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Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention. Preventing axon breakdown is key to treating neurodegeneration. Here, the authors show that after axotomy, DLK kinase drives apoptotic mitochondrial fission in axons. Blocking this reduces axon degeneration and neuron death in both human and mouse models. [ABSTRACT FROM AUTHOR]

The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure. A total-body irradiation (TBI) of 3 Gy was administered to female C3H/Hen mice. Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Animals remained on the respective control or rapamycin diets and were followed for their entire lifespan (total of 795 mice). The endpoint for the study was tumor formation (not to exceed 1 cm) or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumors (pathology evaluated on all animals). Kaplan-Meier survival curves revealed that all three concentrations of rapamycin afforded a significant survival advantage by delaying the time at which tumors appeared and reduction of the incidence of certain tumor types such as hepatocellular carcinomas. The survival advantage was dependent on the rapamycin concentration used. Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment. [ABSTRACT FROM AUTHOR]

The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure. A total-body irradiation (TBI) of 3 Gy was administered to female C3H/Hen mice. Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Animals remained on the respective control or rapamycin diets and were followed for their entire lifespan (total of 795 mice). The endpoint for the study was tumor formation (not to exceed 1 cm) or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumors (pathology evaluated on all animals). Kaplan-Meier survival curves revealed that all three concentrations of rapamycin afforded a significant survival advantage by delaying the time at which tumors appeared and reduction of the incidence of certain tumor types such as hepatocellular carcinomas. The survival advantage was dependent on the rapamycin concentration used. Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment. [ABSTRACT FROM AUTHOR]

The mechanisms of action of pyrimidine nucleoside derivatives on model lipid membranes of various compositions were studied. A systematic analysis of the tested agents' effects on the membrane physicochemical properties was performed. Differential scanning microcalorimetry data indicated that the ability of nucleoside derivatives to disorder membrane lipids depended on the types of nucleoside bases and membrane-forming lipids. The 5′-norcarbocyclic uracil derivatives were found to be ineffective, while N4-alkylcytidines demonstrated the most pronounced effects, significantly decreasing the dipalmitoylphosphocholine melting temperature and cooperativity of phase transition. The elongation of hydrophobic acyl radicals potentiated the disordering action of N4-alkylcytidines, while an increase in hydrophilicity due to replacing deoxyribose with ribose inhibited this effect. The ability of compounds to form transmembrane pores was also tested. It was found that 5-alkyluridines produced single, ion-permeable pores in phosphatidylglycerol membranes, and that methoxy-mycolic acid and trehalose monooleate potentiated the pore-forming activity of alkyloxymethyldeoxyuridines. The results obtained open up perspectives for the development of innovative highly selective anti-tuberculosis agents, which may be characterized by a low risk of developing drug resistance due to the direct action on the membranes of the pathogen. [ABSTRACT FROM AUTHOR]

S-Adenosyl-L-methionine (SAM)-mediated methylation of biomolecules controls their function and regulates numerous vital intracellular processes. Analogs of SAM with a reporter group in place of the S-methyl group are widely used to study these processes. However, many of these analogs are chemically unstable that largely limits their practical application. We have developed a new compound, SAM-Ph, which contains an H-phosphinic group (-P(O)(H)OH) instead of the SAM carboxylic group. SAM-PH is significantly more stable than SAM, retains functional activity in catechol-O-methyltransferase and methyltransferase WBSCR27 reactions. The last is associated with Williams-Beuren syndrome. Rac-SAM-PH was synthesized chemically, while (R,S)-SAM-PH and its analogs were prepared enzymatically either from H-phosphinic analogs of methionine (Met-PH) or H-phosphinic analog of S-adenosyl-L-homocysteine (SAH-Ph) using methionine adenosyltransferase 2A or halide methyltransferases, respectively. SAH-PH undergoes glycoside bond cleavage in the presence of methylthioadenosine nucleosidase like natural SAH. Thus, SAM-PH and its analogs are promising new tools for investigating methyltransferases and incorporating reporter groups into their substrates. [ABSTRACT FROM AUTHOR]

Enzymatic transglycosylation of the fleximer base 4-(4-aminopyridine-3-yl)-1H-pyrazole using recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of "non-typical" minor products of the reaction. In addition to "typical" N1-pyrazole nucleosides, a 4-imino-pyridinium riboside and a N1-pyridinium-N1-pyrazole bis-ribose derivative were formed. N1-Pyrazole 2′-deoxyribonucleosides and a N1-pyridinium-N1-pyrazole bis-2′-deoxyriboside were formed. But 4-imino-pyridinium deoxyriboside was not formed in the reaction mixture. The role of thermodynamic parameters of key intermediates in the formation of reaction products was elucidated. To determine the mechanism of binding and activation of heterocyclic substrates in the E. coli PNP active site, molecular modeling of the fleximer base and reaction products in the enzyme active site was carried out. As for N1-pyridinium riboside, there are two possible locations for it in the PNP active site. The presence of a relatively large space in the area of amino acid residues Phe159, Val178, and Asp204 allows the ribose residue to fit into that space, and the heterocyclic base can occupy a position that is suitable for subsequent glycosylation. Perhaps it is this "upside down" arrangement that promotes secondary glycosylation and the formation of minor bis-riboside products. [ABSTRACT FROM AUTHOR]

