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In an era where social media platforms burgeon with diverse content, compelling moderation is imperative to filter harmful materials. Traditional methods often grapple with the dual challenges of accuracy and computational efficiency levels. These conventional approaches typically rely on text-based or image-based analysis, neglecting the complex interplay of multimodal content prevalent in social media scenarios. This limitation leads to suboptimal content filtering, often missing contextually nuanced or visually deceptive harmful content sets. Addressing these challenges, in response to the pressing need for effective social media content moderation, we introduce a pioneering approach that combines Convolutional Neural Networks (CNNs) and Transformers. We aim to enhance accuracy and computational efficiency in filtering harmful multimodal content prevalent on social media platforms. By integrating CNNs and Transformers, we achieve nuanced visual content extraction and contextual textual understanding, thus improving the identification of harmful content. Additionally, our model utilises a Bi-directional Attention Mechanism (BAM) and Genetic Algorithms (GAs) for efficient text-visual fusion and hyper-parameter optimisation, respectively. Empirical testing on datasets from Google, Facebook, and Kaggle demonstrates the superior performance of our model in terms of precision, accuracy, recall, AUC, specificity, and response delay in detecting harmful content. The proposed Multimodal Social Media Content Moderation Using Hybrid Graph Theory & Bio-inspired Optimization (MSCMGTB) model consistently achieves superior precision, accuracy, recall, AUC, and specificity with rates ranging from 86.78% to 98.82% across varying dataset sizes, highlighting its efficacy in content moderation as well as reduced the delay time to classify social media contents as compared to Social Graph Neural Network (SGNN), CrediBot, and Adaptive LDA (ALDA) techniques. The model also preempts potentially harmful content posters, offering enhanced pre-emption metrics.

Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier, coupled with microbial dysbiosis, has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis. In vivo Rab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability, and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7-dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.

Abstract A recently emerged sub-lineage of Omicron, BA.5, together with BA.4, caused a fifth wave of coronavirus disease (COVID-19) in South Africa and subsequently emerged as a predominant strain globally due to its high transmissibility. The lethality of BA.5 infection has not been studied in an acute hACE2 transgenic (hACE2.Tg) mouse model. Here, we investigated tissue-tropism and immuno-pathology induced by BA.5 infection in hACE2.Tg mice. Our data show that intranasal infection of BA.5 in hACE2.Tg mice resulted in attenuated pulmonary infection and pathology with diminished COVID-19-induced clinical and pathological manifestations. BA.5, similar to Omicron (B.1.1.529), infection led to attenuated production of inflammatory cytokines, anti-viral response and effector T cell response as compared to the ancestral strain of SARS-CoV-2, Wuhan-Hu-1. We show that mice recovered from B.1.1.529 infection showed robust protection against BA.5 infection associated with reduced lung viral load and pathology. Together, our data provide insights as to why BA.5 infection escapes previous SARS-CoV-2 exposure induced-T cell immunity but may result in milder immuno-pathology and alleviated chances of re-infectivity in Omicron-recovered individuals.

Mechanistic understanding of antibiotic persistence is a prerequisite in controlling the emergence of MDR cases in Tuberculosis (TB). We have reported that the cholesterol-induced activation of VapC12 ribonuclease is critical for disease persistence in TB. In this study, we observed that relative to the wild type, mice infected with ΔvapC12 induced a pro-inflammatory response, had a higher pathogen load, and responded better to the anti-TB treatment. In a high-dose infection model, all the mice infected with ΔvapC12 succumbed early to the disease. Finally, we reported that the above phenotype of ΔvapC12 was dependent on the presence of the TLR4 receptor. Overall, the data suggests that failure of a timely resolution of the early inflammation by the ΔvapC12 infected mice led to hyperinflammation, altered T-cell response and high bacterial load. In conclusion, our findings suggest the role of the VapC12 toxin in modulating the innate immune response of the host in ways that favor the long-term survival of the pathogen inside the host.

