The long-term effects of childhood circumstances on older individuals: A systematic review.

Childhood experiences are known to shape individuals' development and can influence various aspects of life later on. Understanding the long-term effects is crucial for informing interventions and policies aimed at promoting healthy aging. This review aimed to explore the long-term effects of childhood experiences on older individuals. This systematic review comprised three distinct phases. Firstly, a systematic review was conducted, exploring databases such as Google Scholar, PubMed, EMBASE, PsycINFO, and the Web of Science. Out of the 2116 studies initially identified, 24 studies were selected based on the inclusion criteria. Secondly, these inclusion criteria were applied to ensure that the chosen studies specifically delved into the connection between childhood experiences and outcomes in older individuals. Finally, data extraction and synthesis techniques were employed to analyze findings, facilitating the drawing of conclusions concerning the enduring impacts of childhood experiences on the well-being of older individuals. The review's findings revealed how negative experiences in childhood continue to affect older individuals in various ways. These early-life events have far-reaching consequences, profoundly impacting their physical health, making them more susceptible to chronic diseases and weakening their immune system. Additionally, they affect mental health, leading to conditions like depression, anxiety, and substance abuse. Cognitive function is also affected, resulting in memory problems and cognitive decline. Furthermore, these experiences impact social relationships, affecting trust, emotional control, and social isolation in later life. This review highlighted the enduring influence of childhood circumstances on the health and well-being of older individuals. Policymakers and health care practitioners should consider these findings when developing strategies to support healthy aging and mitigate the long-term effects of adverse childhood experiences.

4-(Benzyloxy)phenol-induced p53 exhibits antimycobacterial response triggering phagosome-lysosome fusion through ROS-dependent intracellular Ca2+ pathway in THP-1 cells.

Drug-resistant tuberculosis (TB) outbreak has emerged as a global public health crisis. Therefore, new and innovative therapeutic options like host-directed therapies (HDTs) through novel modulators are urgently required to overcome the challenges associated with TB. In the present study, we have investigated the anti-mycobacterial effect of 4-(Benzyloxy)phenol. Cell-viability assay asserted that 50 µM of 4-(Benzyloxy)phenol was not cytotoxic to phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. It was observed that 4-(Benzyloxy)phenol activates p53 expression by hindering its association with KDM1A. Increased ROS, intracellular Ca2+ and phagosome-lysosome fusion, were also observed upon 4-(Benzyloxy)phenol treatment. 4-(Benzyloxy)phenol mediated killing of intracellular mycobacteria was abrogated in the presence of specific inhibitors of ROS, Ca2+ and phagosome-lysosome fusion like NAC, BAPTA-AM, and W7, respectively. We further demonstrate that 4-(Benzyloxy)phenol mediated enhanced ROS production is mediated by acetylation of p53. Blocking of p53 acetylation by Pifithrin-α (PFT- α) enhanced intracellular mycobacterial growth by blocking the mycobactericidal effect of 4-(Benzyloxy)phenol. Altogether, the results showed that 4-(Benzyloxy)phenol executed its anti-mycobacterial effect by modulating p53-mediated ROS production to regulate phagosome-lysosome fusion through Ca2+ production.

RNAi-Based Therapy: Combating Shrimp Viral Diseases.

Shrimp aquaculture has become a vital industry, meeting the growing global demand for seafood. Shrimp viral diseases have posed significant challenges to the aquaculture industry, causing major economic losses worldwide. Conventional treatment methods have proven to be ineffective in controlling these diseases. However, recent advances in RNA interference (RNAi) technology have opened new possibilities for combating shrimp viral diseases. This cutting-edge technology uses cellular machinery to silence specific viral genes, preventing viral replication and spread. Numerous studies have shown the effectiveness of RNAi-based therapies in various model organisms, paving the way for their use in shrimp health. By precisely targeting viral pathogens, RNAi has the potential to provide a sustainable and environmentally friendly solution to combat viral diseases in shrimp aquaculture. This review paper provides an overview of RNAi-based therapy and its potential as a game-changer for shrimp viral diseases. We discuss the principles of RNAi, its application in combating viral infections, and the current progress made in RNAi-based therapy for shrimp viral diseases. We also address the challenges and prospects of this innovative approach.

