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Abstract There is no biomarker reflecting right ventricular dysfunction in HFrEF patients used in clinical practice. We have aimed to look for a circulating marker of RV dysfunction employing a quantitative proteomic strategy. The Olink Proteomics Multiplex panels (Cardiovascular Disease II, III, Cardiometabolic, and Inflammation Target Panels) identified FGF-23 to be the most differentially abundant (more than 2.5-fold) in blood plasma of HF patients with severe RV dysfunction (n = 30) compared to those with preserved RV function (n = 31). A subsequent ELISA-based confirmatory analysis of circulating FGF-23 in a large cohort of patients (n = 344, 72.7% NYHA III/IV, LVEF 22.5%, 54.1% with moderate/severe RV dysfunction), followed by multivariable regression analysis, revealed that the plasma FGF-23 level was most significantly associated with RV dysfunction grade (p = 0.0004) and congestion in the systemic circulation (p = 0.03), but not with LV-ejection fraction (p = 0.69) or estimated glomerular filtration rate (eGFR, p = 0.08). FGF-23 was associated with the degree of RV dysfunction in both sub-cohorts (i.e. in patients with and without congestion, p

Abstract JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1β/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1–3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).

BackgroundFrontotemporal lobe disorders (FTD) are amongst the most common brain neurodegenerative disorders. Their relatively covert, frequently subtle presentations and diverse etiologies, pose major challenges in diagnosis and treatments. Recent studies have yielded insights that the etiology in the majority are due to environmental and sporadic causes, rather than genetic in origin.AimsTo retrospectively examine the cognitive and behavioral impairments in the veteran population to garner the range of differing syndrome presentations and etiological subcategories with a specific focus on frontotemporal lobe disorders.MethodologyThe design is a retrospective, observational registry, case series with the collection of epidemiological, clinical, cognitive, laboratory and radiological data on people with cognitive and behavioral disorders. Inclusion criteria for entry were veterans evaluated exclusively at Orlando VA Healthcare System, neurology section, receiving a diagnosis of FTD by standard criteria, during the observation period dated from July 2016 to March 2021. Frontotemporal disorders (FTD) were delineated into five clinical 5 subtypes. Demographic, cardiovascular risk factors, cognitive, behavioral neurological, neuroimaging data and presumed etiological categories, were collected for those with a diagnosis of frontotemporal disorder.ResultsOf the 200 patients with FTD, further cognitive, behavioral neurological evaluation with standardized, metric testing was possible in 105 patients. Analysis of the etiological groups revealed significantly different younger age of the traumatic brain injury (TBI) and Gulf War Illness (GWI) veterans who also had higher Montreal Cognitive Assessment (MOCA) scores. The TBI group also had significantly more abnormalities of hypometabolism, noted on the PET brain scans. Behavioral neurological testing was notable for the findings that once a frontotemporal disorder had been diagnosed, the four different etiological groups consistently had abnormal FRSBE scores for the 3 principal frontal presentations of (i) abulia/apathy, (ii) disinhibition, and (iii) executive dysfunction as well as abnormal Frontal Behavioral Inventory (FBI) scores with no significant difference amongst the etiological groups. The most common sub-syndromes associated with frontotemporal syndromes were the Geschwind-Gastaut syndrome (GGS), Klüver-Bucy syndrome (KBS), involuntary emotional expression disorder (IEED), cerebellar cognitive affective syndrome (CCA), traumatic encephalopathy syndrome (TES) and prosopagnosia. Comparisons with the three principal frontal lobe syndrome clusters (abulia, disinhibition, executive dysfunction) revealed a significant association with abnormal disinhibition FRSBE T-scores with the GGS. The regression analysis supported the potential contribution of disinhibition behavior that related to this complex, relatively common behavioral syndrome in this series. The less common subsyndromes in particular, were notable, as they constituted the initial overriding, presenting symptoms and syndromes characterized into 16 separate conditions.ConclusionBy deconstructing FTD into the multiple sub-syndromes and differing etiologies, this study may provide foundational insights, enabling a more targeted precision medicine approach for future studies, both in treating the sub-syndromes as well as the underlying etiological process.

The K-12 health and physical education professions are largely guided and supported by three entities. They include state departments of education, national and state professional associations, and teacher education programs (i.e., health education teacher education [HETE] and physical education teacher education [PETE]). From the outside looking in, it may seem that HETE and PETE programs are not dissimilar, yet both disciplines continue to operate largely within individual vacuums, each being historically undermined and marginalized. Therefore, questions regarding the purpose and relevance of K-12 health and physical education programs are continually raised. These common challenges may have a negative impact on recruitment of health and physical education teachers, retention of HETE and PETE programs, and ultimately the learning outcomes of youth in schools. In this article, we review critical challenges faced by both HETE and PETE programs with the hope that this can lead to collaboration, advocacy, and meaningful change.