The current research focuses the light on the characterization of buoyancy-driven non-linear mixed convection and non-linear radiation in a Newtonian flow over a non-linearly stretching vertical sheet, and this type of flow has useful applications in many industrial processes, such as the paper and pulp industry, polymer industry, electronic device cooling, solar collectors, gas turbine plants, and nuclear power. Using appropriate transformations, governing PDEs for non-linear mixed convection are reduced to higher-order non-linear ODEs and those are numerically solved. Along with tabular presentations of computed results, the graphical representations are generated to elucidate the effects of involved parameters on convection transport properties and their inter-relations. It demonstrates that flow velocity increases near the surface and decreases away from the surface as the non-linear convection parameter increases. Furthermore, increments in the thermal buoyancy, temperature ratio and non-linear radiation parameters result in the boost of velocity. The temperature decreases as linear and non-linear buoyancy-related parameters (non-linear convection and thermal buoyancy parameters) are of higher levels. In contrast, the temperature rises with two non-linear thermal radiation-related parameters (thermal ratio and non-linear radiation parameters). For greater values of the non-linear stretching related parameter, a lower velocity and a higher temperature are witnessed. The non-linear convection, thermal buoyancy, thermal ratio and non-linear radiation parameters contribute toward the reduction of the magnitude of surface-drag force and growth of the surface cooling rate. But, with the non-linearity in surface stretching there are significant percentage hikes of surface-drag force magnitude and surface cooling rate.

Background: Treating of recalcitrant viral verrucae either individually or in combination is inconvenient and frustrating both for patients and treating physician. There is no treatment, which is 100% effective for warts. Objectives: To compare the use of intralesional 5-flourouracil and intralesional bleomycin with respect to efficacy and side effects in treatment of recalcitrant palmo-plantar verrucae. Materials and Methods: A prospective comparative study was conducted toassess the eeficacy of intralesional bleomycin injection with intralesional 5-Fluoro Uracil (FU) in resistant palmo-plantar warts. Results: Intralesional bleomycin was found to be more efficacious than intralesional 5-FU in treatment of recalcitrant palmo-plantar warts however much more side effects were noted in intralesional bleomycin than intralesional 5-FU. None of the side-effects were found to be life threatening. Moreover 5-FU is cheaper and easily procurable than injection bleomycin. Conclusion: Both intralesional bleomycin and 5-FU injections can be safely used in the treatment of recalcitrant palmo-plantar verrucae.

The present article explores flow of ternary hybrid nanofluid (THN) between two parallel plates in which upper one is in squeezing motion. The study of squeezing flow has its importance in industrial applications, like the flow between pistons and nozzles in the engine of vehicles. THN (graphene-graphene oxide-silver/water) is used to improve the efficiency of heat carrier fluid by the synergetic effects of nanoparticles. Magnetic field and thermal radiation effects are also included in the problem. Governing mathematical form of the problem is constructed by using a modified Buongiorno nanofluid model. Dimensionless system of ODEs reduced from PDEs through transformations and further simplified towards the solution with the numerical approach ‘bvp4c’, a MATLAB based solver. The reliability of the outcomes is confirmed by matching them with the previously published works. The findings reveal that the nanofluid velocity reduces with squeezing and magnetic parameters in the mid-section between the plates and its temperature can be controlled by the amount of nanoparticles dispersed into it, Prandtl number and the radiation effect. Overshoot in the concentration is attained for higher temperature gradient forces. Also, local Nusselt and local Sherwood numbers show contrasting trends for the upper and lower plates with the types of nanofluid (ternary/binary/unary), Prandtl number and radiation effect, but remain stationary with compression and magnetic effect. That means better transfer characteristics are found for ternary nanofluid, radiation and magnetic effects for the lower plate, but drag also intensifies; so suitable choices are considered for practical purposes. By the comparative analysis, it can be concluded that the performance of ternary hybrid nanofluid is relatively more efficient than binary and unary for heat transfer applications.