Soybean lectin-triggered IL-6 secretion induces autophagy to kill intracellular mycobacteria through P2RX7 dependent activation of the JAK2/STAT3/Mcl-1 pathway.

Cytokine therapy and cytokine-mediated autophagy have been used as prominent host-directed therapy (HDT) approaches to restrain M. tb growth in the host cell. In the present study, we have dissected the anti-tubercular activity of Soybean lectin (SBL) through cytokine-mediated autophagy induction in differentiated THP-1 (dTHP-1) cells. A significant increase in IL-6 expression was observed in both uninfected and mycobacteria infected dTHP-1 cells through the P2RX7 mediated pathway via PI3K/Akt/CREB-dependent signalling after SBL treatment. Inhibition of IL-6 level using IL-6 neutralizing antibody or associated signalling significantly enhanced the mycobacterial load in SBL-treated dTHP-1 cells. Further, autocrine signalling of IL-6 through its receptor-induced Mcl-1 expression activated autophagy via JAK2/STAT3 pathway, and inhibition of this pathway affected autophagy. Finally, blocking the IL-6-regulated autophagy through NSC 33994 (a JAK2 inhibitor) or S63845 (an Mcl-1 inhibitor) led to a notable increase in intracellular mycobacterial growth in SBL-treated cells. Taken together, these results indicate that SBL interacts with P2RX7 to regulate PI3K/Akt/CREB network to release IL-6 in dTHP-1 cells. The released IL-6, in turn, activates the JAK2/STAT3/Mcl-1 pathway upon interaction with IL-6Rα to modulate autophagy that ultimately controls mycobacterial growth in macrophages.

Ac-93253 inhibits intracellular growth of mycobacteria in human macrophages by inducing apoptosis in mitochondrial-dependent manner.

Recent studies suggest that apoptosis in macrophages plays a significant role in host defence against intracellular pathogens like viruses, fungi, protozoan, and bacteria, including Mycobacterium tuberculosis (M. tb). It is still unclear if micromolecules inducing apoptosis could be an attractive approach to combat the intracellular burden of M. tb. Hence, the present study has investigated the anti-mycobacterial effect of apoptosis mediated through phenotypic screening of micromolecules. Through MTT and trypan blue exclusion assay, 0.5 µM of Ac-93253 was found to be non-cytotoxic even after 72 h of treatment in phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. Significant regulation in the expression of various pro-apoptotic genes like Bcl-2, Bax, and Bad and the cleaved caspase 3 was observed upon treatment with a non-cytotoxic dose of Ac-93253. Ac-93253 treatment also leads to DNA fragmentation and increased phosphatidylserine accumulation in the plasma membrane's outer leaflet. Further, Ac-93253 also effectively reduced the growth of mycobacteria in infected macrophages, Z-VAD-FMK a broad-range apoptosis inhibitor significantly brought back the mycobacterial growth in Ac-93253 treated macrophages. These findings suggest apoptosis may be the probable effector response through which Ac-93253 manifests its anti-mycobacterial property.

Efficacy of Intraperitoneal 0.2% Ropivacaine With Dexmedetomidine Versus 0.2% Ropivacaine With Ketamine in Laparoscopic Surgeries: A Randomized Controlled Trial.