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Aims. The objective of this study was to compare bone invasion type with histopathological, clinical and immunohistochemical prognostic factors. Methods. The study included 49 patients who were treated for oral squamous cell carcinoma. Of which, 30 patients, with presence of bone invasion on histopathology, were divided according to the type of bone invasion (erosive, infiltrative, mixed). Each invasion type was compared to microvascular density using the CD34 marker. Results. The bone invasion was observed in 30 out of 49 patients (61.22%). On McNemar's test, statistically significant association was observed between bone invasion types and histopathological grade. In contrast, no significant correlation was observed between bone invasion type, and tumour volume or nodal metastases. In tumours with bone invasion of the infiltrative type, higher frequency of locoregional relapses was observed. The 5-year survival, since diagnosis, was approximately 60% in the erosive group, 40% in the mixed group, and merely 15% in the infiltrative group. Conclusion. Peritumoural microvascular density was not significantly related to bone invasion types. Whereas, a significantly higher intratumoural microvascular density was observed in infiltrative type of the bone invasion, when compared to the erosive and mixed type.

Abstract Various cellular quality control mechanisms support proteostasis. While, ribosome-associated chaperones prevent the misfolding of nascent chains during translation, importins were shown to prevent the aggregation of specific cargoes in a post-translational mechanism prior the import into the nucleoplasm. Here, we hypothesize that importins may already bind ribosome-associated cargo in a co-translational manner. We systematically measure the nascent chain association of all importins in Saccharomyces cerevisiae by selective ribosome profiling. We identify a subset of importins that bind to a wide range of nascent, often uncharacterized cargoes. This includes ribosomal proteins, chromatin remodelers and RNA binding proteins that are aggregation prone in the cytosol. We show that importins act consecutively with other ribosome-associated chaperones. Thus, the nuclear import system is directly intertwined with nascent chain folding and chaperoning.

The task of tree species classification through deep learning has been challenging for the forestry community, and the lack of standardized datasets has hindered further progress. Our work presents a solution in the form of a large bark image dataset called CentralBark, which enhances the deep learning-based tree species classification. Additionally, we have laid out an efficient and repeatable data collection protocol to assist future works in an organized manner. The dataset contains images of 25 central hardwood and Appalachian region tree species, with over 19,000 images of varying diameters, light, and moisture conditions. We tested 25 species: elm, oak, American basswood, American beech, American elm, American sycamore, bitternut hickory, black cherry, black locust, black oak, black walnut, eastern cottonwood, hackberry, honey locust, northern red oak, Ohio buckeye, Osage-orange, pignut hickory, sassafras, shagbark hickory silver maple, slippery elm, sugar maple, sweetgum, white ash, white oak, and yellow poplar. Our experiment involved testing three different models to assess the feasibility of species classification using unaltered and uncropped images during the species-classification training process. We achieved an overall accuracy of 83.21% using the EfficientNet-b3 model, which was the best of the three models (EfficientNet-b3, ResNet-50, and MobileNet-V3-small), and an average accuracy of 80.23%.

The purpose of this study was to develop a concise composite measure of mindset and intellectual development in order to inform pedagogical strategies to support students' intellectual growth. A development sample of undergraduate students (n = 295) completed the 37-item pilot Mindset and Intellectual Development Scale (MINDS). The dataset was analyzed using Principal Component Analysis to determine the orthogonal dimensionality of the scale and for item reduction. The MINDS was shown to have eleven items describing two orthogonal dimensions: Intellectual Maturity and Mindset. An additional item was included to control for the social desirability bias. The MINDS collapsed what often are seen as separate dimensions of learning in order to capture a more robust underlying construct of intellectual development with which to assess undergraduate students' metacognitive states.

BackgroundImmunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient’s life expectancy varies between months and decades.MethodsWe first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months).ResultsRNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and de novo (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma.ConclusionRNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.

IntroductionThis paper investigates the links between deforestation and key economic, social, environmental, and geographical variables. We focus on per capita GDP, total forest cover, and the population across a diverse sample of countries from five continents for the last three decades.MethodsThis study utilizes a regression model using panel data to show the impact of key economic, and social variables on deforestation. Also, set of dummy variables is introduced in the paper. To enable the investigation, we use a set of dummies to capture their influence. The random effect specifications are used in this investigation. The research focuses on a period ranging from 1990 to 2020.ResultsResults show how different socio-economic variables influence deforestation. For example, disruptive events like the COVID-19 pandemic and the financial crisis had a negative effect on forest area development across all models. GDP per capita has different impact depending on the size of a country. Former colonies seem to have more deforestation.ConclusionsThe global environmental challenges posed by human activities and their impact on the state of forest have become increasingly evident. It is necessary to undertake policy and governance reforms to establish a solid legal framework, strengthen enforcement mechanisms, and foster transparency and accountability. The promotion of sustainable agriculture and agroforestry practices can substantially alleviate pressure on forests. Furthermore, it is necessary to mitigate disruptive events like pandemics by establishing specific strategies and creating contingency plans.