Breast cancer is the most common malignancy in women worldwide and despite significant advancements in detection, treatment, and management of cancer, it is still the leading cause of malignancy related deaths in women. Understanding the fundamental biology of breast cancer and creating fresh diagnostic and therapeutic strategies have gained renewed focus in recent studies. In the onset and spread of breast cancer, a group of enzymes known as kinases are extremely important. Small-molecule kinase inhibitors have become a promising class of medications for the treatment of breast cancer owing to their capacity to specifically target kinases involved in the growth and progression of cancer. The creation of targeted treatments that block these kinases and the signalling pathways that they activate has completely changed how breast cancer is treated. Many of these targeted treatments have been approved for the treatment of breast cancer as clinical trials have demonstrated their great efficacy. CDK4/6 inhibitors, like palbociclib, abemaciclib, and ribociclib, EGFR inhibitors such as gefitinib and erlotinib and HER2-targeting small-molecule kinases like neratinib and tucatinib are some examples that have shown potential in treating breast cancer. Yet, there are still difficulties in the development of targeted medicines for breast cancer, such as figuring out which patient subgroups may benefit from these therapies and dealing with drug resistance problems. Notwithstanding these difficulties, kinase-targeted treatments for breast cancer still have a lot of potential. The development of tailored medicines will continue to be fuelled by the identification of novel targets and biomarkers for breast cancer as a result of advancements in genomic and proteomic technology.

The dynamic spectrum of microRNA (miRNA) has grown significantly over the years with its identification and exploration in cancer therapeutics and is currently identified as an important resource for innovative strategies due to its functional behavior for gene regulation and modulation of complex biological networks. The progression of cancer is the consequence of uncontrolled, nonsynchronous procedural faults in the biological system. Diversified and variable cellular response of cancerous cells has always raised challenges in effective cancer therapy. miRNAs, a class of non-coding RNAs (ncRNAs), are the natural genetic gift, responsible to preserve the homeostasis of cell to nurture. The unprecedented significance of endogenous miRNAs has exhibited promising therapeutic potential in cancer therapeutics. Currently, miRNA mimic miR-34, and an antimiR aimed against miR-122 has entered the clinical trials for cancer treatments. This review, highlights the recent breakthroughs, challenges, clinical trials, and advanced delivery vehicles in the administration of miRNA therapies for precision oncology.

Heat transfer in Carreau–Yasuda fluid with mixed convection, effect of Cattaneo–Christov model of heat flux past a vertical flat plate has been studied in this paper. Using appropriate transformations, governing PDEs are reduced to higher order non-linear non-dimensional ODEs and subsequently these are solved using “bvp4c” package of MATLAB. The Carreau–Yasuda fluid is used to explore the behaviour of fluids having shear-thinning and shear-thickening characters for several values of the parameter called power law exponent involved in the fluid model. The effects of different physical parameters, such as Weissenberg number(We), thermal relaxation parameter(α), Carreau–Yasuda fluid parameter(d), mixed convection parameter(λ) and Prandtl number(Pr) on velocity and temperature has been investigated and depicted through graphs. Results reveals that for lower value of Pr velocity of fluid enhances with higher value of λ and reverse effect is witnessed for larger Pr. Also, velocity rises for shear-thinning fluid(STNF) and decreases for shear-thickening fluid(STKF) with We and d. Temperature exhibits growing behaviour for Cattaneo–Christov model of heat flux near the plate in comparison with Fourier's model, whereas velocity exhibits growing behaviour with α. For larger We, temperature in Carreau–Yasuda model upsurges for STKF and falls for STNF. The surface drag-force displays higher values for both STNF and STKF with growth in λ. The cooling rate rises/declines with We for STNFs/STKFs.

