An antibody that inhibits TGF-ß1 release from latent extracellular matrix complexes attenuates the progression of renal fibrosis.

Inhibitors of the transforming growth factor-ß (TGF-ß) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-ß homologs has safety liabilities. TGF-ß1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-ß-binding proteins (LTBPs) present TGF-ß1 in the extracellular matrix, and TGF-ß1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-ß1 presented by LTBPs but did not bind to TGF-ß1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-ß1 that is not accessible on GARP- or LRRC33-presented TGF-ß1, explaining the antibody's selectivity for LTBP-complexed TGF-ß1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-ß1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-ß inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-ß1 as an approach for treating fibrosis.

Explorations in Creepiness: Tolerance for Ambiguity and Susceptibility to "Not Just Right Experiences" Predict the Ease of Getting "Creeped Out".

This study was designed to explore the role played by ambiguity in the experience of creepiness, as well as the relevance of personality traits for predicting individual differences in susceptibility to getting "creeped out," In an online study, a mixed sample of 278 college undergraduates and adults (60 males, 206 females, 12 nonbinary or chose not to report; Mean age = 31.43, range 18-68) recruited through social network platforms filled out scales measuring their tolerance for ambiguity and their susceptibility to having "Not Just Right Experiences." They then rated 25 images (12 normal, 13 prejudged to be creepy or confusing) on creepiness and several other adjective dimensions. The findings indicated that individuals who were less tolerant of ambiguity and those highly susceptible to not just right experiences perceived ambiguous or creepy persons, places, and objects to be more creepy, confusing and disturbing. Both measures were negatively related to time spent looking at confusing or creepy images, and females were generally more easily creeped out by creepy and confusing images than were males. The results support the conclusion that current models of creepiness are correct; the emotional experience of getting "creeped out" does indeed appear to be triggered by the need to resolve ambiguity.

Using machine learning to dissect host kinases required for Leishmania internalization and development.

The Leishmania life cycle alternates between promastigotes, found in the sandfly, and amastigotes, found in mammals. When an infected sandfly bites a host, promastigotes are engulfed by phagocytes (i.e., neutrophils, dendritic cells, and macrophages) to establish infection. When these phagocytes die or break down, amastigotes must be re-internalized to survive within the acidic phagolysosome and establish disease. To define host kinase regulators of Leishmania promastigote and amastigote uptake and survival within macrophages, we performed an image-based kinase regression screen using a panel of 38 kinase inhibitors with unique and overlapping kinase targets. We also targeted inert beads to complement receptor 3 (CR3) or Fcγ receptors (FcR) as controls by coating them with complement/C3bi or IgG respectively. Through this approach, we identified several host kinases that regulate receptor-mediated phagocytosis and/or the uptake of L. amazonensis. Findings included kinases previously implicated in Leishmania uptake (such as SRC family kinases (SFK), Abl family kinases (ABL1/c-Abl, ABL2/Arg), and spleen tyrosine kinase (SYK)); we also uncovered many novel kinases. These methods also predicted kinases necessary for promastigotes to convert to amastigotes or for amastigotes to survive within macrophages. Overall, our results suggest that the concerted action of multiple interconnected networks of host kinases are needed over the course of Leishmania infection, and that the kinases required for the parasite's life cycle substantially differ depending on which receptors are bound and the life cycle stage that is internalized. In addition, using our screen, we identified kinases that preferentially regulate the uptake of parasites over beads, indicating that the methods required for Leishmania to be internalized by macrophages differ significantly from generalized phagocytic mechanisms. Our findings are intended to be used as a hypothesis generation resource for the broader scientific community studying the roles of kinases in host-pathogen interactions.

Survival trends for left and right sided colon cancer using population-based SEER database: A forty-five-year analysis from 1975 to 2019.

