People make mistakes: Obtaining accurate ground truth from continuous annotations of subjective constructs.

Accurately representing changes in mental states over time is crucial for understanding their complex dynamics. However, there is little methodological research on the validity and reliability of human-produced continuous-time annotation of these states. We present a psychometric perspective on valid and reliable construct assessment, examine the robustness of interval-scale (e.g., values between zero and one) continuous-time annotation, and identify three major threats to validity and reliability in current approaches. We then propose a novel ground truth generation pipeline that combines emerging techniques for improving validity and robustness. We demonstrate its effectiveness in a case study involving crowd-sourced annotation of perceived violence in movies, where our pipeline achieves a .95 Spearman correlation in summarized ratings compared to a .15 baseline. These results suggest that highly accurate ground truth signals can be produced from continuous annotations using additional comparative annotation (e.g., a versus b) to correct structured errors, highlighting the need for a paradigm shift in robust construct measurement over time.

Racial/ethnic differences in the clinical presentation and survival of breast cancer by subtype.

Background: Breast cancer (BC) affects racial and ethnic groups differently, leading to disparities in clinical presentation and outcomes. It is unclear how Hispanic ethnicity affects BC outcomes based on geographic location and proximity to the United States (U.S.)/Mexico border. We hypothesized that the impact of race/ethnicity on BC outcomes depends on geographic location and country of origin within each BC subtype. Methods: We analyzed BC data from the Texas Cancer Registry by race/ethnicity/birthplace according to BC subtype (luminal A/luminal B/human epidermal growth factor receptor 2 [HER2]/triple-negative breast cancer[TNBC]). Other covariates included age, geographic location (U.S., Mexico), residency (border, non-border), treatments, and comorbidities. Crude and adjusted effects of race/ethnicity and birthplace on overall survival (OS) were analyzed using Cox regression methods. Results: Our analysis of 76,310 patient records with specific BC subtypes revealed that Hispanic and non-Hispanic Black (NHB) patients were diagnosed at a younger age compared with non-Hispanic White (NHW) patients for all BC subtypes. For the 19,748 BC patients with complete data on race/ethnicity/birthplace/residency, Hispanic patients had a higher mortality risk in the Luminal A subtype, regardless of birthplace, whereas U.S.-born Hispanics had a higher risk of death in the TNBC subtype. In contrast, NHB patients had a higher mortality risk in the Luminal A and HER2 subtypes. Residence along the U.S./Mexico border had little impact on OS, with better outcomes in Luminal A patients and worse outcomes in Luminal B patients aged 60-74 years. Conclusion: Race/ethnicity, geographic birth location, and residency were significant predictors of survival in BC. Migration, acculturation, and reduced healthcare access may contribute to outcome differences.

Differential Expression of lncRNAs in HIV Patients with TB and HIV-TB with Anti-Retroviral Treatment.

Tuberculosis (TB) is the leading cause of death among people with HIV-1 infection. To improve the diagnosis and treatment of HIV-TB patients, it is important to understand the mechanisms underlying these conditions. Here, we used an integrated genomics approach to analyze and determine the lncRNAs that are dysregulated in HIV-TB patients and HIV-TB patients undergoing anti-retroviral therapy (ART) using a dataset available in the public domain. The analyses focused on the portion of the genome transcribed into non-coding transcripts, which historically have been poorly studied and received less focus. This revealed that Mtb infection in HIV prominently up-regulates the expression of long non-coding RNA (lncRNA) genes DAAM2-AS1, COL4A2-AS1, LINC00599, AC008592.1, and CLRN1-AS1 and down-regulates the expression of lncRNAs AC111000.4, AC100803.3, AC016168.2, AC245100.7, and LINC02073. It also revealed that ART down-regulates the expression of some lncRNA genes (COL4A2-AS1, AC079210.1, MFA-AS1, and LINC01993) that are highly up-regulated in HIV-TB patients. Furthermore, the interrogation of the genomic regions that are associated with regulated lncRNAs showed enrichment for biological processes linked to immune pathways in TB-infected conditions. However, intriguingly, TB patients treated with ART showed completely opposite and non-overlapping pathways. Our findings suggest that lncRNAs could be used to identify critical diagnostic, prognostic, and treatment targets for HIV-TB patients.