Objective: PE_PGRS33 is a member of multi-gene family restricted to pathogenic Mycobacteria and their functions remain elusive. PE_PGRS33 is highly polymorphic in nature to evade host’s immune response. Therefore, we investigated PE_PGRS33 gene polymorphisms in clinical isolates and functional characterization using in vitro experiments. Methods: A total of 103 clinical isolates were recruited. Genomic DNA was extracted, PE_PGRS33 gene amplification, sequencing. Afterward, we have cloned, expressed PE_PGRS33 wild type and three polymorphic alleles in M. smegmatis. Further, performed in vitro stresses assays, THP-1 differentiated macrophage infection assays followed by quantification of cytokine expression. Results: We have identified nine novel polymorphisms and also demonstrated that in comparison to M. smegmatis expressing wild type/Mut_alleles displayed altered in growth kinetics and colony morphology. M. smegmatis harbouring Mut_allele3 survived better under oxidative, acidic stress and were resistant to lysozyme treatment. qRT-PCR of cytokines TNF-α, IL-12 and IL-10 after infection with recombinant M. smegmatis showed two Mut_allele (Mut_allele1 and Mut_allele3) induced higher expression of TNF-α, IL-12, while IL-10 expression was decreased in both mutant alleles as compared to wild type PE_PGRS33 at each experimental time point. Conclusion: Results of our functional study suggest that PE_PGRS33 gene polymorphisms aid in the survival or persistence of M. tuberculosis and differentially modulate the expression of various cytokines. Overall this study suggests that Mtb clinical strains harbouring different PE_PGRS33 alleles could act as a virulence determinant by differentially regulating pathways essential for the pathogen’s ability to adapt inside the host.

The wavelet transform is widely used in the task of hyperspectral image compression (HSIC). They have achieved outstanding performance in the compression of a hyperspectral (HS) image, which has attracted great interest. However, transform based hyperspectral image compression algorithm (HSICA) has low-coding gain than the other state of art HSIC algorithms. To solve this problem, this manuscript proposes a curvelet transform based HSIC algorithm. The curvelet transform is a multiscale mathematical transform that represents the curve and edges of the HS image more efficiently than the wavelet transform. The experiment results show that the proposed compression algorithm has high-coding gain, low-coding complexity, at par coding memory requirement, and works for both (lossy and lossless) compression. Thus, it is a suitable contender for the compression process in the HS image sensors.

Tuberculosis (TB) patients show dysregulated immunity, iron metabolism, and anemia. In this study, circulatory cytokines, trace metals, and iron-related proteins (hepcidin, ferroportin, transferrin, Dmt1, Nramp1, ferritin, ceruloplasmin, hemojuvelin, aconitase, and transferrin receptor) were monitored in case (active tuberculosis patients: ATB) and control (non-tuberculosis: NTB and healthy) study populations (n = 72, male: 100%, mean age, 42.94 years; range, 17–83 years). Using serum elemental and cytokine levels, a partial least square discriminate analysis model (PLS-DA) was built, which clustered ATB patients away from NTB and healthy controls. Based on the PLS-DA variable importance in projection (VIP) score and analysis of variance (ANOVA), 13 variables were selected as important biosignatures [IL-18, IL-10, IL-13, IFN-γ, TNF-α, IL-5, IL-12 (p70), IL-1β, copper, zinc, selenium, iron, and aluminum]. Interestingly, low iron and selenium levels and high copper and aluminum levels were observed in ATB subjects. Low circulatory levels of transferrin, ferroportin, and hemojuvelin with higher ferritin and ceruloplasmin levels observed in ATB subjects demonstrate an altered iron metabolism, which partially resolved upon 6 months of anti-TB therapy. The identified biosignature in TB patients demonstrated perturbed iron homeostasis with anemia of inflammation, which could be useful targets for the development of host-directed adjunct therapeutics.

