Manure-biochar compost mitigates the soil salinity stress in tomato plants by modulating the osmoregulatory mechanism, photosynthetic pigments, and ionic homeostasis.

One of the main abiotic stresses that affect plant development and lower agricultural productivity globally is salt in the soil. Organic amendments, such as compost and biochar can mitigate the opposing effects of soil salinity (SS) stress. The purpose of this experiment was to look at how tomato growth and yield on salty soil were affected by mineral fertilization and manure-biochar compost (MBC). Furthermore, the study looked at how biochar (organic amendments) work to help tomato plants that are stressed by salt and also a mechanism by which biochar addresses the salt stress on tomato plants. Tomato yield and vegetative growth were negatively impacted by untreated saline soil, indicating that tomatoes are salt-sensitive. MBC with mineral fertilization increased vegetative growth, biomass yield, fruit yield, chlorophyll, and nutrient contents, Na/K ratio of salt-stressed tomato plants signifies the ameliorating effects on tomato plant growth and yield, under salt stress. Furthermore, the application of MBC with mineral fertilizer decreased H2O2, but increased leaf relative water content (RWC), leaf proline, total soluble sugar, and ascorbic acid content and improved leaf membrane damage, in comparison with untreated plants, in response to salt stress. Among the composting substances, T7 [poultry manure-biochar composting (PBC) (1:2) @ 3 t/ha + soil-based test fertilizer (SBTF)] dose exhibited better-improving effects on salt stress and had maintained an order of T7 > T9 > T8 > T6 in total biomass and fruit yield of tomato. These results suggested that MBC might mitigate the antagonistic effects of salt stress on plant growth and yield of tomatoes by improving osmotic adjustment, antioxidant capacity, nutrient accumulation, protecting photosynthetic pigments, and reducing ROS production and leaf damage in tomato plant leaves.

A Possible Nocebo Effect in Children Following the Flint Water Crisis: Evidence From Schoolteacher Perceptions and Neuropsychological Evaluations.

OBJECTIVE: Special education enrollment increased in Flint following the 2014-2015 Flint Water Crisis, but lead exposure is not plausibly responsible. Labeling Flint children as lead poisoned and/or brain damaged may have contributed to rising special education needs (ie, nocebo effect). To better document this possibility, we surveyed schoolteachers and reviewed neuropsychological assessments of children for indications of negative labeling. METHODS: A survey of Flint and Detroit (control) public schoolteachers using a modified Illness Perception Questionnaire was conducted 5 years post-crisis. We also examined neuropsychological assessments from a recently settled class lawsuit. RESULTS: Relative to Detroit (n = 24), Flint teachers (n = 11) believed that a higher proportion of their students had harmful lead exposure (91.8% Flint vs 46% Detroit; P = 0.00034), were lead poisoned (51.3% vs 24.3%; P = 0.018), or brain damaged (28.8% vs 12.9%; P = 0.1), even though blood lead of Flint children was always less than half of that of Detroit children. Neuropsychological assessments diagnosed lead poisoning and/or brain damage from water lead exposure in all tested children (n = 8), even though none had evidence of elevated blood lead and a majority had prior learning disability diagnoses. CONCLUSION: Teachers' responses and neuropsychological assessments suggest Flint children were harmed by a nocebo effect.

UBR7 E3 Ligase Suppresses Interferon-ß Mediated Immune Signaling by Targeting Sp110 in Hepatitis B Virus-Induced Hepatocellular Carcinoma.