BACKGROUND: Effective pain management modalities are the armamentarium for enhanced recovery in laparoscopic surgeries. Intraperitoneal instillation of local anaesthetics with adjuvants is advantageous in minimizing pain. So, we designed this study with the aim to compare the analgesic effectiveness of intraperitoneal ropivacaine with adjuvants like dexmedetomidine versus ketamine for postoperative analgesia. OBJECTIVE:  The objective of this study is to assess the total duration of analgesia and total rescue analgesic dose requirements in the first 24 hours postoperatively. MATERIALS AND METHODS: A total of 105 consenting patients for elective laparoscopic surgeries were enrolled and divided into three groups by computer-generated randomization as follows: Group 1: 30 ml of 0.2% ropivacaine with ketamine 0.5 mg/kg diluted to 1 ml; Group 2: 30 ml of 0.2% ropivacaine with dexmedetomidine 0.5 mcg/kg diluted to 1 ml; Group 3: 30 ml of 0.2% ropivacaine with 1 ml of normal saline. The postoperative visual analogue scale (VAS) score, total duration of analgesia, and total analgesic dose were calculated and compared among the three groups. RESULTS: The postoperative analgesic duration after intraperitoneal instillation of Group 2 was longer as compared to Group 1. The total analgesic requirement was lower in Group 2 as compared to Group 1, and the p-value was significant (p ≤ 0.001) for both parameters. Demographic parameters and VAS scores among the three groups were not statistically significant. CONCLUSION: We conclude that intraperitoneal instillation of local anaesthetics with adjuvants is effective for postoperative analgesia in laparoscopic surgeries, and ropivacaine 0.2% with dexmedetomidine 0.5 mcg/kg is more effective when compared to ropivacaine 0.2% with ketamine 0.5 mg/kg.

Involvement of epigenetics in affecting host immunity during SARS-CoV-2 infection.

Coronavirus disease 19 (COVID-19) is caused by a highly contagious RNA virus Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), originated in December 2019 in Wuhan, China. Since then, it has become a global public health concern and leads the disease table with the highest mortality rate, highlighting the necessity for a thorough understanding of its biological properties. The intricate interaction between the virus and the host immune system gives rise to diverse implications of COVID-19. RNA viruses are known to hijack the host epigenetic mechanisms of immune cells to regulate antiviral defence. Epigenetics involves processes that alter gene expression without changing the DNA sequence, leading to heritable phenotypic changes. The epigenetic landscape consists of reversible modifications like chromatin remodelling, DNA/RNA methylation, and histone methylation/acetylation that regulates gene expression. The epigenetic machinery contributes to many aspects of SARS-CoV-2 pathogenesis, like global DNA methylation and receptor angiotensin-converting enzyme 2 (ACE2) methylation determines the viral entry inside the host, viral replication, and infection efficiency. Further, it is also reported to epigenetically regulate the expression of different host cytokines affecting antiviral response. The viral proteins of SARS-CoV-2 interact with various host epigenetic enzymes like histone deacetylases (HDACs) and bromodomain-containing proteins to antagonize cellular signalling. The central role of epigenetic factors in SARS-CoV-2 pathogenesis is now exploited as promising biomarkers and therapeutic targets against COVID-19. This review article highlights the ability of SARS-CoV-2 in regulating the host epigenetic landscape during infection leading to immune evasion. It also discusses the ongoing therapeutic approaches to curtail and control the viral outbreak.

ESAT-6 impedes IL-18 mediated phagosome lysosome fusion via microRNA-30a upon Calcimycin treatment in mycobacteria infected macrophages.

The weaponry possessed by Mycobacterium tuberculosis (M. tb) in the form of immunodominant antigens hijack the host immune system to give a survival advantage to this intracellular fiend, but the mechanism of this control is not entirely known. Since we have previously reported the mechanism of autophagy inhibition by early secreted antigenic target 6 kDa (ESAT-6) through microRNA (miR)-30a-3p in Calcimycin treated differentiated THP-1 (dTHP-1) cells, the present study was undertaken to deduce the effect of miR-30a on the immunomodulatory profile of ESAT-6 treated cells and the mechanism involved thereof, if any. Initially, the effect of recombinant ESAT-6 (rESAT-6) on the immunomodulatory profile in Calcimycin-treated phorbol 12-myristate 13-acetate (PMA) dTHP-1 cells was checked. Later, transfection studies using miR-30a-3p inhibitor or -5p mimic highlighted the contrary roles of different arms of the same miRNA in regulating IL-18 response by ESAT-6 in dTHP-1 cells after Calcimycin treatment. By using either IL-18 neutralizing antibody or inhibitors of phosphoinositide 3-kinase (PI3K)/NF-κB/phagosome-lysosome fusion in the miRNA-30a transfected background, IL-18 mediated signaling and intracellular killing of mycobacteria was reversed in the presence of ESAT-6. Overall, the results of this study conclusively prove the contrary roles of miR-30a-3p and miR-30a-5p in regulating IL-18 signaling by ESAT-6 in dTHP-1 cells upon Calcimycin treatment that affected phagosome-lysosome fusion and intracellular survival of mycobacteria.