The recent coronavirus disease (COVID-19) outbreak is one of its kind in the history of public health that has created a major global threat. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a zoonotic source and hence, reverse zoonosis (disease transmission from humans to animals) increases the risk and rate of SARS-CoV-2 infection. Serological and molecular analyses and experimental infection studies have identified SARS-CoV-2 infection in several animal species in various countries. Different domestic and wild animals, including cats, dogs, tigers, lions, puma, snow leopard, minks, and pet ferrets, are infected naturally with SARS-CoV-2, mostly through suspected human to animal transmission. In addition, in vivo experimental inoculation studies have reported the susceptibility of cats, ferrets, hamsters, Egyptian fruit bats, and non-human primates to the virus. These experimentally infected species are found to be capable of virus transmission to co-housed animals of the same species. However, SARS-CoV-2 showed poor replication in livestock species such as pigs, chickens, and ducks with no detection of viral RNA after the animals were deliberately inoculated with the virus or exposed to the infected animals. As the pets/companion animals are more susceptible to COVID-19, the infection in animals needs an in-depth and careful study to avoid any future transmissions. The one health approach is the best inter-disciplinary method to understand the consequences of viral spread and prevention in novel host populations for the betterment of public health. Further in this review, we will explain in detail the different natural and experimentally induced cases of human to animal SARS-CoV-2 infection.

The physical phenomena of nanofluid at high temperature motivate us to analyze problems with temperature-reliant fluid properties, like viscosity and thermal conductivity. Since in glass blowing, viscosity and thermal conductivity of the fluid may gets affected in such high temperature. This communication deals with the unsteady flow of nanofluid generated by nonlinear expansion of the surface. Temperature-dependent fluid viscosity and thermal conductivity are considered in the investigation of the problem. The flow of nanofluid is modeled using famous the Buongiorno's two-phase model, which includes the simultaneous effect of Brownian motion and thermophoresis diffusion. Appropriate transformations are adopted to obtain the ODEs from governing PDEs. Then MATLAB ‘bvp4c’ computation is used to solve the problem and to get a clear insight of the influences of various parameters. Graphical comparisons are made to check the accuracy of used numerical method. The study explores that heat transfer rate significantly enhances by the index of nonlinearity, variable viscosity and thermal conductivity parameters. Unsteadiness of the flow can be used as a controlling parameter to reduce the surface drag, heat and nano-mass transfer rate. Variable viscosity parameter leads to enhance the velocity near the surface and reducing the concentration of the nanoparticles. The thermal and concentration boundary layer thickens with thermal conductivity parameters. Nanofluid temperature and concentration of nanoparticles decay with nonlinear expanding index.

The present manuscript deals with bioconvective induced magnetohydrodynamic (MHD) flow of non-Newtonian fluids with simultaneous effects of multiple slips, heat source/sink, and nonlinear thermal radiation. Flows of Maxwell and Casson fluids are considered separately, but a single governing momentum conservation equation is constructed by combining these two flow models. Transformed governing equations are solved by MATLAB solver ‘bvp4c’. The objective of the current study is to check the comparative behaviour of two non-Newtonian fluids viz., Maxwell and Casson in presence of induced MHD effect with the bioconvective phenomenon and slip effect. The main findings reveal the growth of velocity and fall of microorganisms’ motile density with induced magnetic number. With higher values of Peclet number and microorganism concentration difference parameter, the microbe's motile density significantly reduces. The temperature hike is witnessed with heat generation/absorption, thermal radiation, and temperature ratio parameters. Also, for a fixed set of values of parameters the Casson fluid velocity is more prominent than the Maxwell fluid velocity and the scenario is the opposite for the motile density of microorganisms. Velocity increases, whereas motile density decreases with raising the amount of magnetic Prandtl number. Casson fluids have more velocity than Maxwell fluids, whereas the movement of the motile density of microorganisms is showing prominency for Maxwell fluids. The magnitude of surface drag and surface cooling rate are at a higher level for Casson fluid in comparison with Maxwell fluid. The motile density number enhances with the microorganism concentration difference parameter and Peclet number.