Multimodal analysis of temporal affective variability within treatment for depression.

OBJECTIVE: Affective flexibility, the capacity to respond to life's varying environmental changes in a dynamic and adaptive manner, is considered a central aspect of psychological health in many psychotherapeutic approaches. The present study examined whether affective two-dimensional (i.e., arousal and valence) temporal variability extracted from voice and facial expressions would be associated with positive changes over the course of psychotherapy, at the session, client, and treatment levels. METHOD: A total of 22,741 mean vocal arousal and facial expression valence observations were extracted from 137 therapy sessions in a sample of 30 clients treated for major depressive disorder by nine therapists. Before and after each session, the clients self-reported their level of well-being on the outcome rating scale. Session-level affective temporal variability was assessed as the mean square of successive differences between consecutive two-dimensional affective measures. RESULTS: Session outcome was positively associated with temporal variability at the session level (i.e., within clients, between sessions) and at the client level (i.e., between clients). Importantly, these associations held when controlling for average session- and client-level valence scores. In addition, the expansion of temporal variability throughout treatment was associated with steeper positive session outcome trajectories over the course of treatment. CONCLUSIONS: The continuous assessment of both vocal and facial affective expressions and the ability to extract measures of affective temporal variability from within-session data may enable therapists to better respond and modulate clients' affective flexibility; however, further research is necessary to determine whether there is a causal link between affective temporal variability and psychotherapy outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Durable partial response to pembrolizumab, lenvatinib, and letrozole in a case of recurrent uterine carcinosarcoma with ESR1 gene amplification.

•ESR1 gene amplification occurs in 7% of uterine carcinosarcoma.•The presence of ESR1 gene amplification in recurrent uterine carcinosarcoma may be targeted by aromatase inhibitors.•ESR1 gene amplification may be identified through immunohistochemical staining for estrogen receptor followed by fluorescence in situ hybridization or tumor targeted gene sequencing.

ZMYND8 Is a Regulator of Sonic Hedgehog Signaling in ATRA-Mediated Differentiation of Neuroblastoma Cells.

Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8) is a crucial epigenetic regulator that plays a multifaceted role in governing a spectrum of vital cellular processes, encompassing proliferation, apoptosis, migration, tumor suppression, and differentiation. It has emerged as a key player in neuronal differentiation by orchestrating the expression of neuronal lineage-committed genes. The present study uncovers the role of ZMYND8 in regulating the Sonic Hedgehog (SHH) signaling axis, which is crucial for neuronal differentiation. Genetic deletion of ZMYND8 leads to a significant reduction in SHH pathway genes, GLI1, and PTCH1 expression during all-trans-retinoic acid (ATRA)-induced differentiation. ZMYND8 and RNA pol II S5P are found to co-occupy the GLI1 and PTCH1 gene promoters, positively impacting their gene transcription upon ATRA treatment. Interestingly, ZMYND8 is found to counteract the inhibitory effects of Cyclopamine that block the upstream SHH pathway protein SMO, resulting in enhanced neurite formation in neuroblastoma cells following their treatment with ATRA. These results indicate that ZMYND8 is an epigenetic regulator of the SHH signaling pathway and has tremendous therapeutic potential in ATRA-mediated differentiation of neuroblastoma.

Live Attenuated Vaccines against Tuberculosis: Targeting the Disruption of Genes Encoding the Secretory Proteins of Mycobacteria.

Tuberculosis (TB), a chronic infectious disease affecting humans, causes over 1.3 million deaths per year throughout the world. The current preventive vaccine BCG provides protection against childhood TB, but it fails to protect against pulmonary TB. Multiple candidates have been evaluated to either replace or boost the efficacy of the BCG vaccine, including subunit protein, DNA, virus vector-based vaccines, etc., most of which provide only short-term immunity. Several live attenuated vaccines derived from Mycobacterium tuberculosis (Mtb) and BCG have also been developed to induce long-term immunity. Since Mtb mediates its virulence through multiple secreted proteins, these proteins have been targeted to produce attenuated but immunogenic vaccines. In this review, we discuss the characteristics and prospects of live attenuated vaccines generated by targeting the disruption of the genes encoding secretory mycobacterial proteins.