A newly discovered E3 ubiquitin ligase, UBR7, plays a crucial role in histone H2BK120 monoubiquitination. Here, we report a novel function of UBR7 in promoting hepatitis B virus (HBV) pathogenesis, which further leads to HBV-induced hepatocellular carcinoma (HCC). Transcriptomics analysis from HCC patients revealed the deregulation of UBR7 in cancer. Remarkably, targeting UBR7, particularly its catalytic function, led to a significant decrease in viral copy numbers. We also identified the speckled family protein Sp110 as an important substrate of UBR7. Notably, Sp110 has been previously shown to be a resident of promyelocytic leukemia nuclear bodies (PML-NBs), where it remains SUMOylated, and during HBV infection, it undergoes deSUMOylation and exits the PML body. We observed that UBR7 ubiquitinates Sp110 at critical residues within its SAND domain. Sp110 ubiquitination downregulates genes in the type I interferon response pathway. Comparative analysis of RNA-Seq from the UBR7/Sp110 knockdown data set confirmed that the IFN-ß signaling pathway gets deregulated in HCC cells in the presence of HBV. Single-cell RNA-Seq analysis of patient samples further confirmed the inverse correlation between the expression of Sp110/UBR7 and the inflammation score. Notably, silencing of UBR7 induces IRF7 phosphorylation, thereby augmenting interferon (IFN)-ß and the downstream interferon-stimulated genes (ISGs). Further, wild-type but not the ubiquitination-defective mutant of Sp110 could be recruited to the type I interferon response pathway genes. Our study establishes a new function of UBR7 in non-histone protein ubiquitination, promoting viral persistence, and has important implications for the development of therapeutic strategies targeting HBV-induced HCC.

A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance.

Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity.

To Ub or not to Ub: The epic dilemma of histones that regulate gene expression and epigenetic cross-talk.

A dynamic array of histone post-translational modifications (PTMs) regulate diverse cellular processes in the eukaryotic chromatin. Among them, histone ubiquitination is particularly complex as it alters nucleosome surface area fostering intricate cross-talk with other chromatin modifications. Ubiquitin signaling profoundly impacts DNA replication, repair, and transcription. Histones can undergo varied extent of ubiquitination such as mono, multi-mono, and polyubiquitination, which brings about distinct cellular fates. Mechanistic studies of the ubiquitin landscape in chromatin have unveiled a fascinating tapestry of events that orchestrate gene regulation. In this review, we summarize the key contributors involved in mediating different histone ubiquitination and deubiquitination events, and discuss their mechanism which impacts cell transcriptional identity and DNA damage response. We also focus on the proteins bearing epigenetic reader modules critical in discerning site-specific histone ubiquitination, pivotal for establishing complex epigenetic crosstalk. Moreover, we highlight the role of histone ubiquitination in different human diseases including neurodevelopmental disorders and cancer. Overall the review elucidates the intricate orchestration of histone ubiquitination impacting diverse cellular functions and disease pathogenesis, and provides insights into the current challenges of targeting them for therapeutic interventions.

Competition for engineering tenure-track faculty positions in the United States.

How likely are engineering PhD graduates to get a tenure-track faculty position in the United States? To answer this question, we analyzed aggregated yearly data on PhD graduates and tenure-track/tenured faculty members across all engineering disciplines from 2006 to 2021, obtained from the American Society of Engineering Education. The average likelihood for securing a tenure-track faculty position for engineering overall during this 16-year period was 12.4% (range = 10.9-18.5%), implying that roughly 1 in 8 PhD graduates attain such positions. After a significant decline from 18.5 to 10.9% between 2006 and 2014 (R2 = 0.62; P < 0.05), a trend consistent with a period of rising competition, the outlook has since stabilized between 11.3 and 12% (R2 = 0.04; P > 0.05). Given that most engineering PhD graduates will never secure a tenure-track faculty position, emphasizing alternative career tracks during doctoral training could align expectations better with reality.

Safety incident reporting and barriers (SIRaB) study: Strategies and approaches for investigating patient safety events in a hospital set-up.

BACKGROUND: Unsafe patient events not only entail a clinical impact but also lead to economic burden in terms of prolonged hospitalization or unintended harm and delay in care delivery. Monitoring and time-bound investigation of patient safety events (PSEs) is of paramount importance in a healthcare set-up. OBJECTIVES: To explore the safety incident reporting behaviour and the barriers in a hospital set-up. METHODS: The study had two sections: (a) Retrospective assessment of all safety incidents in the past 1 year, and (b) Understanding the barriers of safety reporting by interviewing the major stakeholders in patient safety reporting framework. Further root cause analysis and failure mode effect analysis were performed for the situation observed. Results were statistically analyzed. RESULTS: Of the total of 106 PSEs reported voluntarily to the system, the highest reporting functional group was that of nurses (40.57%), followed by physicians (18.87%) and pharmacists (17.92%). Among the various factors identified as barriers in safety incident reporting, fear of litigation was the most observed component. The most commonly observed event was those pertaining to medication management, followed by diagnostic delay. Glitches in healthcare delivery accounted for 8.73% of the total reported PSEs, followed by 5.72% of events occurring due to inter-stakeholder communication errors. 4.22% of the PSEs were attributed to organizational managerial dysfunctionalities. Majority of medication-related PSE has moderate risk prioritization gradation. CONCLUSION: Effective training and sensitization regarding the need to report the patient unsafe incidents or near misses to the healthcare system can help avert many untoward experiences. The notion of 'No Blame No Shame' should be well inculcated within the minds of each hospital unit such that even if an error occurs, its prompt reporting does not get harmed.