We explore how political and psychological factors condition the effectiveness of PSAs promoting COVID-19 vaccines. Targeting college students, we utilize a pretest-posttest experiment to examine how different PSAs (emotional, informational, and humorous) influence students' emotional reactions and assessments of the PSAs. Further, we assess whether the PSAs are able to influence learning and persuasion. We find certain PSAs are more effective at changing people's attitudes about the COVID-19 vaccine and the impact of these messages depends on people's political and psychological predispositions. The informational PSA produces learning, regardless of students' receptivity to pro-vaccine messaging. However, the humorous and emotional PSAs encourages learning only for those who are already receptive to the vaccine. These findings have implications for future public health campaigns aimed at college students, suggesting PSA campaigns developed to battle new health crises should be launched quickly before people develop strong attitudes about the emerging crisis. [ABSTRACT FROM AUTHOR]

Summary: Obesity is reported to increase stroke risk, with adipocyte‐derived cytokines or adipokines implicated as mediators. However, the relationship between adipokines and stroke is not well clarified. Thus, we aimed to evaluate the association of adipokines with stroke using fully adjusted risk estimates that incorporated body mass index in a meta‐analysis. Data from 52 studies (62,428 patients) were pooled in a random‐effects meta‐analysis. Adiponectin was independently associated with a lower risk of pre‐existing stroke (adjusted odds ratio: 0.64 [95% confidence interval: 0.46–0.88], p < 0.01), whereas leptin (1.08 [1.00–1.17], p = 0.04), resistin (1.06 [1.04–1.08], p < 0.01) and visfatin (1.04 [1.01–1.07], p = 0.01) are associated with a higher risk of stroke, but none with incident stroke. Adipokines independently associated with an ischaemic stroke subtype were adiponectin (0.48 [0.30–0.77], p < 0.01), leptin (1.10 [1.01–1.20], p = 0.04), and resistin (1.06 [1.04–1.08], p < 0.01). Fatty acid‐binding protein‐4 (FABP‐4) independently predicted 6‐month poor functional outcomes in stroke patients (adjusted hazard ratio: 1.09 [1.06–1.12], p < 0.01); whereas both FABP‐4 (1.17 [1.03–1.34], p = 0.01) and visfatin (1.24 [1.00–1.55], p = 0.05) were predictive of 6‐month mortality. Adipokines are associated with a greater risk of pre‐existing stroke, but not with the relationship with incident stroke. Adipokines, such as FABP‐4 and visfatin, may serve as biomarkers of stroke severity and worsening of stroke outcomes. [ABSTRACT FROM AUTHOR]

Great strides have been made in the past decade to lower barriers to clinical pharmacogenomics implementation. Nevertheless, PGx consultation prior to prescribing therapeutics is not yet mainstream. This review addresses the current climate surrounding PGx implementation, focusing primarily on strategies for implementation at academic institutions, particularly at The University of Chicago, and provides an up-to-date guide of resources supporting the development of PGx programs. Remaining challenges and recent strategies for overcoming these challenges to implementation are discussed. [ABSTRACT FROM AUTHOR]

A rational design and fabrication approach is proposed for suspended multicore fibers, resulting in the creation of dual‐core and triple‐core suspended fibers with different diameters and one‐side cladding. These fibers are tailored for near‐infrared spectroscopy applications. The multicore‐suspended fibers offer an amplified electromagnetic field effect due to the exposure of the core to the analyte, leading to a significant 16 dB drop in transmittance at the fingerprint absorption line of the analyte. Numerical models indicate that the suspended core with a diameter of 3.52 μ$\umu$m exhibits a superior evanescent field in the boundary between the core and the contact point with the cladding, in comparison to the tested cores with diameters of 3.99 and 12.06 μ$\umu$m. The successful fabrication of these multicore‐suspended fibers represents a promising advancement toward achieving highly sensitive molecular signature detection capabilities. [ABSTRACT FROM AUTHOR]

Applying tessellated origami patterns to the design of mechanical materials can enhance properties such as strength-to-weight ratio and impact absorption ability. Another advantage is the predictability of the deformation mechanics since origami materials typically deform through the folding and unfolding of their creases. This work focuses on creating 4D printed flexible tubular origami based on three different origami patterns: the accordion, the Kresling and the Yoshimura origami patterns, fabricated with a flexible polylactic acid (PLA) filament with heat-activated shape memory effect. The shape memory characteristics of the self-unfolding structures were then harnessed at 60°C, 75°C and 90°C. Due to differences in the folding patterns of each origami design, significant differences in behaviour were observed during shape programming and actuation. Among the three patterns, the accordion proved to be the most effective for actuation as the overall structure can be compressed following the folding crease lines. In comparison, the Kresling pattern exhibited cracking at crease locations during deformation, while the Yoshimura pattern buckled and did not fold as expected at the crease lines. To demonstrate a potential application, an accordion-patterned origami 4D printed tube for use in hand rehabilitation devices was designed and tested as a proof-of-concept prototype incorporating self-unfolding origami. [ABSTRACT FROM AUTHOR]