SARS-CoV-2 Spike Mutations, L452R, T478K, E484Q and P681R, in the Second Wave of COVID-19 in Maharashtra, India.

As the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic expands, genomic epidemiology and whole genome sequencing are being used to investigate its transmission and evolution. Against the backdrop of the global emergence of "variants of concern" (VOCs) during December 2020 and an upsurge in a state in the western part of India since January 2021, whole genome sequencing and analysis of spike protein mutations using sequence and structural approaches were undertaken to identify possible new variants and gauge the fitness of the current circulating strains. Phylogenetic analysis revealed that newly identified lineages B.1.617.1 and B.1.617.2 were predominantly circulating. The signature mutations possessed by these strains were L452R, T478K, E484Q, D614G and P681R in the spike protein, including within the receptor-binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R, T478K and E484Q revealed that these may possibly result in increased ACE2 binding while P681R in the furin cleavage site could increase the rate of S1-S2 cleavage, resulting in better transmissibility. The two RBD mutations, L452R and E484Q, indicated decreased binding to select monoclonal antibodies (mAbs) and may affect their neutralization potential. Further in vitro/in vivo studies would help confirm the phenotypic changes of the mutant strains. Overall, the study revealed that the newly emerged variants were responsible for the second wave of COVID-19 in Maharashtra. Lineage B.1.617.2 has been designated as a VOC delta and B.1.617.1 as a variant of interest kappa, and they are being widely reported in the rest of the country as well as globally. Continuous monitoring of these and emerging variants in India is essential.

P2X7 receptor in multifaceted cellular signalling and its relevance as a potential therapeutic target in different diseases.

P2X7 receptor, a purinergic receptor family member, is abundantly expressed on many cells, including immune, muscle, bone, neuron, and glia. It acts as an ATP-activated cation channel that permits the influx of Ca2+, Na+ and efflux of K+ ions. The P2X7 receptor plays crucial roles in many physiological processes including cytokine and chemokine secretion, NLRP3 inflammasome activation, cellular growth and differentiation, locomotion, wound healing, transcription factors activation, cell death and T-lymphocyte survival. Past studies have demonstrated the up-regulation and direct association of this receptor in many pathophysiological conditions such as cancer, diabetics, arthritis, tuberculosis (TB) and inflammatory diseases. Hence, targeting this receptor is considered a worthwhile approach to lessen the afflictions associated with the disorders mentioned above by understanding the receptor architecture and downstream signalling processes. Here, in the present review, we have dissected the structural and functional aspects of the P2X7 receptor, emphasizing its role in various diseased conditions. This information will provide in-depth knowledge about the receptor and help to develop apt curative methodologies for the betterment of humanity in the coming years.

Hypothermia Effectively Treats Tumors with Temperature-Sensitive p53 Mutations.