BACKGROUND: Survival differences between left-sided colon cancer (LSCC) and right-sided colon cancer (RSCC) has been previously reported with mixed results, with various study periods not accounting for other causes of mortality. PURPOSE: We sought to assess the trends in colon cancer cause- specific survival (CSS) and overall survival (OS) based on sidedness. METHOD: Fine-Gray competing risk and Cox models were used to analyze Surveillance, Epidemiology, and End Results (SEER) population-based cohort from 1975 to 2019. Various interval periods were identified based on the timeline of clinical adoption of modern chemotherapy (1975-1989, interval period A; 1990-2004, B; and 2005-2019, C). RESULTS: Of the 227,637 patients, 50.1% were female and 46.2% were RSCC. RSCC was more common for African Americans (51.5%), older patients (age ≥65; 51.4%), females (50.4%), while LSCC was more common among Whites (53.1%; p < 0.001), younger patients (age 18-49, 64.6%; 50-64, 62.3%; p < 0.001), males (58.1%; p < 0.001). The Median CSS for LSCC and RCC were 19.3 and 16.7 years respectively for interval period A (1975-1989). Median CSS for interval periods B and C were not reached (more than half of the cohort was still living at the end of the follow-up period). Adjusted CSS was superior for LSCC versus RSCC for the most recent interval period C (HR 0.89; 0.86-0.92; p < 0.001). LSCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LSCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS per stage for all interval periods. OS was better for LSCC irrespective of stage, with gradual improvement over time. CONCLUSION: LSCC was associated with superior survival compared to right sided tumors. With the adoption of modern chemotherapy regimens, prognosis between LSCC and RSCC became more divergent in favor of LSCC. Colon cancer clinical trials should strongly consider tumor sidedness as an enrollment factor.

Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing.

Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid-liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.

Analyzing Preceding factors affecting behavioral intention on communicational artificial intelligence as an educational tool.

During the pandemic, artificial intelligence was employed and utilized by students around the globe. Students' conduct changed in a variety of ways when schooling returned to regular instruction. This study aimed to analyze the student's behavioral intention and actual academic use of communicational AI (CAI) as an educational tool. This study identified the variables by utilizing an integrated framework based on the Unified Theory of Acceptance and Use of Technology (UTAUT2) and self-determination theory. Through the use of an online survey and Structural Equation Modeling, data from 533 respondents were analyzed. The results showed that perceived relatedness has the most significant effect on the behavioral intention of students in using CAI as an educational tool, followed by perceived autonomy. It showed that students use CAI based on the objective and the possibility of increasing their productivity, rather than any other purpose in the education setting. Among the UTAUT2 domains, only facilitating conditions, habit, and performance expectancy provided a significant direct effect on behavioral intention and an indirect effect on actual academic use. Further implications were presented. Moreover, the methodology and framework of this study could be extended and applied to educational technology-related studies. Lastly, the outcome of this study may be considered in analyzing the behavioral intention of the students as the teaching-learning environment is still continuously expanding and developing.

Distribution and toxicity of dihydroxybenzenes in drinking water sources in Nigeria.

This study provides, for the first time, data on the distribution and toxicity of catechol (CAT) and hydroquinone (HQ) in drinking water sources from Africa. Groundwater (boreholes and hand-dug wells) and surface water in three Southwestern States in Nigeria served as sampling sites. The concentrations of CAT and HQ in groundwater and surface water were determined throughout a period of 12 months, evaluating the effects of seasonal variation (rainy and dry seasons). Mean concentrations of CAT in water samples were higher than those of HQ. In this study, CAT was more frequently detected, with its mean concentration in groundwater samples higher in the rainy season (430 µg L-1) than in the dry season (175 µg L-1). Multivariate analysis using the Principal Component Analysis Software suggests that in most sample sites, CAT and HQ in water samples were from entirely different anthropogenic sources. The most impacted population groups were the toddlers and infants. Similarly, maximum and median concentrations of CAT in water samples pose serious risks to Daphnia at both acute and chronic levels. The results from this study suggest the need for further control of these dihydroxybenzenes through regular monitoring and removal from drinking water during treatment.

Perceptions of the Personalities of Namesaked Children as a Function of Their Sex and Birth Order.

One-hundred-seventeen participants rated hypothetical individuals on the "Big Five" personality traits, narcissism, intelligence, and creativity. Hypothetical individuals differed according to namesake status (named after a parent/relative or not), sex, and birth order. Namesaking interacted with both sex and birth order on ratings of many personality traits, but sex and birth order were stronger predictors of personality stereotypes than was namesaking. The results indicate that namesaking children may have implications for the expectations that others will have about their personalities, but the nature of these expectations will rely heavily upon the child's gender and birth order.