Environmental policies to address water quality impairments in the San Joaquin River of California have focused on the reduction of salinity and selenium-contaminated subsurface agricultural drainage loads from westside sources. On 31 December 2019, all of the agricultural drainage from a 44,000 ha subarea on the western side of the San Joaquin River basin was curtailed. This policy requires the on-site disposal of all of the agricultural drainage water in perpetuity, except during flooding events, when emergency drainage to the River is sanctioned. The reuse of this saline agricultural drainage water to irrigate forage crops, such as 'Jose' tall wheatgrass and alfalfa, in a 2428 ha reuse facility provides an economic return on this pollutant disposal option. Irrigation with brackish water requires careful management to prevent salt accumulation in the crop root zone, which can impact forage yields. The objective of this study was to optimize the sustainability of this reuse facility by maximizing the evaporation potential while achieving cost recovery. This was achieved by assessing the spatial and temporal distribution of the root zone salinity in selected fields of 'Jose' tall wheatgrass and alfalfa in the drainage reuse facility, some of which have been irrigated with brackish subsurface drainage water for over fifteen years. Electromagnetic soil surveys using an EM-38 instrument were used to measure the spatial variability of the salinity in the soil profile. The tall wheatgrass fields were irrigated with higher salinity water (1.2-9.3 dS m-1) compared to the fields of alfalfa (0.5-6.5 dS m-1). Correspondingly, the soil salinity in the tall wheatgrass fields was higher (12.5 dS m-1-19.3 dS m-1) compared to the alfalfa fields (8.97 dS m-1-14.4 dS m-1) for the years 2016 and 2017. Better leaching of salts was observed in the fields with a subsurface drainage system installed (13-1 and 13-2). The depth-averaged root zone salinity data sets are being used for the calibration of the transient hydro-salinity computer model CSUID-ID (a one-dimensional version of the Colorado State University Irrigation Drainage Model). This user-friendly decision support tool currently provides a useful framework for the data collection needed to make credible, field-scale salinity budgets. In time, it will provide guidance for appropriate leaching requirements and potential blending decisions for sustainable forage production. This paper shows the tie between environmental drainage policy and the role of local governance in the development of sustainable irrigation practices, and how well-directed collaborative field research can guide future resource management.

The positivity principle states that people learn better from instructors who display positive emotions rather than negative emotions. In two experiments, students viewed a short video lecture on a statistics topic in which an instructor stood next to a series of slides as she lectured and then they took either an immediate test (Experiment 1) or a delayed test (Experiment 2). In a between-subjects design, students saw an instructor who used her voice, body movement, gesture, facial expression, and eye gaze to display one of four emotions while lecturing: happy (positive/active), content (positive/passive), frustrated (negative/active), or bored (negative/passive). First, learners were able to recognize the emotional tone of the instructor in an instructional video lecture, particularly by more strongly rating a positive instructor as displaying positive emotions and a negative instructor as displaying negative emotions (in Experiments 1 and 2). Second, concerning building a social connection during learning, learners rated a positive instructor as more likely to facilitate learning, more credible, and more engaging than a negative instructor (in Experiments 1 and 2). Third, concerning cognitive engagement during learning, learners reported paying more attention during learning for a positive instructor than a negative instructor (in Experiments 1 and 2). Finally, concerning learning outcome, learners who had a positive instructor scored higher than learners who had a negative instructor on a delayed posttest (Experiment 2) but not an immediate posttest (Experiment 1). Overall, there is evidence for the positivity principle and the cognitive-affective model of e-learning from which it is derived.

Previously, the small molecule inhibitor of transcriptional enhanced associate domain (TEAD) MGH-CP1 has been described in stem cells. Here, the authors demonstrate the utility of MGH-CP1 in cancer therapy and find treatment to increase Akt pathway activation via TEAD-Vgll3 activation, presenting a rationale for combination with Akt inhibition.

BackgroundRight ventricular (RV) function is currently being evaluated solely according to the properties of RV myocardium. We have tested a concept that in patients with heart failure with reduced ejection fraction (HFrEF), RV assessment should integrate the information about both RV function as well as size.MethodsA total of 836 stable patients with HFrEF (LVEF 23.6 ± 5.8%, 82.8% males, 68% NYHA III/IV) underwent echocardiographic evaluation and were prospectively followed for a median of 3.07 (IQRs 1.11; 4.89) years for the occurrence of death, urgent heart transplantation or implantation of mechanical circulatory support.ResultsRV size (measured as RV-basal diameter, RVD1) was significantly associated with an adverse outcome independent of RV dysfunction grade (p = 0.0002). The prognostic power of RVD1 was further improved by indexing to body surface area (RVD1i, p 0.03, p 60), patients with milder degree of RV dysfunction but more dilated RV had similar outcome as those with more severe degree of RV dysfunction but smaller RV size (all p > 0.50), independent of tricuspid regurgitation severity and degree of pulmonary hypertension.ConclusionRV dilatation is a manifestation of RV dysfunction. The evaluation of RV performance should integrate the information about both RV size and function.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.