Disrupting the interaction between a p53 gain-of-function mutant and the transcriptional co-activator PC4 reverses drug resistance in cancer cells.

PC4 is a chromatin-associated protein and transcriptional coactivator whose role in gene regulation by wild-type p53 is now well known. Little is known about the roles of PC4 in tumor cells bearing mutant p53 genes. We show that PC4 associates with one of the tumor-associated gain-of-function p53 mutants, R273H. This association drives its recruitment to two promoters, UBE2C and MDR1, known to be responsible for imparting aggressive growth and resistance to many drugs. Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.

Epigenetic reprogramming of T cells: unlocking new avenues for cancer immunotherapy.

T cells, a key component of cancer immunotherapy, undergo a variety of histone modifications and DNA methylation changes since their bone marrow progenitor stages before developing into CD8+ and CD4+ T cells. These T cell types can be categorized into distinct subtypes based on their functionality and properties, such as cytotoxic T cells (Tc), helper T cells (Th), and regulatory T cells (Treg) as subtypes for CD8+ and CD4+ T cells. Among these, the CD4+ CD25+ Tregs potentially contribute to cancer development and progression by lowering T effector (Teff) cell activity under the influence of the tumor microenvironment (TME). This contributes to the development of therapeutic resistance in patients with cancer. Subsequently, these individuals become resistant to monoclonal antibody therapy as well as clinically established immunotherapies. In this review, we delineate the different epigenetic mechanisms in cancer immune response and its involvement in therapeutic resistance. Furthermore, the possibility of epi-immunotherapeutic methods based on histone deacetylase inhibitors and histone methyltransferase inhibitors are under investigation. In this review we highlight EZH2 as the principal driver of cancer cell immunoediting and an immune escape regulator. We have addressed in detail how understanding T cell epigenetic regulation might bring unique inventive strategies to overcome drug resistance and increase the efficacy of cancer immunotherapy.

Development of Empirical and Artificial Neural Network Model for the Prediction of Sorption Time to Assess the Potential of CO2 Sequestration in Coal.

Geological sequestration of CO2 in a coal seam is considered an attractive option to reduce the carbon footprint. It has an additional advantage of enhancing the recovery of coalbed methane, which has less sorption affinity toward coal in comparison to CO2. Desorption of gases from coal is controlled by various parameters, including reservoir depth and coal rank. A representative factor for desorption and diffusion in coal is the sorption time. It is an indicator which helps in estimation and evaluation of gas movement in the coal seam. Coals exhibiting high sorption time allow greater quantities of CO2 injection and hold potential for CO2 sequestration. Therefore, reliable and cost-effective estimation of sorption time is very important prior to investment in projects related to CO2 sequestration. Generally, proximate and gas content analyses are part of the preliminary analysis of coal for the assessment of its potential as a coal-bed methane reservoir. In this study, data generated using these analyses were found very useful for estimating the sorption time and CO2 sequestration potential of coal. The coal samples were collected from different depths of the Mand Raigarh coalfield for testing, and an empirical equation and artificial neural network (ANN)-based model have been developed to predict the sorption time of coal. The developed empirical equation predicts the sorption time with a coefficient of determination value of 0.88 and a root mean squared error value of ±1.07 days. Furthermore, the developed ANN model has been found to be very efficient in prediction with a correlation coefficient value of 0.97.

A small HDM2 antagonist peptide and a USP7 inhibitor synergistically inhibit the p53-HDM2-USP7 circuit.