Advances in additive manufacturing are leading to the emergence of new printable applications, including sensors for healthcare monitoring and bioengineering scaffolds. Research is driven by designing new printable inks including composites that can be extruded and respond to changes in their surroundings and patterning these materials on the microscale. In modern printing techniques, an emerging modified three‐dimensional (3D) printing method: materials extrusion has been utilized for customizable electronics because of its high compatibility with various inks, low cost, and versatility to different levels of complexity. Material extrusion enables not only the printing of 2D and 3D architecture of the electrode structure but also the bioprinting of structures such as conductive scaffolds. In this review, fundamental insights into rational printable ink formulation including colloidal suspensions, gels, polymer melts, composites, printing criteria, processes, and applications toward printable electronics using composites composed of nanomaterials and biopolymers are fully discussed. New manufacturing insights on how to further improve the resolution and simplify the printing process of responsive materials are discussed, which have not been seen in currently published representative reviews. It is envisioned that this review provides high scientific merits to readers working in wearable devices, biological smart materials, and flexible nanoelectronics. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a complex condition, and its clinical course often includes periods of decompensation that represent a deterioration in clinical status. During these periods, patients may experience worsening HF symptoms requiring hospitalization. Heart failure that necessitates hospitalization increases the risk of mortality and rehospitalization. In order to help facilitate appropriate care of patients hospitalized with HF, the American College Cardiology (ACC) published an expert consensus decision pathway (ECDP) that focuses on a multidisciplinary approach. The ECDP is divided into multiple nodes and pharmacists play integral roles in each one. There are many opportunities for pharmacists to optimize medical therapy, reinforce adherence, and provide medication and disease state education throughout hospitalization. This review article will highlight inpatient medication management of HF for hospital pharmacists. [ABSTRACT FROM AUTHOR]

Background: In light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis. Methods: Vangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice. Cell migration was assessed by scratch and organoid invasion assays, Vangl protein subcellular localization was assessed by confocal fluorescence microscopy, and RhoA activation was assessed in real time by fluorescence imaging with an advanced FRET biosensor. The impact of Wnt/PCP suppression on mammary tumor growth and metastasis was assessed by determining the effect of conditional Vangl2 knockout on the MMTV-NDL mouse mammary tumor model. Results: We observed that Vangl2 knockdown suppresses the motility of all breast cancer cell lines examined, and overexpression drives the invasiveness of collectively migrating MMTV-PyMT organoids. Vangl2-dependent RhoA activity is localized in real time to a subpopulation of motile leader cells displaying a hyper-protrusive leading edge, Vangl protein is localized to leader cell protrusions within leader cells, and actin cytoskeletal regulator RhoA is preferentially activated in the leader cells of a migrating collective. Mammary gland-specific knockout of Vangl2 results in a striking decrease in lung metastases in MMTV-NDL mice, but does not impact primary tumor growth characteristics. Conclusions: We conclude that Vangl-dependent Wnt/PCP signaling promotes breast cancer collective cell migration independent of breast tumor subtype and facilitates distant metastasis in a genetically engineered mouse model of breast cancer. Our observations are consistent with a model whereby Vangl proteins localized at the leading edge of leader cells in a migrating collective act through RhoA to mediate the cytoskeletal rearrangements required for pro-migratory protrusion formation. [ABSTRACT FROM AUTHOR]

Use of herbicides in agriculture has raised concerns over environmental degradation and weed resistance development, hence, alternative weed control methods are a demand. Three barley (Hordeum vulgare L.) cultivars were studied under field, pot and petri dish conditions for their suppression ability against Taeniatherum caput-medusae (L.) Nevski (medusahead) and Bromus tectorum L. (cheatgrass). In addition, the smut fungus Ustilago phrygica Magnus was evaluated for its potential use as a biological agent to control these weeds. All barley cultivars (Athinaida, Thessaloniki, Thermi) inhibited completely the growth of both weed species (weeds germinated, emerged, developed, and died one month before barley harvest) grown under field conditions. In contrast, although growth of all barley cultivars was not affected by the presence of T. caput-medusae, their growth was slightly (non-significantly) affected by B. tectorum. Both barley cultivars (Athinaida and Thessaloniki) grown in pots inhibited completely growth of T. caput-medusae, but this was not the case for B. tectorum. As a result of this, growth of the two barley cultivars was reduced by B. tectorum only, whereas the reduction was greater in acidic than in alkaline soil. Regarding cultivar response, the growth of barley cultivar Thessaloniki, grown with B. tectorum under pot conditions, was affected less as compared with that of Athinaida. Seed germination of T. caput-medusae and B. tectorum was completely inhibited by extracts from all barley cultivars, supporting the evidence for allelopathic activity. Artificial inoculations performed by vacuum infiltration with U. phrygica did not show any promising effects of the fungus as a biological agent to control the weeds. [ABSTRACT FROM AUTHOR]

Background: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach. Methods: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log2fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state. Results: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm). Conclusions: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia. [ABSTRACT FROM AUTHOR]

Between 2018 and 2021, several mastic trees (Pistacia lentiscus var. Chia) sampled in the field and the nursery of the Chios Mastiha Growers Association (CMGA) were analyzed to determine the cause of dominant diseases. Symptoms included defoliation, leaf, and twig blight, wilting and/or apoplexy of trees and apoplexy of young hardwood cuttings. Moreover, brown discoloration had also been observed on older woody parts of the trees such as branches and tree trunks. Several pathogens have been isolated and identified as the causing agents. Neopestalotiopsis and Alternaria species were isolated consistently from necrotic tissues of mastic trees (branches, twigs, and leaves) in the field and the nursery. All fungal isolates' pathogenicity was confirmed by applying Koch's postulates on young mastic trees under glasshouse conditions. Fungal pathogens were identified by sequence analyses of the ITS, β-tubulin, and histone gene regions. Alternaria species were analyzed further by sequencing the endopolygalacturonase (endoPG) and the Alternaria major allergen (Alta1) genes. More specifically, the isolates were identified as Neopestalotiopsis clavispora, Alternaria arborescens, and A. alternata based on morphological features and sequence analyses. This is the first report of N. clavispora, A. arborescens, and A. alternata on P. lentiscus var. Chia. [ABSTRACT FROM AUTHOR]