Progress and prospect of nanotechnology for cardiac fibrosis treatment.

Cardiac fibrosis is the excessive accumulation of extracellular matrix components in the heart, leading to reduced cardiac functionality and heart failure. This review provides an overview of the therapeutic applications of nanotechnology for the treatment of cardiac fibrosis. We first delve into the fundamental pathophysiology of cardiac fibrosis, highlighting the key molecular players, including Matrix Metalloproteinases, Transforming Growth Factor-beta, and several growth factors, cytokines, and signaling molecules. Each target presents a unique opportunity to develop targeted nano-therapies. We then focus on recent advancements in nanotechnology and how nanoparticles can be engineered to deliver drugs or therapeutic genes. These advanced delivery approaches have shown significant potential to inhibit fibrosis-promoting factors, thereby mitigating the fibrotic response and potentially reversing disease progression. In addition, we discuss the challenges associated with developing and translating nanotechnology-based drug delivery systems, including ensuring biocompatibility, safety, and regulatory compliance. This review highlights how nanotechnology can bridge the gap between lab research and clinical practice for treating cardiac fibrosis.

A machine learning approach to improve implementation monitoring of family-based preventive interventions in primary care.

Background: Evidence-based parenting programs effectively prevent the onset and escalation of child and adolescent behavioral health problems. When programs have been taken to scale, declines in the quality of implementation diminish intervention effects. Gold-standard methods of implementation monitoring are cost-prohibitive and impractical in resource-scarce delivery systems. Technological developments using computational linguistics and machine learning offer an opportunity to assess fidelity in a low burden, timely, and comprehensive manner. Methods: In this study, we test two natural language processing (NLP) methods [i.e., Term Frequency-Inverse Document Frequency (TF-IDF) and Bidirectional Encoder Representations from Transformers (BERT)] to assess the delivery of the Family Check-Up 4 Health (FCU4Health) program in a type 2 hybrid effectiveness-implementation trial conducted in primary care settings that serve primarily Latino families. We trained and evaluated models using 116 English and 81 Spanish-language transcripts from the 113 families who initiated FCU4Health services. We evaluated the concurrent validity of the TF-IDF and BERT models using observer ratings of program sessions using the COACH measure of competent adherence. Following the Implementation Cascade model, we assessed predictive validity using multiple indicators of parent engagement, which have been demonstrated to predict improvements in parenting and child outcomes. Results: Both TF-IDF and BERT ratings were significantly associated with observer ratings and engagement outcomes. Using mean squared error, results demonstrated improvement over baseline for observer ratings from a range of 0.83-1.02 to 0.62-0.76, resulting in an average improvement of 24%. Similarly, results demonstrated improvement over baseline for parent engagement indicators from a range of 0.81-27.3 to 0.62-19.50, resulting in an approximate average improvement of 18%. Conclusions: These results demonstrate the potential for NLP methods to assess implementation in evidence-based parenting programs delivered at scale. Future directions are presented. Trial registration: NCT03013309 ClinicalTrials.gov.

Research has shown that evidence-based parenting programs effectively prevent the onset and escalation of child and adolescent behavioral health problems. However, if they are not implemented with fidelity, there is a potential that they will not produce the same effects. Gold-standard methods of implementation monitoring include observations of program sessions. This is expensive and difficult to implement in delivery settings with limited resources. Using data from a trial of the Family Check-Up 4 Health program in primary care settings that served Latino families, we investigated the potential to make use of a form of machine learning called natural language processing (NLP) to monitor program delivery. NLP-based ratings were significantly associated with independent observer ratings of fidelity and participant engagement outcomes. These results demonstrate the potential for NLP methods to monitor implementation in evidence-based parenting programs delivered at scale.

Wearable and Mobile Technologies for the Evaluation and Treatment of Obsessive-Compulsive Disorder: Scoping Review.