The p53 tumor suppressor is frequently inactivated by mutations in cancer. Most p53 mutations are located in the DNA-binding domain, causing local disruption of DNA-binding surface or global misfolding. Rescuing the structural defect of mutant p53 is an attractive therapeutic strategy, but its potential remains unproven due to a lack of drugs capable of efficiently rescuing misfolded p53. Although mutant p53 in tumors is inactive at 37°C, approximately 15% are temperature sensitive (ts) and regain DNA-binding activity at 32°C to 34°C (ts mutants). This temperature is achievable using a therapeutic hypothermia procedure established for resuscitated cardiac arrest patients. To test whether hypothermia can be used to target tumors with ts p53 mutations, the core temperature of tumor-bearing mice was lowered to 32°C using the adenosine A1 receptor agonist N6-cyclohexyladenoxine that suppresses brain-regulated thermogenesis. Hypothermia treatment (32 hours at 32°C × 5 cycles) activated endogenous ts mutant p53 in xenograft tumors and inhibited tumor growth in a p53-dependent fashion. Tumor regression and durable remission in a ts p53 lymphoma model was achieved by combining hypothermia with chemotherapy. The results raise the possibility of treating tumors expressing ts p53 mutations with hypothermia. SIGNIFICANCE: Pharmacologic inhibition of brain-regulated thermogenesis and induction of 32°C whole-body hypothermia specifically targets tumors with temperature-sensitive p53 mutations, rescuing p53 transcriptional activity and inducing tumor regression.See related commentary by Hu and Feng, p. 3762.

A Remarkable Fluorescence Quenching Based Amplification in ATP Detection through Signal Transduction in Self-Assembled Multivalent Aggregates.

Signal transduction is essential for the survival of living organisms, because it allows them to respond to the changes in external environments. In artificial systems, signal transduction has been exploited for the highly sensitive detection of analytes. Herein, a remarkable signal transduction, upon ATP binding, in the multivalent fibrillar nanoaggregates of anthracene conjugated imidazolium receptors is reported. The aggregates of one particular amphiphilic receptor sensed ATP in high pm concentrations with one ATP molecule essentially quenching the emission of thousands of receptors. A cooperative merging of the multivalent binding and signal transduction led to this superquenching and translated to an outstanding enhancement of more than a millionfold in the sensitivity of ATP detection by the nanoaggregates; in comparison to the "molecular" imidazolium receptors. Furthermore, an exceptional selectivity to ATP over other nucleotides was demonstrated.

An endogenous growth approach on the role of energy, human capital, finance and technology in explaining manufacturing value-added: A multi-country analysis.

The multi-dimensional benefits offered by the manufacturing sector in economic growth and development make academicians and policymakers to consider this sector still as an engine of growth. The unique qualities of this sector occupy a predominant place in the development policies around the world. Against these insights gained from economic literature, the study empirically investigates the role of energy, human capital, finance and technology in influencing manufacturing value-added in an endogenous growth framework by assessing short-run and long-run relation through ARDL bounds test approach followed by VECM causality test. The results testify the existence of energy-led, finance-led (supply leading), technology-led, and human capital-led growth hypotheses. These results give important insights and directions to have long term well-framed policy perspectives to develop financial institutions, the uninterrupted energy flow to the manufacturing sector, a blend of education and skill intensive programs and, an import strategy specially designed to obtain the spillover benefit of foreign technology.

Inhibition of p53 DNA binding by a small molecule protects mice from radiation toxicity.

Transcription factors are attractive therapeutic targets that are considered non-druggable because they do not have binding sites for small drug-like ligands. We established a cell-free high-throughput screening assay to search for small molecule inhibitors of DNA binding by transcription factors. A screen was performed using p53 as a target, resulting in the identification of NSC194598 that inhibits p53 sequence-specific DNA binding in vitro (IC50 = 180 nM) and in vivo. NSC194598 selectively inhibited DNA binding by p53 and homologs p63/p73, but did not affect E2F1, TCF1, and c-Myc. Treatment of cells with NSC194598 alone paradoxically led to p53 accumulation and modest increase of transcriptional output owing to disruption of the MDM2-negative feedback loop. When p53 was stabilized and activated by irradiation or chemotherapy drug treatment, NSC194598 inhibited p53 DNA binding and induction of target genes. A single dose of NSC194598 increased the survival of mice after irradiation. The results suggest DNA binding by p53 can be targeted using small molecules to reduce acute toxicity to normal tissues by radiation and chemotherapy.

Estimating the causal relationship between electricity consumption and industrial output: ARDL bounds and Toda-Yamamoto approaches for ten late industrialized countries.