The metabolic effects of intermittent versus continuous feeding in critically ill patients.

Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.

Nucleus accumbens local circuit for cue-dependent aversive learning.

Response to threatening environmental stimuli requires detection and encoding of important environmental features that dictate threat. Aversive events are highly salient, which promotes associative learning about stimuli that signal this threat. The nucleus accumbens is uniquely positioned to process this salient, aversive information and promote motivated output, through plasticity on the major projection neurons in the brain area. We describe a nucleus accumbens core local circuit whereby excitatory plasticity facilitates learning and recall of discrete aversive cues. We demonstrate that putative nucleus accumbens substance P release and long-term excitatory plasticity on dopamine 2 receptor-expressing projection neurons are required for cue-dependent fear learning. Additionally, we find that fear learning and recall is dependent on distinct projection neuron subtypes. Our work demonstrates a critical role for nucleus accumbens substance P in cue-dependent aversive learning.

Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer.

Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action.

Coordination between aminoacylation and editing to protect against proteotoxicity.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that ligate amino acids to tRNAs, and often require editing to ensure accurate protein synthesis. Recessive mutations in aaRSs cause various neurological disorders in humans, yet the underlying mechanism remains poorly understood. Pathogenic aaRS mutations frequently cause protein destabilization and aminoacylation deficiency. In this study, we report that combined aminoacylation and editing defects cause severe proteotoxicity. We show that the ths1-C268A mutation in yeast threonyl-tRNA synthetase (ThrRS) abolishes editing and causes heat sensitivity. Surprisingly, experimental evolution of the mutant results in intragenic mutations that restore heat resistance but not editing. ths1-C268A destabilizes ThrRS and decreases overall Thr-tRNAThr synthesis, while the suppressor mutations in the evolved strains improve aminoacylation. We further show that deficiency in either ThrRS aminoacylation or editing is insufficient to cause heat sensitivity, and that ths1-C268A impairs ribosome-associated quality control. Our results suggest that aminoacylation deficiency predisposes cells to proteotoxic stress.

Emotionally clocked out: cell-type specific regulation of mood and anxiety by the circadian clock system in the brain.

Circadian rhythms are self-sustained oscillations of biological systems that allow an organism to anticipate periodic changes in the environment and optimally align feeding, sleep, wakefulness, and the physiological and biochemical processes that support them within the 24 h cycle. These rhythms are generated at a cellular level by a set of genes, known as clock genes, which code for proteins that inhibit their own transcription in a negative feedback loop and can be perturbed by stress, a risk factor for the development of mood and anxiety disorders. A role for circadian clocks in mood and anxiety has been suggested for decades on the basis of clinical observations, and the dysregulation of circadian rhythms is a prominent clinical feature of stress-related disorders. Despite our understanding of central clock structure and function, the effect of circadian dysregulation in different neuronal subtypes in the suprachiasmatic nucleus (SCN), the master pacemaker region, as well as other brain systems regulating mood, including mesolimbic and limbic circuits, is just beginning to be elucidated. In the brain, circadian clocks regulate neuronal physiological functions, including neuronal activity, synaptic plasticity, protein expression, and neurotransmitter release which in turn affect mood-related behaviors via cell-type specific mechanisms. Both animal and human studies have revealed an association between circadian misalignment and mood disorders and suggest that internal temporal desynchrony might be part of the etiology of psychiatric disorders. To date, little work has been conducted associating mood-related phenotypes to cell-specific effects of the circadian clock disruptions. In this review, we discuss existing literature on how clock-driven changes in specific neuronal cell types might disrupt phase relationships among cellular communication, leading to neuronal circuit dysfunction and changes in mood-related behavior. In addition, we examine cell-type specific circuitry underlying mood dysfunction and discuss how this circuitry could affect circadian clock. We provide a focus for future research in this area and a perspective on chronotherapies for mood and anxiety disorders.