BACKGROUND: Smartphones and wearable biosensors can continuously and passively measure aspects of behavior and physiology while also collecting data that require user input. These devices can potentially be used to monitor symptom burden; estimate diagnosis and risk for relapse; predict treatment response; and deliver digital interventions in patients with obsessive-compulsive disorder (OCD), a prevalent and disabling psychiatric condition that often follows a chronic and fluctuating course and may uniquely benefit from these technologies. OBJECTIVE: Given the speed at which mobile and wearable technologies are being developed and implemented in clinical settings, a continual reappraisal of this field is needed. In this scoping review, we map the literature on the use of wearable devices and smartphone-based devices or apps in the assessment, monitoring, or treatment of OCD. METHODS: In July 2022 and April 2023, we conducted an initial search and an updated search, respectively, of multiple databases, including PubMed, Embase, APA PsycINFO, and Web of Science, with no restriction on publication period, using the following search strategy: ("OCD" OR "obsessive" OR "obsessive-compulsive") AND ("smartphone" OR "phone" OR "wearable" OR "sensing" OR "biofeedback" OR "neurofeedback" OR "neuro feedback" OR "digital" OR "phenotyping" OR "mobile" OR "heart rate variability" OR "actigraphy" OR "actimetry" OR "biosignals" OR "biomarker" OR "signals" OR "mobile health"). RESULTS: We analyzed 2748 articles, reviewed the full text of 77 articles, and extracted data from the 25 articles included in this review. We divided our review into the following three parts: studies without digital or mobile intervention and with passive data collection, studies without digital or mobile intervention and with active or mixed data collection, and studies with a digital or mobile intervention. CONCLUSIONS: Use of mobile and wearable technologies for OCD has developed primarily in the past 15 years, with an increasing pace of related publications. Passive measures from actigraphy generally match subjective reports. Ecological momentary assessment is well tolerated for the naturalistic assessment of symptoms, may capture novel OCD symptoms, and may also document lower symptom burden than retrospective recall. Digital or mobile treatments are diverse; however, they generally provide some improvement in OCD symptom burden. Finally, ongoing work is needed for a safe and trusted uptake of technology by patients and providers.

Modeling inter-individual differences in ambulatory-based multimodal signals via metric learning: a case study of personalized well-being estimation of healthcare workers.

Introduction: Intelligent ambulatory tracking can assist in the automatic detection of psychological and emotional states relevant to the mental health changes of professionals with high-stakes job responsibilities, such as healthcare workers. However, well-known differences in the variability of ambulatory data across individuals challenge many existing automated approaches seeking to learn a generalizable means of well-being estimation. This paper proposes a novel metric learning technique that improves the accuracy and generalizability of automated well-being estimation by reducing inter-individual variability while preserving the variability pertaining to the behavioral construct. Methods: The metric learning technique implemented in this paper entails learning a transformed multimodal feature space from pairwise similarity information between (dis)similar samples per participant via a Siamese neural network. Improved accuracy via personalization is further achieved by considering the trait characteristics of each individual as additional input to the metric learning models, as well as individual trait base cluster criteria to group participants followed by training a metric learning model for each group. Results: The outcomes of the proposed models demonstrate significant improvement over the other inter-individual variability reduction and deep neural baseline methods for stress, anxiety, positive affect, and negative affect. Discussion: This study lays the foundation for accurate estimation of psychological and emotional states in realistic and ambulatory environments leading to early diagnosis of mental health changes and enabling just-in-time adaptive interventions.

Pathogenic mycoplasmas of humans regulate the long noncoding RNAs in epithelial cells.