This research investigates the effects of electricity consumption (major independent variable), per capita income, real exchange rate, import and export on manufacturing output by using yearly time series data for the period of 1980-2016 with regard to 10 late industrialized nations. The ARDL bound testing approach, the way to deal with cointegration is applied to estimate the long-run connection between the variables. While, error correction method (ECM) is used to find the short-run dynamics. To test the causality among the variables, Toda-Yamamoto test is performed. The results demonstrate the existence of short-run and long-run relationship among the variables and Toda-Yamamoto causality results support the existence of growth, conservation, feedback and neutrality hypotheses for different nations. The difference in the results can be attributed to structural and macroeconomic parameters. In general, this research brings out a fresh lead of knowledge for late industrialized nations to strengthen their economic development through proficient utilization of energy consumption.

Antioxidant and anticancer activity of synthesized 4-amino-5-((aryl substituted)-4H-1,2,4-triazole-3-yl)thio-linked hydroxamic acid derivatives.

OBJECTIVES: The antioxidant and anticancer activity of twelve 5-substituted-4-amino-1,2,4-triazole-linked hydroxamic acid derivatives were evaluated. METHODS: Previously synthesized 2-((4-amino-5-substituted-4H-1,2,4-triazol-3-yl)thio)-N-hydroxyacetamide and 3-((4-amino-5-substituted-4H-1,2,4-triazol-3-yl)thio)-N-hydroxypropanamide (6a-6l) were evaluated for in vitro antioxidant and in vivo anticancer activity. MDA-MB-231, MCF-7 and HCT 116 cell lines were used to evaluate IC50 values, in vitro. Ehrlich ascites carcinoma (EAC)-induced mice model was used to evaluate in vivo anticancer potential. Different biological markers were examined for drug-related toxicities. KEY FINDINGS: Compound 6b revealed more potent antioxidant property among all tested compounds, even than the ascorbic acid. The IC50 values of compound 6b were found to be 5.71 ± 2.29 µg/ml (DPPH assay) and 4.12 ± 0.5 µg/ml (ABTS assay). Histopathology of liver sections of drug-treated mice was evaluated. Survival analysis showed that compound 6b could increase the life span as of the standard drug. CONCLUSIONS: After the assessment of all in vivo anticancer study related data, it was found that compound 6b possess superior anticancer potency in terms of efficacy and toxicity. From this experimental design, it could be concluded that further modification of this prototypical structure will lead to develop more potent antioxidant as well as an anticancer agent in the future.

Interaction between p53 N terminus and core domain regulates specific and nonspecific DNA binding.

The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. Dynamic control of p53 degradation and DNA binding in response to stress signals are critical for tumor suppression. The p53 N terminus (NT) contains two transactivation domains (TAD1 and TAD2), a proline-rich region (PRR), and multiple phosphorylation sites. Previous work revealed the p53 NT reduced DNA binding in vitro. Here, we show that TAD2 and the PRR inhibit DNA binding by directly interacting with the sequence-specific DNA binding domain (DBD). NMR spectroscopy revealed that TAD2 and the PRR interact with the DBD at or near the DNA binding surface, possibly acting as a nucleic acid mimetic to competitively block DNA binding. In vitro and in vivo DNA binding analyses showed that the NT reduced p53 DNA binding affinity but improved the ability of p53 to distinguish between specific and nonspecific sequences. MDMX inhibits p53 binding to specific target promoters but stimulates binding to nonspecific chromatin sites. The results suggest that the p53 NT regulates the affinity and specificity of DNA binding by the DBD. The p53 NT-interacting proteins and posttranslational modifications may regulate DNA binding, partly by modulating the NT-DBD interaction.

Assisted π-stacking: a strong synergy between weak interactions.

Synergy between a pair of weak non-covalent interactions can predispose a molecular self-assembly towards a specific pathway. We report assisted π-stacking, a synergy between aromatic π-stacking and n →π* interactions that exhibits an unprecedented strength and thermal stability. Natural bond orbital analysis reveals the non-additive nature of the interaction.