Simple Summary: Both IAP and WEE1 inhibitors have demonstrated therapeutic efficacy in in vitro pre-clinical models of head and neck squamous cell carcinoma (HNSCC). Here, we demonstrate that dual treatment with IAP and WEE1 inhibitors sensitizes both HPV-negative and HPV-positive HNSCC cells to both TNFα-dependent and radiation-associated cell death, demonstrating a potential therapeutic combination to treat these cancers. Head and neck squamous cell carcinoma (HNSCC) remains a prevalent diagnosis with current treatment options that include radiotherapy and immune-mediated therapies, in which tumor necrosis factor-α (TNFα) is a key mediator of cytotoxicity. However, HNSCC and other cancers often display TNFα resistance due to activation of the canonical IKK–NFκB/RELA pathway, which is activated by, and induces expression of, cellular inhibitors of apoptosis proteins (cIAPs). Our previous studies have demonstrated that the IAP inhibitor birinapant sensitized HNSCC to TNFα-dependent cell death in vitro and radiotherapy in vivo. Furthermore, we recently demonstrated that the inhibition of the G2/M checkpoint kinase WEE1 also sensitized HNSCC cells to TNFα-dependent cell death, due to the inhibition of the pro-survival IKK-NFκB/RELA complex. Given these observations, we hypothesized that dual-antagonist therapy targeting both IAP and WEE1 proteins may have the potential to synergistically sensitize HNSCC to TNFα-dependent cell death. Using the IAP inhibitor birinapant and the WEE1 inhibitor AZD1775, we show that combination treatment reduced cell viability, proliferation and survival when compared with individual treatment. Furthermore, combination treatment enhanced the sensitivity of HNSCC cells to TNFα-induced cytotoxicity via the induction of apoptosis and DNA damage. Additionally, birinapant and AZD1775 combination treatment decreased cell proliferation and survival in combination with radiotherapy, a critical source of TNFα. These results support further investigation of IAP and WEE1 inhibitor combinations in preclinical and clinical studies in HNSCC. [ABSTRACT FROM AUTHOR]

In recent years, pro‐oncogenic mechanisms of the tumour microenvironment (ТМЕ) have been actively discussed. One of the main cytokines of the TМЕ is interleukin‐1 beta (IL‐1β), which exhibits proinflammatory properties. Some studies have shown an association between an increase in IL‐1β levels and tumour progression. The purpose of this review is to analyse the pathogenic mechanisms induced by IL‐1β in the TМЕ, as well as the diagnostic significance of the presence of IL‐1β in patients with cancer and the efficacy of treatment with IL‐1β inhibitors. According to the literature, IL‐1β can induce an increase in tumour angiogenesis due to its effects on the differentiation of epithelial cells, pro‐angiogenic molecule secretion and expression of adhesion molecules, thus increasing tumour growth and metastasis. IL‐1β is also involved in the suppression of anti‐tumour immune responses. The expression and secretion of IL‐1β has been noted in various types of tumours. In some clinical studies, an elevated level of IL‐1β was found to be associated with low efficacy of anti‐cancer therapy and a poor prognosis. In most experimental and clinical studies, the use of IL‐1β inhibitors contributed to a decrease in tumour mass and an increase in the response to anti‐tumour drugs. [ABSTRACT FROM AUTHOR]

Non-lethal doses of ionizing radiation (IR) delivered to humans because of terrorist events, nuclear accidents or radiotherapy can result in carcinogenesis. Means of protecting against carcinogenesis are lacking. We questioned the role of the gut microbiome in IR-induced carcinogenesis. The gut microbiome was modulated by administering broad spectrum antibiotics (Ab) in the drinking water. Mice were given Ab 3 weeks before and 3 weeks after 3 Gy total body irradiation (TBI) or for 6 weeks one month after TBI. Three weeks of Ab treatment resulted in a 98% reduction in total 16S rRNA counts for 4 out of 6 of the phylum groups detected. However, 3 more weeks of Ab treatment (6 weeks total) saw an expansion in the phylum groups Proteobacteria and Actinobacteria. The Ab treatment altered the bacteria diversity in the gut, and shortened the lifespan when Ab were administered before and after TBI. Mortality studies indicated that the adverse Ab lifespan effects were due to a decrease in the time in which solid tumors started to appear and not to any changes in hematopoietic or benign tumors. In contrast, when Ab were administered one month after TBI, lifespan was unchanged compared to the control TBI group. Use of broad-spectrum antibiotics to simulate the germ-free condition did not afford an advantage on carcinogenesis or lifespan. [ABSTRACT FROM AUTHOR]

Background: Loss of control eating (LOC-E) in youth predicts the later development of full-syndrome binge-eating disorder (BED), and therefore, could be a relevant target for prevention treatments. To develop these treatments, it is important to understand the underlying disease processes and mechanisms. Based on the putative role of neurocognitive impairments in the pathogenesis of LOC-E, treatments that modulate these neurocognitive factors warrant further exploration. For instance, stimulants are an effective treatment for impulsivity in youth with attention deficit/hyperactivity disorder (ADHD) and have been shown to improve symptoms of BED in adults. Notably, stimulants have not been examined as a treatment for LOC-E in youth. To explore this gap, we aim to measure change in LOC-E episodes and secondary outcomes in youth with comorbid ADHD and LOC-E who are being started on stimulants. Methods: We will collect prospective observational data on forty 8-to-13-year-old youth diagnosed with comorbid ADHD and LOC-E who are initiating a stimulant for ADHD. Prior to stimulant initiation, participants will complete baseline measures including LOC-E episode frequency in the last 3 months (primary outcome), and secondary outcomes including disordered eating cognitions, emotions and behaviors, ADHD symptom severity, parental LOC-E, impulsivity and reward sensitivity, and anxiety/mood severity. Outcome measurements will be gathered again at 3-months after initiating the stimulant. Within-patient standardized effect sizes with 95% confidence intervals will be calculated from baseline to 3-month follow-up for all outcomes. Discussion: Many individuals with LOC-E or binge eating do not fully remit over the course of psychotherapy. Whereas psychotherapy may address psychological and sociocultural domains associated with LOC-E, some individuals with neurocognitive impairments (e.g., ADHD) and neurobiological deficits (e.g., low intrasynaptic dopamine or norepinephrine) may benefit from adjunctive treatment that targets those factors. This will be the first study to provide pilot data for future studies that could examine both the effect of stimulants on LOC-E in youth and underlying mechanisms. Trial registration: Trial registration number: NCT05592119 [ABSTRACT FROM AUTHOR]