HDM2, an E3 ubiquitin ligase, is a crucial regulator of many proliferation-related pathways. It is also one of the primary regulators of p53. USP7, a deubiquitinase, also plays a key role in the regulation of both p53 and HDM2, thus forming a small regulatory network with them. This network has emerged as an important drug target. Development of a synergistic combination targeting both proteins is desirable and important for regulating this module. We have developed a small helically constrained peptide that potently inhibited p53-HDM2 interaction and exerted anti-proliferative effects on p53+/+ cells. A combination of this peptide-when attached to cell entry and nuclear localization tags-and a USP7 inhibitor showed synergistic anti-proliferative effects against cells harboring wild-type alleles of p53. Synergistic inhibition of two important drug targets may lead to novel therapeutic strategies.

Did a Nocebo Effect Contribute to the Rise in Special Education Enrollment Following the Flint, Michigan Water Crisis?

Background: Exposure to waterborne lead during the Flint Water Crisis during April 2014-October 2015 is believed to have caused increased special education enrollment in Flint children. Method: This retrospective population-based cohort study utilized de-identified data for children under six years of age who had their blood lead tested during 2011 to 2019, and special education outcomes data for children enrolled in public schools for corresponding academic years (2011-12 to 2019-20) in Flint, Detroit (control city) and the State of Michigan. Trends in the following crisis-related covariates were also evaluated: waterborne contaminants, poverty, nutrition, city governance, school district policies, negative community expectations, media coverage and social media interactions. Results: Between 2011 and 2019, including the 2014-15 crisis period, the incidence of elevated blood lead in Flint children (≥ 5µg/dL) was always at least 47% lower than in the control city of Detroit (p < .0001) and was also never significantly higher than that for all children tested in Michigan (p = 0.33). Nonetheless, special education enrollment in Flint spiked relative to Detroit and Michigan (p < .0001). There is actually an inverse relationship between childhood blood lead and special education enrollment in Flint. Conclusion: This study failed to confirm any positive association between actual childhood blood lead levels and special education enrollment in Flint. Negative psychological effects associated with media predictions of brain damage could have created a self-fulfilling prophecy via a nocebo effect. The findings demonstrate a need for improved media coverage of complex events like the Flint Water Crisis.

NSF Fellows' perceptions about incentives, research misconduct, and scientific integrity in STEM academia.

There is increased concern about perverse incentives, quantitative performance metrics, and hyper-competition for funding and faculty positions in US academia. Recipients of the prestigious National Science Foundation Graduate Research Fellowships (n = 244) from Civil and Environmental Engineering (45.5%) and Computer Science and Engineering (54.5%) were anonymously surveyed to create a baseline snapshot of their perceptions, behaviors and experiences. NSF Fellows ranked scientific advancement as the top metric for evaluating academics followed by publishing in high-impact journals, social impact of research, and publication/citation counts. The self-reported rate of academic cheating was 16.7% and of research misconduct was 3.7%. Thirty-one percent of fellows reported direct knowledge of graduate peers cheating, and 11.9% had knowledge of research misconduct by colleagues. Only 30.7% said they would report suspected misconduct. A majority of fellows (55.3%) felt that mandatory ethics trainings left them unprepared for dealing with ethical issues. Fellows stated academic freedom, flexible schedules and opportunity to mentor students were the most positive aspects of academia, whereas pressures for funding, publication, and tenure were cited as the most negative aspects. These data may be useful in considering how to better prepare STEM graduate trainees for academic careers.

Recruiting African American Prostate Cancer Survivors for a Population-based Biobank Study.