Non-coding RNAs (ncRNAs), specifically long ncRNAs (lncRNAs), regulate cellular processes by affecting gene expression at the transcriptional, post-transcriptional, and epigenetic levels. Emerging evidence indicates that pathogenic microbes dysregulate the expression of host lncRNAs to suppress cellular defense mechanisms and promote survival. To understand whether the pathogenic human mycoplasmas dysregulate host lncRNAs, we infected HeLa cells with Mycoplasma genitalium (Mg) and Mycoplasma penumoniae (Mp) and assessed the expression of lncRNAs by directional RNA-seq analysis. HeLa cells infected with these species showed up-and-down regulation of lncRNAs expression, indicating that both species can modulate host lncRNAs. However, the number of upregulated (200 for Mg and 112 for Mp) and downregulated lncRNAs (30 for Mg and 62 for Mp) differ widely between these two species. GREAT analysis of the noncoding regions associated with differentially expressed lncRNAs showed that Mg and Mp regulate a discrete set of lncRNA plausibly related to transcription, metabolism, and inflammation. Further, signaling network analysis of the differentially regulated lncRNAs exhibited diverse pathways such as neurodegeneration, NOD-like receptor signaling, MAPK signaling, p53 signaling, and PI3K signaling, suggesting that both species primarily target signaling mechanisms. Overall, the study's results suggest that Mg and Mp modulate lncRNAs to promote their survival within the host but in distinct manners.

Mycobacterium smegmatis secreting methionine sulfoxide reductase A (MsrA) modulates cellular processes in mouse macrophages.

Methionine sulfoxide reductase A (MsrA) is an antioxidant repair enzyme that reduces the oxidized methionine (Met-O) in proteins to methionine (Met). Its pivotal role in the cellular processes has been well established by overexpressing, silencing, and knocking down MsrA or deleting the gene encoding MsrA in several species. We are specifically interested in understanding the role of secreted MsrA in bacterial pathogens. To elucidate this, we infected mouse bone marrow-derived macrophages (BMDMs) with recombinant Mycobacterium smegmatis strain (MSM), secreting a bacterial MsrA or M. smegmatis strain (MSC) carrying only the control vector. BMDMs infected with MSM induced higher levels of ROS and TNF-α than BMDMs infected with MSC. The increased ROS and TNF-α levels in MSM-infected BMDMs correlated with elevated necrotic cell death in this group. Further, RNA-seq transcriptome analysis of BMDMs infected with MSC and MSM revealed differential expression of protein and RNA coding genes, suggesting that bacterial-delivered MsrA could modulate the host cellular processes. Finally, KEGG pathway enrichment analysis identified the down-regulation of cancer-related signaling genes in MSM-infected cells, indicating that MsrA can potentially regulate the development and progression of cancer.

ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation.

Zinc Finger transcription factors are crucial in modulating various cellular processes, including differentiation. Chromatin reader Zinc Finger MYND (Myeloid, Nervy, and DEAF-1) type containing 8 (ZMYND8), an All-Trans Retinoic Acid (ATRA)-responsive gene, was previously shown to play a crucial role in promoting the expression of neuronal-lineage committed genes. Here, we report that ZMYND8 promotes neuronal differentiation by positively regulating canonical MAPT protein-coding gene isoform, a key player in the axonal development of neurons. Additionally, ZMYND8 modulates gene-isoform switching by epigenetically silencing key regulatory regions within the MAPT gene, thereby suppressing the expression of non-protein-coding isoforms such as MAPT213. Genetic deletion of ZMYND8 led to an increase in the MAPT213 that potentially suppressed the parental MAPT protein-coding transcript expression related to neuronal differentiation programs. In addition, ectopic expression of MAPT213 led to repression of MAPT protein-coding transcript. Similarly, ZMYND8-driven transcription regulation was also observed in other neuronal differentiation-promoting genes. Collectively our results elucidate a novel mechanism of ZMYND8-dependent transcription regulation of different neuronal lineage committing genes, including MAPT, to promote neural differentiation.

Functional Characterization of lncRNA152 as an Angiogenesis-Inhibiting Tumor Suppressor in Triple-Negative Breast Cancers.

Long noncoding RNAs have been implicated in many of the hallmarks of cancer. Herein, we found that the expression of lncRNA152 (lnc152; a.k.a. DRAIC), which we annotated previously, is highly upregulated in luminal breast cancer (LBC) and downregulated in triple-negative breast cancer (TNBC). Knockdown of lnc152 promotes cell migration and invasion in LBC cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In mice, lnc152 inhibited the growth of TNBC cell xenografts, as well as metastasis of TNBC cells in an intracardiac injection model. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes controlling angiogenesis. Using pull down assays followed by LC/MS-MS, we identified RBM47, a known tumor suppressor in breast cancer, as a lnc152-interacting protein. The effects of lnc152 in TNBC cells are mediated, in part, by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC. IMPLICATIONS: This study identifies lncRNA152 as an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC by upregulating the expression of the tumor suppressor RBM47. As such, lncRNA152 may serve as a biomarker to track aggressiveness of breast cancer, as well as therapeutic target for treating TNBC.