A small family composed of BRI1 KINASE INHIBITOR1 (BKI1) and MEMBRANE‐ASSOCIATED KINASE REGULATORS (MAKRs) has recently captured the attention of plant biologists, due to their involvement in developmental processes downstream of hormones and Receptor‐Like Kinases (RLK) signalling. BKI1/MAKRs are intrinsically disordered proteins (so‐called unstructured proteins) and as such lack specific domains. Instead, they are defined by the presence of two conserved linear motifs involved in the interaction with lipids and proteins, respectively. Here, we first relate the discovery of the MAKR gene family. Then, we review the individual function of characterized family members and discuss their shared and specific modes of action. Finally, we explore and summarize the structural, comparative and functional genomics data available on this gene family. Together, this review aims at building a comprehensive reference about BKI1/MAKR protein function in plants. [ABSTRACT FROM AUTHOR]

The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from—but related to—those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics. The regulation of plasma glucose levels is effected by insulin. Here, the authors reveal atomic detail of how peptides distinct from insulin bind to and activate the insulin receptor, with implications for design of small-molecule insulin mimetics. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop three supervised self-organizing map (SOM) models for the automatic recognition of a systemic resistance state in plants after application of a resistance inducer. The pathosystem Fusarium oxysporum f. sp. radicis-lycopersici (FORL) + tomato was used. The inorganic, defense inducer, Acibenzolar-S-methyl (benzo-[1,2,3]-thiadiazole-7-carbothioic acid-S-methyl ester, ASM), reported to induce expression of defense genes in tomato, was applied to activate the defense mechanisms in the plant. A handheld fluorometer, FluorPen FP 100-MAX-LM by SCI, was used to assess the fluorescence kinetics response of the induced resistance in tomato plants. To achieve recognition of resistance induction, three models of supervised SOMs, namely SKN, XY-F, and CPANN, were used to classify fluorescence kinetics data, in order to determine the induced resistance condition in tomato plants. To achieve this, a parameterization of fluorescence kinetics curves was developed corresponding to fluorometer variables of the Kautsky Curves. SKN was the best supervised SOM, achieving 97.22% to 100% accuracy. Gene expression data were used to confirm the accuracy of the supervised SOMs. [ABSTRACT FROM AUTHOR]

With growing environmental concerns over synthetic polymers, natural polymeric materials, such as hemicellulose, are considered a good sustainable alternative. Curaua fibers could be an excellent source of biopolymer as they have a relatively high hemicellulose content (15 wt%) and only a small amount of lignin (7 wt%). In this work, hemicellulose was extracted by an alkaline medium using KOH and the influence of the alkali concentration, temperature, and time was studied. A hemicellulose film was produced by water casting and its mechanical, thermal, and morphological properties were characterized. The results show that the best method, which resulted in the highest hemicellulose yield and lowest contamination from lignin, was using 10% (w/v) KOH concentration, 25 °C, and time of 3 h. The hemicellulose film exhibited better thermal stability and elongation at break than other polymeric films. It also exhibited lower rigidity and higher flexibility than other biodegradable polymers, including polylactic acid (PLA) and polyhydroxybutyrate (PHB). [ABSTRACT FROM AUTHOR]

People with cloacal malformation and 46,XX cloacal exstrophy are at risk of developing Müllerian outflow tract obstruction (OTO). Management of OTO requires expertise of many medical and surgical specialties. The primary presenting symptom associated with OTO is cyclical and later continuous pain and can be initially quelled with hormonal suppression as a temporizing measure to allow for patient maturation. The decision for timing and method of definitive treatment to establish a patent outflow tract that can also be used for penetrative sexual activity and potential fertility is a complicated one and incredibly variable based on patient age alone. To understand the management approach to OTO, we put forth five phases with associated recommendations: (1) caregiver and patient education and evaluation before obstruction; (2) presentation, diagnosis, and symptom temporization; (3) readiness assessment; (4) peri-procedural management; (5) long-term surveillance. This review will emphasize the importance of interdisciplinary team management of the complex shared medical, surgical, and psychological decision making required to successfully guide developing patients with outflow obstruction secondary to cloacal malformations and cloacal exstrophy through adolescence. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is the oldest human infection disease. Mortality from TB significantly decreased in the 20th century, because of vaccination and the widespread use of antibiotics. However, about a third of the world's population is currently infected with Mycobacterium tuberculosis (Mtb) and the death rate from TB is about 1.4–2 million people per year. In the second half of the 20th century, new extensively multidrug-resistant strains of Mtb were identified, which are steadily increasing among TB patients. Therefore, there is an urgent need to develop new anti-TB drugs, which remains one of the priorities of pharmacology and medicinal chemistry. The antimycobacterial activity of nucleoside derivatives and analogues was revealed not so long ago, and a lot of studies on their antibacterial properties have been published. Despite the fact that there are no clinically used drugs based on nucleoside analogues, some progress has been made in this area. This review summarizes current research in the field of the design and study of inhibitors of mycobacteria, primarily Mtb. [ABSTRACT FROM AUTHOR]

Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2′-deoxy-5-iodocytidine and 5-bromovinyl-2′-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of the biological activity of new nucleoside analogues, namely, 5′-norcarbocyclic derivatives of substituted 5-arylamino- and 5-aryloxyuracils, against RNA viruses. [ABSTRACT FROM AUTHOR]

Fire‐protective clothing are manufactured using heat and flame resistant fibers that are made of high‐performance polymers. These polymers exhibit a gradual reduction in their performance after long‐term exposure under various aging conditions. This study investigates the thermal aging behavior of a high‐temperature resistance polymer, polyetherimide (PEI), at elevated temperatures in air. Changes in the ultimate tensile strength (UTS), glass transition temperature, and surface properties are observed. In addition, infrared spectroscopy identifies chemical bonds in PEI being consumed because of chain scission. Applying the time–temperature superposition principle to the UTS data gives an activation energy of 112 kJ mol−1 for the effect of thermal aging on the mechanical strength of PEI. This value is similar to what has been reported for fire‐protective clothing fabrics, which opens the possibility to use PEI as a sensing material for the development of end‐of‐life sensors for fire‐protective fabrics. [ABSTRACT FROM AUTHOR]

When infants are identified with a difference of sex development (DSD), a thoughtful approach to imaging is essential to appropriate clinical management. This review provides a comprehensive guide for radiologists who are tasked with performing this critical assignment. We review the embryologic basis of DSDs, with attention to the imaging findings that can indicate specific diagnoses. We also discuss techniques for optimal imaging, including strategies for identifying the gonads by US, tactics for performing genitograms with fluoroscopy and contrast-enhanced US, and the appropriate utilization of MRI. Finally, we review the clinical data and imaging findings that characterize some of the most common DSDs, including congenital adrenal hyperplasia, complete androgen insensitivity syndrome and gonadal dysgenesis. [ABSTRACT FROM AUTHOR]

Background: Specific phobias represent the largest category of anxiety disorders. Previous work demonstrated that stimulating the ventromedial prefrontal cortex (vmPFC) with repetitive Transcranial Magnetic Stimulation (rTMS) may improve response to exposure therapy for acrophobia. Objective: To examine feasibility of accelerating extinction learning in subjects with spider phobia using intermittent Theta Burst Stimulation (iTBS) rTMS of vmPFC. Methods: In total, 17 subjects with spider phobia determined by spider phobia questionnaires [Spider Phobia Questionnaire (SPQ) and Fear of Spiders questionnaire (FSQ)] underwent ratings of fear of spiders as well as behavioral and skin conductance data during a behavioral avoidance test (BAT). Subjects then received a sequential protocol of in vivo spider exposure followed by iTBS for three sessions administered to either active or control treatment sites (vmPFC [n = 8] or vertex [n = 9], respectively), followed 1 week later by repetition of questionnaires and BAT. All subjects improved significantly regardless of group across both questionnaires (FSQ η 2 = 0.43, p = 0.004; SPQ η 2 = 0.39, p = 0.008) and skin conductance levels during BAT (Wald χ 2 = 30.9, p < 0.001). Subjects in the vmPFC group tolerated lower treatment intensity than in the control group, and there was a significant correlation between treatment intensity, BAT subjective distress improvement, and physiologic measures (all ρ > 0.5). Conclusion: This proof-of-concept study provides preliminary evidence that a sequential exposure and iTBS over vmPFC is feasible and may have rTMS intensitydependent effects on treatment outcomes, providing evidence for future areas of study in the use of rTMS for phobias. [ABSTRACT FROM AUTHOR]

The pathogenesis of arrhythmias is complex and multifactorial. The role of inflammation in the pathogenesis of both atrial and ventricular arrhythmias (VA) has been explored. However, developing successful pharmacotherapy regimens based on those pathways has proven more of a challenge. This narrative review provides an overview of five common arrhythmias impacted by inflammation, including atrial fibrillation (AF), myocardial infarction, arrhythmogenic cardiomyopathy, cardiac sarcoidosis, and QT prolongation, and the potential role for anti‐inflammatory therapy in their management. We identified arrhythmias and arrhythmogenic disease states with the most evidence linking pathogenesis to inflammation and conducted comprehensive searches of United States National Library of Medicine MEDLINE® and PubMed databases. Although a variety of agents have been studied for the management of AF, primarily in an effort to reduce postoperative AF following cardiac surgery, no standard anti‐inflammatory agents are used in clinical practice at this time. Although inflammation following myocardial infarction may contribute to the development of VA, there is no clear benefit with the use of anti‐inflammatory agents at this time. Similarly, although inflammation is clearly linked to the development of arrhythmias in arrhythmogenic cardiomyopathy, data demonstrating a benefit with anti‐inflammatory agents are limited. Cardiac sarcoidosis, an infiltrative disease eliciting an immune response, is primarily treated by immunosuppressive therapy and steroids, despite a lack of primary literature to support such regimens. In this case, anti‐inflammatory agents are frequently used in clinical practice. The pathophysiology of arrhythmias is complex, and inflammation likely plays a role in both onset and duration, however, for most arrhythmias the role of pharmacotherapy targeting inflammation remains unclear. [ABSTRACT FROM AUTHOR]