Glioblastoma multiforme (GBM) is the most widespread and aggressive subtype of glioma in adult patients. Numerous long non-coding RNAs (lncRNAs) are deregulated or differentially expressed in GBM. These lncRNAs possess unique regulatory functions in GBM cells, ranging from high invasion/migration to recurrence. This review outlines the present status of specific involvement of lncRNAs in GBM pathogenesis, with a focus on their association with key molecular and cellular regulatory mechanisms. Also, we highlighted the potential of different novel RNA-based strategies that may be beneficial for therapeutic purposes.

Cancer remains the second leading cause of mortality globally. In combating cancer, conventional chemotherapy and/or radiotherapy are administered as first-line therapy. However, these are usually accompanied with adverse side effects that decrease the quality of patient’s lives. As such, natural bioactive compounds have gained an attraction in the scientific and medical community as evidence of their anticancer properties and attenuation of side effects mounted. In particular, quassinoids have been found to exhibit a plethora of inhibitory activities such as anti-proliferative effects on tumor development and metastasis. Recently, bruceine D, a quassinoid isolated from the shrub Brucea javanica (L.) Merr. (Simaroubaceae), has come under immense investigation on its antineoplastic properties in various human cancers including pancreas, breast, lung, blood, bone, and liver. In this review, we have highlighted the antineoplastic effects of bruceine D and its mode of actions in different tumor models.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the Golden Syrian hamster causes lung pathology that resembles human coronavirus disease (COVID-19). However, extrapulmonary pathologies associated with SARS-CoV-2 infection and post-COVID sequelae remain to be understood. Here, we show, using a hamster model, that the early phase of SARS-CoV-2 infection leads to an acute inflammatory response and lung pathologies, while the late phase of infection causes cardiovascular complications (CVCs) characterized by ventricular wall thickening associated with increased ventricular mass/body mass ratio and interstitial coronary fibrosis. Molecular profiling further substantiated our findings of CVC as SARS-CoV-2-infected hamsters showed elevated levels of serum cardiac troponin I, cholesterol, low-density lipoprotein, and long-chain fatty acid triglycerides. Serum metabolomics profiling of SARS-CoV-2-infected hamsters identified N-acetylneuraminate, a functional metabolite found to be associated with CVC, as a metabolic marker was found to be common between SARS-CoV-2-infected hamsters and COVID-19 patients. Together, we propose hamsters as a suitable animal model to study post-COVID sequelae associated with CVC, which could be extended to therapeutic interventions.

Creativity, in one sense, can be seen as an effort or action to bring novelty. Following this, we explore how a robot can be creative by bringing novelty in a human–robot interaction (HRI) scenario. Studies suggest that proactivity is closely linked with creativity. Proactivity can be defined as acting or interacting by anticipating future needs or actions. This study aims to explore the effect of proactive behavior and the relation of such behaviors to the two aspects of creativity: 1) the perceived creativity observed by the user in the robot’s proactive behavior and 2) creativity of the user by assessing how creativity in HRI can be shaped or influenced by proactivity. We do so by conducting an experimental study, where the robot tries to support the user on the completion of the task regardless of the end result being novel or not and does so by exhibiting anticipatory proactive behaviors. In our study, the robot instantiates a set of verbal communications as proactive robot behavior. To our knowledge, the study is among the first to establish and investigate the relationship between creativity and proactivity in the HRI context, based on user studies. The initial results have indicated a relationship between observed proactivity, creativity, and task achievement. It also provides valuable pointers for further investigation in this domain.

The global rise of antibiotic-resistant strains of Salmonella has necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against Salmonella. Further, using the proteome analysis of Salmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of Salmonella via mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of Salmonella within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by Salmonella infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against Salmonella infection and might be useful for the treatment of other intracellular infections.