BACKGROUND: Prostate cancer affects African American men disproportionately compared with men of other racial/ethnic groups. To identify biological bases for this health disparity, we sought to create a state-wide biobank of African American prostate cancer survivors in Florida. METHODS: African American men diagnosed with prostate cancer between 2013 and 2017 and living in Florida at diagnosis were identified through the State of Florida's cancer registry. Individuals were approached via mail and telephone, assessed for eligibility, and asked for informed consent. χ2 and t tests were conducted to identify differences between eligible and reachable individuals (i.e., had valid contact information) versus consented participants. RESULTS: Of the 5,960 eligible and reachable individuals, 3,904 were eligible and contacted at least once, and 578 consented [overall consent rate = 10% (578/5,960); adjusted consent rate = 15% (578/3,904)]. Statistically significant (Ps < 0.05) but small differences in demographic and clinical variables were observed. Consented participants were less likely to be older than 64 (35% vs. 41%) and less likely to have received radiotherapy (36% vs. 41%) and hormone therapy (16% vs. 21%), but more likely to have regional prostate cancer (13% vs. 11%) and have undergone surgery (44% vs. 39%). Consented participants did not differ from reachable individuals on other demographic and clinical factors (Ps > 0.05). CONCLUSIONS: Recruiting African American prostate cancer survivors to biobanking research through a cancer registry is feasible. However, the consent rate was low, and existing challenges limit consent and participation. IMPACT: Strategies for overcoming barriers to informed consent and increasing participation in biospecimen research are needed to address cancer disparities.

Understanding Nutritional Knowledge and Experiences in Families With a Child Newly Diagnosed With Type 1 Diabetes.

Nutrition is an integral part of diabetes management. Caregiver nutritional knowledge has been implicated in glycemic management of youth with type 1 diabetes. This study assessed the nutritional knowledge of parents/caregivers of children newly diagnosed with type 1 diabetes. Findings suggest there is a need for more targeted support and training during the initial diagnosis and a desire for more technology-related resources such as virtual nutritionist-guided grocery shopping visits. Integrating these interventions into routine care for children with type 1 diabetes will help address the current gaps in caregiver nutritional literacy and their ability to provide appropriate care.

Epigenetic-Metabolic Interplay in the DNA Damage Response and Therapeutic Resistance of Breast Cancer.

Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic-metabolic interplay profoundly affects genomic stability of the cancer cells as well as their resistance to genotoxic therapies. These observations identify defining mechanisms of cancer epigenetics-metabolism-DNA repair axis that can be critical for devising novel, targeted therapeutic approaches that could sensitize cancer cells to conventional treatment strategies.

Role of the Histone Acetyl Transferase MOF and the Histone Deacetylase Sirtuins in Regulation of H4K16ac During DNA Damage Repair and Metabolic Programming: Implications in Cancer and Aging.

The accurate repair of genomic damage mediated by ionizing radiation (IR), chemo- or radiomimetic drugs, or other exogenous agents, is necessary for maintenance of genome integrity, preservation of cellular viability and prevention of oncogenic transformation. Eukaryotes have conserved mechanisms designed to perceive and repair the damaged DNA quite efficiently. Among the different types of DNA damage, double strand breaks (DSB) are the most detrimental. The cellular DNA DSB response is a hierarchical signaling network that integrates damage sensing and repair with chromatin structural changes that involve a range of pre-existing and induced covalent modifications. Recent studies have revealed that pre-existing histone modifications are important contributors within this signaling/repair network. This chapter discusses the role of a critical histone acetyl transferase (HAT) known as MOF (males absent on the first) and the histone deacetylases (HDACs) Sirtuins on histone H4K16 acetylation (H4K16ac) and DNA damage repair. We also discuss the role of this important histone modification in light of metabolic rewiring and its role in regulating human pathophysiologic states.

Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer.

Glucose metabolism plays a vital role in regulating cellular homeostasis as it acts as the central axis for energy metabolism, alteration in which may lead to serious consequences like metabolic disorders to life-threatening diseases like cancer. Malignant cells, on the other hand, help in tumor progression through abrupt cell proliferation by adapting to the changed metabolic milieu. Metabolic intermediates also vary from normal cells to cancerous ones to help the tumor manifestation. However, metabolic reprogramming is an important phenomenon of cells through which they try to maintain the balance between normal and carcinogenic outcomes. In this process, transcription factors and chromatin modifiers play an essential role to modify the chromatin landscape of important genes related directly or indirectly to metabolism. Our chapter surmises the importance of glucose metabolism and the role of metabolic intermediates in the cell. Also, we summarize the influence of histone effectors in reprogramming the cancer cell metabolism. An interesting aspect of this chapter includes the detailed methods to detect the aberrant metabolic flux, which can be instrumental for the therapeutic regimen 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.