The impact of COVID-19 on mortality, length of stay, and cost of care among patients with gastrointestinal malignancies: A propensity score-matched analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the coronavirus 19 (COVID-19) pandemic have had a lasting impact on the care of cancer patients. The impact on patients with gastrointestinal (GI) malignancies remains incompletely understood. We aimed to assess the impact of COVID-19 on mortality, length of stay (LOS), and cost of care among patients with GI malignancies, and identify differences in outcomes based on primary tumor site. METHODS: We analyzed discharge encounters collected from the National Inpatient Sample (NIS) between March 2020 and December 2020 using propensity score matching (PSM) and COVID-19 as the treatment effect. RESULTS: Of the 87,684 patient discharges with GI malignancies, 1892 were positive for COVID-19 (C+) and eligible for matching in the PSM model. Following PSM analysis, C+ with GI tumors demonstrated increased incidence of mortality compared to their COVID-19-negative (C-) counterparts (21.3% vs. 11.9%, p < 0.001). C+ patients with colorectal cancer (CRC) had significantly higher mortality compared to those who were C- (40% vs. 24%; p = 0.035). In addition, C+ patients with GI tumors had a longer mean LOS (9.4 days vs. 6.9 days; p < 0.001) and increased cost of care ($26,048.29 vs. $21,625.2; p = 0.001) compared to C- patients. C+ patients also had higher odds of mortality secondary to myocardial infarction relative to C- patients (OR = 3.54, p = 0.001). CONCLUSIONS: C+ patients with GI tumors face approximately double the odds of mortality, increased LOS, and increased cost of care compared to their C- counterparts. Outcome disparities were most pronounced among patients with CRC.

Academic productivity metrics correlate positively with industry funding amongst orthopedic shoulder and elbow surgeons.

Background: Research efforts can produce practice-changing results with widespread implications for patient care. While critical to the advancement of the field, such efforts do not often provide direct compensation. However, a researcher's academic productivity may facilitate industry relationships, either as the impetus for the affiliation or a result of collaboration. Methods: Queries of the Centers for Medicaid and Medicare Services publicly available Open Payments System allowed for extraction of industry compensation data for orthopedic surgeons in 7 categories, including royalties and licensing fees, consulting fees, gifts, honoria, and 3 unique speaking fees delineations. This system identifies physicians by taxonomy identifications; however, Centers for Medicaid and Medicare Services does not have a unique code for shoulder and elbow surgeons. Therefore, identification of shoulder and elbow surgeons proceeded utilizing the American Shoulder and Elbow Surgeons (ASES) society 2019 membership directory. Cross-referencing this membership list with extracted Open Payments data provided industry funding information for all ASES members. Physicians then underwent an academic productivity assessment. Queries of Web of Science, Scopus, and Google Scholar User Profile databases provided the Hirsch index (h-index) and m-index for each surgeon. Bivariate and multivariate analyses produced statistical results. Results: From 2016 to 2020, 631,130, 158, and 72 ASES members earned mean annual industry compensation <$1000, between $1001 and $10,000, between $10,001 and $100,000, and >$100,000, respectively. Royalties (91.5%) predominated in the top earning group, compared with consulting fees (58.0%, 55.0%) in the 2 middle-tier groups. H-index and m-index correlated positively with total compensation (h-index: r = 0.18, P < .001; m-index: r = 0.10, P < .001). The highest income group (>$100,000) had higher h-index and m-index scores than either intermediate ($1001-$10,000, $10,001-$100,000) or lowest (<$1000) compensation groups (From lowest to highest income bracket-h-index: 14.8 vs. 16.4 vs. 19.4 vs. 32, P < .001; m-index: 0.79 vs. 0.85 vs. 0.91 vs. 1.18, P = .003). Multivariable analysis of factors associated with increased industry compensation identified only h-index (B = 8046, P < .001) as having a significant association with physician compensation, with each single unit increase in h-index associated with an 18% increase in industry funding. Conclusion: Among a group of academic shoulder and elbow surgeons, industry compensation correlates positively with academic productivity metrics, with an associated $8046/yr increase in industry funding for each single-unit increase in h-index over 9. Future studies may focus on more clearly defining the causal directionality of these results.

Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.

Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and severely impairs SKD3Y272C function under oxidizing conditions and in living cells. While Cys267 and Tyr272 are found in all SKD3 isoforms, isoform-1 features an additional α-helix that may compete with substrate-binding as suggested by crystal structure analyses and in silico modeling, underscoring the importance of the N-domain to SKD3 function.