This study demonstrates that the impact energy absorption capabilities of flexible sheets can be significantly enhanced by implementing tessellated designs into their structure. Configurations of three tessellated geometries were tested; they included a triangular-based, a rectangular-based, and a novel square-based pattern. Due to their geometrical complexity, multiple configurations of these tessellations were printed from a rubber-like material using an inkjet printer with two different thicknesses (2 and 4 mm), and their ability to absorb impact energy was compared to an unpatterned inkjet-printed sheet. In addition, the effect of multi-sheets stacking was also tested. Due to the tailored structure, the impact testing showed that the single-layer sheets were more effective at absorbing impact loads, and experience less deformation, than their two-layer counterparts. The 4 mm thick tessellated patterns were most effective at absorbing impact loads; all three thick patterns measured about 40% lower impact forces transferred to the base of the samples compared to the unpatterned counterparts. [ABSTRACT FROM AUTHOR]

Nitrogen-functionalization is an effective means of improving the catalytic performances of nanozymes. In the present work, plasma-assisted nitrogen modification of nanocolumnar Ni GLAD films was performed using an ammonia plasma, resulting in an improvement in the peroxidase-like catalytic performance of the porous, nanostructured Ni films. The plasma-treated nanozymes were characterized by TEM, SEM, XRD, and XPS, revealing a nitrogen-rich surface composition. Increased surface wettability was observed after ammonia plasma treatment, and the resulting nitrogen-functionalized Ni GLAD films presented dramatically enhanced peroxidase-like catalytic activity. The optimal time for plasma treatment was determined to be 120 s; when used to catalyze the oxidation of the colorimetric substrate TMB in the presence of H2O2, Ni films subjected to 120 s of plasma treatment yielded a much higher maximum reaction velocity (3.7⊆10−8 M/s vs. 2.3⊆10−8 M/s) and lower Michaelis-Menten coefficient (0.17 mM vs. 0.23 mM) than pristine Ni films with the same morphology. Additionally, we demonstrate the application of the nanozyme in a gravity-driven, continuous catalytic reaction device. Such a controllable plasma treatment strategy may open a new door toward surface-functionalized nanozymes with improved catalytic performance and potential applications in flow-driven point-of-care devices. [ABSTRACT FROM AUTHOR]

Photomediated Giese reactions are at the forefront of radical chemistry, much like the classical tin‐mediated Giese reactions were nearly forty years ago. With the global recognition of organometallic photocatalysts for the mild and tunable generation of carbon‐centered radicals, chemists have developed a torrent of strategies to form previously inaccessible radical intermediates that are capable of engaging in intermolecular conjugate addition reactions. This Review summarizes advances in photoredox‐mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon‐centered radical intermediates that can engage in radical conjugate addition processes. [ABSTRACT FROM AUTHOR]

Photomediated Giese reactions are at the forefront of radical chemistry, much like the classical tin‐mediated Giese reactions were nearly forty years ago. With the global recognition of organometallic photocatalysts for the mild and tunable generation of carbon‐centered radicals, chemists have developed a torrent of strategies to form previously inaccessible radical intermediates that are capable of engaging in intermolecular conjugate addition reactions. This Review summarizes advances in photoredox‐mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon‐centered radical intermediates that can engage in radical conjugate addition processes. [ABSTRACT FROM AUTHOR]

The article explores COVID-19 related Internet memes and treats them as samples of creolized text in a study of the way ethnic and cultural peculiarities of memes are perceived by representatives of two radically different cultural paradigms: the Russians and Chinese. A survey is used as a method of the investigation. Russian and Chinese students, and visual arts experts evaluated Russian and Chinese COVID-19 memes according to several criteria concerning their content, verbal constituent element and visual characteristics. The study concluded that the social and culture-specific components mostly contribute to forming the opinion of the meme and its appreciation. Awareness of both the cultural background and the current social and nation-specific situation is required to decode a full amount of information contained in a meme. Equally important is the visual component in understanding the meme. Thus, the study contributes not only to studying event-specific memes but also broadens the scope of research on memes as a sample of visual culture. [ABSTRACT FROM AUTHOR]

Background: Spironolactone reduces morbidity and mortality in patients with heart failure (HF) with reduced ejection fraction (EF) and decreases hospitalizations in HF with preserved EF. To minimize the risk of hyperkalemia, patients must have an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 and potassium < 5.0 mEq/L prior to initiation; however, spironolactone is prescribed outside these parameters. The objective of this study was to evaluate the safety and tolerability of spironolactone in patients with HF and chronic kidney disease (CKD). Methods: This single-center, retrospective cohort study evaluated patients ≥ 18 years with HF and CKD stages 3–5 who received ≥ 48 h of spironolactone therapy and were hospitalized from February 2018 to August 2019. The primary outcome was incidence of hyperkalemia (potassium ≥ 5.5 mEq/L). Results: Overall, 121 patients were evaluated: 52.1% (n = 63) had an EF > 40% and 47.9% (n = 58) had an EF ≤ 40% with 69.4% (n = 84) CKD stage 3, 24.8% (n = 30) stage 4, and 5.8% (n = 7) stage 5. Spironolactone was initiated prior to admission (PTA) for 54.5% (n = 66) of patients, while 45.5% (n = 55) of orders were initiated during hospitalization. Eight patients (6.6%) experienced inpatient hyperkalemia—all with PTA spironolactone. Patients who experienced inpatient hyperkalemia had a numerically lower eGFR that was not statistically significant (35.40 vs. 38.22 mL/min/1.73 m2; p = 0.730). Patients with CKD stage 3 (n = 4) had numerically higher rates of inpatient hyperkalemia than stages 4 (n = 1) or 5 (n = 3) (50%, 12.5%, and 37.5% respectively; p < 0.05). Conclusion: Spironolactone may be safe to initiate in hospitalized patients with HF and CKD; however, appropriateness of therapy must be assessed upon admission to the hospital. Larger studies are needed for conclusive results. [ABSTRACT FROM AUTHOR]

