced oxidative stress during high glucose induced cell death in H9c2 cells. H9c2 cultured under high glucose (33 mM) conditions resulted in a noteworthy increase in oxidative stress (free radical species) accompanied by loss of mitochondrial membrane potential, release of cytochrome c, increase in caspase activity and pro-apoptotic protein (Bax). Spirulina extract (1 µg/mL), considerably inhibited increased ROS and RNS levels, reduction in cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax and suppressed the Bax/Bcl2 ratio with induced apoptosis without affecting cell viability. Overall results suggest that Spirulina extract plays preventing role against enhanced oxidative stress during high glucose induced apoptosis in cardiomyoblasts as well as related dysfunction in H9c2 cells.

Intra-Atrial Y-Graft Fontan for Univentricular Heart With Discontinuous Pulmonary Arteries.

The Y-graft Fontan as described today suffers from the disadvantage of being hostage to restrictions imposed upon the design of the limbs of the Y by existent cardiac anatomy. We describe a patient with discontinuous pulmonary arteries following a prior Glenn shunt, who underwent Fontan completion using an intra-atrial Y-limb placement for recruitment of the discontinuous pulmonary artery. Intracardiac placement of the limb(s) of the Y-graft could potentially increase the applicability of this Fontan modification without being constrained by external cardiac anatomy.

Survivin, a molecular target for therapeutic interventions in squamous cell carcinoma.

Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.

Prospects of Graphene as a Potential Carrier-Transport Material in Third-Generation Solar Cells.

Third-generation solar cells are understood to be the pathway to overcoming the issues and drawbacks of the existing solar cell technologies. Since the introduction of graphene in solar cells, it has been providing attractive properties for the next generation of solar cells. Currently, there are more theoretical predictions rather than practical recognitions in third-generation solar cells. Some of the potential of graphene has been explored in organic photovoltaics (OPVs) and dye-sensitized solar cells (DSSCs), but it has yet to be fully comprehended in the recent third-generation inorganic-organic hybrid perovskite solar cells. In this review, the diverse role of graphene in third-generation OPVs and DSSCs will be deliberated to provide an insight on the prospects and challenges of graphene in inorganic-organic hybrid perovskite solar cells.

Growth inhibition and chemo-radiosensitization of head and neck squamous cell carcinoma (HNSCC) by survivin-siRNA lentivirus.

BACKGROUND: Survivin expression is often associated with aggressive tumor behavior and therapy resistance. In this study, we investigated the effect of survivin knockdown by survivin-siRNA lentiviral vector (Svv-Lent) on the response of HNSCC to chemo-radiotherapy, tumor growth and metastasis. METHODS: Four human HNSCC (OSC19, Cal27, Cal33 and FaDu) and one normal HOK cell lines were included in the study, and survivin knockdown was achieved with Svv-Lent treatment. Cell proliferation and apoptosis were measured by MTT and TUNEL assay, respectively. Transwell assays were performed to measure in vitro cell migration and matrigel invasion. Xenograft tumors were developed in nude mice by injecting Cal27 cells subcutaneously and following tail-vein injection of lung and liver metastasis. RESULTS: Knockdown of survivin significantly suppressed HNSCC cell proliferation and induced apoptosis in vitro. Survivin inhibition could also significantly reduce in vitro cell migration and matrigel invasion that might be due to inactivation of matrix metalloproteinases. In vivo studies showed significant repression of Cal27 xenograft tumor growth and tissue metastasis leading to improvement in mice survival in the Svv-Lent treated group compared to controls. Our data indicated that survivin expression in HNSCC cells contributed to chemo-radioresistance, and its down-regulation increased anti-cancer effects of paclitaxel, cisplatin and radiation. CONCLUSIONS: Our findings suggest that sustained survivin expression facilitates HNSCC tumor growth and confers resistance to chemo-radiotherapy. Svv-Lent therapy may be able to enhance the cytotoxic effect of commonly used anticancer drugs such as cisplatin and paclitaxel, and radiotherapy that could provide a promising strategy for the effective control of resistant head and neck cancer.

Dental public health in India: An insight.

Oral diseases are a major public health problem, and their burden is on increase in many low- and middle-income countries. Dental public health (DPH) aims to improve the oral health of the population through preventive and curative services. However, its achievements in India are being questioned probably because of lack of proficiency and skill among DPH personnel. The literature search for the present study was conducted utilizing various search engines and electronic databases such as PubMed and MEDLINE. Documents related to the Central and State Governments of India were also considered. Finally, 26 articles were selected for the present study from which relevant information can be extracted. The present study focuses on some of the important aspects relating to DPH in India such as priority for oral health, DPH workforce and curriculum, utilization of DPH personnel in providing primary oral health care, role of mobile dental vans, and research in DPH. It was concluded that more attention should be given toward preventive oral health care by employing more number of public health dentists in public sector, strengthening DPH education and research, and combining oral health programs with general health-care programs.

Ultrasound-Guided Trigger Point Injection for Myofascial Trigger Points in the Subscapularis and Pectoralis Muscles

No abstract available.