Harnessing the Immune System with Cancer Vaccines: From Prevention to Therapeutics.

Prophylactic vaccination against infectious diseases is one of the most successful public health measures of our lifetime. More recently, therapeutic vaccination against established diseases such as cancer has proven to be more challenging. In the host, cancer cells evade immunologic regulation by multiple means, including altering the antigens expressed on their cell surface or recruiting inflammatory cells that repress immune surveillance. Nevertheless, recent clinical data suggest that two classes of antigens show efficacy for the development of anticancer vaccines: tumor-associated antigens and neoantigens. In addition, many different vaccines derived from antigens based on cellular, peptide/protein, and genomic components are in development to establish their efficacy in cancer therapy. Some vaccines have shown promising results, which may lead to favorable outcomes when combined with standard therapeutic approaches. This review provides an overview of the innate and adaptive immune systems, their interactions with cancer cells, and the development of various different vaccines for use in anticancer therapeutics.

The paradigm of drug resistance in cancer: an epigenetic perspective.

Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their 'non-targetable' nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.

Characterization of the Testis-specific LINC01016 Gene Reveals Isoform-specific Roles in Controlling Biological Processes.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of biological processes. However, the aberrant expression of an isoform from the same lncRNA gene could lead to RNA with altered functions due to changes in their conformations, leading to diseases. Here, we describe a detailed characterization of the gene that encodes long intergenic non-protein-coding RNA 01016 (LINC01016, also known as LncRNA1195) with a focus on its structure, exon usage, and expression in human and macaque tissues. In this study we show that it is among the highly expressed lncRNAs in the testis, exclusively conserved among nonhuman primates, suggesting its recent evolution and is processed into 12 distinct RNAs in testis, cervix, and uterus tissues. Further, we integrate de novo annotation of expressed LINC01016 transcripts and isoform-dependent gene expression analyses to show that human LINC01016 is a multiexon gene, processed through differential exon usage with isoform-specific roles. Furthermore, in cervical, testicular, and uterine cancers, LINC01016 isoforms are differentially expressed, and their expression is predictive of survival in these cancers. This study has revealed an essential aspect of lncRNA biology, rarely associated with coding RNAs, that lncRNA genes are precisely processed to generate isoforms with distinct biological roles in specific tissues.

Mycoplasma genitalium and M. pneumoniae Regulate a Distinct Set of Protein-Coding Genes in Epithelial Cells.

Mycoplasma genitalium and M. pneumoniae are two significant mycoplasmas that infect the urogenital and respiratory tracts of humans. Despite distinct tissue tropisms, they both have similar pathogenic mechanisms and infect/invade epithelial cells in the respective regions and persist within these cells. However, the pathogenic mechanisms of these species in terms of bacterium-host interactions are poorly understood. To gain insights on this, we infected HeLa cells independently with M. genitalium and M. pneumoniae and assessed gene expression by whole transcriptome sequencing (RNA-seq) approach. The results revealed that HeLa cells respond to M. genitalium and M. pneumoniae differently by regulating various protein-coding genes. Though there is a significant overlap between the genes regulated by these species, many of the differentially expressed genes were specific to each species. KEGG pathway and signaling network analyses revealed that the genes specific to M. genitalium are more related to cellular processes. In contrast, the genes specific to M. pneumoniae infection are correlated with immune response and inflammation, possibly suggesting that M. pneumoniae has some inherent ability to modulate host immune pathways.

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation.

Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin-responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non-histone, well-known tumor suppressor protein 53 (p53) and co-regulates a wide array of metabolic genes. Among these, the p53-responsive carbohydrate metabolic genes Tp53-induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose-mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short-term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA-Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53-mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.