ABSTRACT The worldwide increase in the frequency of multidrug-resistant and extensively drug-resistant cases of tuberculosis is mainly due to therapeutic noncompliance associated with a lengthy treatment regimen. Depending on the drug susceptibility profile, the treatment duration can extend from 6 months to 2 years. This protracted regimen is attributed to a supposedly nonreplicating and metabolically inert subset of the Mycobacterium tuberculosis population, called “persisters.” The mechanism underlying stochastic generation and enrichment of persisters is not fully known. We have previously reported that the utilization of host cholesterol is essential for mycobacterial persistence. In this study, we have demonstrated that cholesterol-induced activation of a RNase toxin (VapC12) inhibits translation by targeting proT tRNA in M. tuberculosis. This results in cholesterol-specific growth modulation that increases the frequency of generation of the persisters in a heterogeneous M. tuberculosis population. Also, a null mutant strain of this toxin (ΔvapC12) demonstrated an enhanced growth phenotype in a guinea pig model of M. tuberculosis infection, depicting its role in disease persistence. Thus, we have identified a novel strategy through which cholesterol-specific activation of a toxin-antitoxin module in M. tuberculosis enhances persister formation during infection. The current findings provide an opportunity to target persisters, a new paradigm facilitating tuberculosis drug development. IMPORTANCE The current TB treatment regimen involves a combination of drugs administered for an extended duration that could last for 6 months to 2 years. This could lead to noncompliance and the emergence of newer drug resistance strains. It is widely perceived that the major culprits are the so-called nonreplicating and metabolically inactive “persister” bacteria. The importance of cholesterol utilization during the persistence stage of M. tuberculosis infection and its potential role in the generation of persisters is very intriguing. We explored the mechanism involved in the cholesterol-mediated generation of persisters in mycobacteria. In this study, we have identified a toxin-antitoxin (TA) system essential for the generation of persisters during M. tuberculosis infection. This study verified that M. tuberculosis strain devoid of the VapBC12 TA system failed to persist and showed a hypervirulent phenotype in a guinea pig infection model. Our studies indicate that the M. tuberculosis VapBC12 TA system acts as a molecular switch regulating persister generation during infection. VapBC12 TA system as a drug target offers opportunities to develop shorter and more effective treatment regimens against tuberculosis.

Triple-negative breast cancer (TNBC) is one of the most lethal forms of breast cancer (BC), with a significant disease burden worldwide. Chemoresistance and lack of targeted therapeutics are major hindrances to effective treatments in the clinic and are crucial causes of a worse prognosis and high rate of relapse/recurrence in patients diagnosed with TNBC. In the last decade, long non-coding RNAs (lncRNAs) have been found to perform a pivotal role in most cellular functions. The aberrant functional expression of lncRNAs plays an ever-increasing role in the progression of diverse malignancies, including TNBC. Therefore, lncRNAs have been recently studied as predictors and modifiers of chemoresistance. Our review discusses the potential involvement of lncRNAs in drug-resistant mechanisms commonly found in TNBC and highlights various therapeutic strategies to target lncRNAs in this malignancy.

Amongst the various gynecological malignancies affecting female health globally, ovarian cancer is one of the predominant and lethal among all. The identification and functional characterization of long non-coding RNAs (lncRNAs) are made possible with the advent of RNA-seq and the advancement of computational logarithm in understanding human disease biology. LncRNAs can interact with deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins and their combinations. Moreover, lncRNAs regulate orchestra of diverse functions including chromatin organization and transcriptional and post-transcriptional regulation. LncRNAs have conferred their critical role in key biological processes in human cancer including tumor initiation, proliferation, cell cycle, apoptosis, necroptosis, autophagy, and metastasis. The interwoven function of tumor-suppressor protein p53-linked lncRNAs in the ovarian cancer paradigm is of paramount importance. Several lncRNAs operate as p53 regulators or effectors and modulates a diverse array of functions either by participating in various signaling cascades or via interaction with different proteins. This review highlights the recent progress made in the identification of p53 associated lncRNAs while elucidating their molecular mechanisms behind the altered expression in ovarian cancer tumorigenesis. Moreover, the development of novel clinical and therapeutic strategies for targeting lncRNAs in human cancers harbors great promise.

HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.