In 2018, decline and necrosis were observed on olive tree cuttings (Olea europaea) in a nursery in northern Greece. The pathogen was identified as Alternaria alternata on the basis of conidia morphology and sequence analysis of the internal transcribed region (ITS) and part of the elongation factor 1a (EF-1a). The endopolygalacturonase (endoPG) and the Alternaria major allergen (Alta1) genes were also amplified. A pathogenicity test was performed and Koch's postulates were confirmed by re-isolation of the fungus A. alternata from artificially inoculated cuttings. This is the first report of A. alternata as the cause of decline and necrosis on olive tree cuttings in Greece. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend antithrombotic therapy in patients with nonvalvular atrial fibrillation (NVAF) to reduce the risk of stroke and systemic embolism (SSE) based on an assessment utilizing the CHA2DS2-VASc score. However, a treatment gap exists regarding patients at risk for thromboembolic events. Objectives: The aim of this study was to characterize the use of guideline-directed medical therapy (GDMT) to reduce the risk of SSE in patients with NVAF upon hospital discharge. Methods: This retrospective review evaluated patients admitted to a community hospital with NVAF in 2016. All patients were included except for the following: < 18 years of age, concomitant valvular heart disease, expired during hospitalization, or discharged on hospice care. Descriptive statistics were reported for all parameters. Results: A total of 2739 patients with NVAF were included with 59.9% discharged on GDMT to reduce the risk of SSE. A 1% increase in GDMT at discharge was observed in patients admitted with a history of NVAF (n = 2238; 60.1% vs 61.1%). Patients with first-detected NVAF (n = 501) were discharged on GDMT 54.5% of the time. In patients with a high stroke risk, concomitant heart failure (P =.001) and a lower HAS-BLED score (mean = 2.85 vs 3.18; P <.0001) were associated with receiving GDMT upon discharge. However, patients with increased age (mean = 78.5 vs 76.4; P <.0001), vascular disease (P =.02), prior major bleeding (P <.0001), or first-detected NVAF (P <.0001) were less likely to be discharged on GDMT. Conclusions: Consistent with published registry data, a gap was observed in the use of GDMT to reduce the risk of SSE in patients with NVAF at this institution. Further investigation into methods for improvement is warranted. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend direct-acting oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF) and valvular heart disease (VHD) without a mechanical valve or moderate to severe mitral stenosis. However, real-world data to support the safety and efficacy of DOACs in this patient population are lacking. Objective: Our objective was to assess the safety and effectiveness of DOACs in patients with AF and VHD. Methods: This retrospective chart review evaluated patients aged ≥ 18 years with a diagnosis of AF and at least moderate VHD on echocardiogram. Patients were included if they received ≥ 1 month of DOAC therapy from December 2016 to December 2018. Patients were excluded if they received dual antiplatelet therapy or had additional indications for anticoagulation. The primary outcomes were incidence of stroke or systemic embolism (SSE) and major bleeding. Results: In total, 200 patients were included (disease type: aortic, n = 50; mitral, n = 50; tricuspid, n = 50; multivalve, n = 50). Most patients received apixaban (n = 133 [66.5%]) followed by rivaroxaban (n = 50 [25%]) and dabigatran (n = 17 [8.5%]). No patients received edoxaban. The mean CHA2DS2-VASc score was 4.25 and was similar among DOAC cohorts (p = 0.380). The overall SSE rate was 3.5% and was highest for dabigatran (n = 3 [17.6%]) compared with the other DOACs (apixaban, n = 1 [0.8%]; rivaroxaban, n = 3 [6%]; p = 0.001). Rates were similar among different valve types (aortic, n = 3 [6%]; mitral, n = 1 [2%]; tricuspid, n = 2 [4%]; multivalve, n = 1 [2%]; p = 0.653). The overall rate of major bleeding was 5.5% and did not differ among the DOACs (apixaban, n = 5 [3.8%]; rivaroxaban, n = 4 [8%]; dabigatran, n = 2 [11.8%]; p = 0.264) or valve type (aortic, n = 3 [6%]; mitral, n = 2 [4%]; tricuspid, n = 2 [4%]; multivalve, n = 4 [8%]; p = 0.787). Conclusions: In patients with AF and VHD, rates of major bleeding were similar among the DOACs and valve types; however, more patients receiving dabigatran experienced SSE. Further studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward—that is, at 'The Forefront of Genomics'. In this Perspective, authors from the National Human Genome Research Institute (NHGRI) present a vision for human genomics research for the coming decade. [ABSTRACT FROM AUTHOR]

Pseudomonas chlororaphis ToZa7 is a promising biocontrol agent possessing valuable characteristics and reducing disease severity caused by Fusarium oxysporum f. sp. radicis-lycopersici (Forl) in tomato. In this study, the strain's ability to induce three pathogenesis-related (PR) genes (PR-1a, GLUA, and CHI3) in tomato, was studied using quantitative reverse transcription PCR. The genes PR-1a and GLUA were up-regulated after 120 h exposure to P. chororaphis ToZa7 (15.22- and 13.11-fold, respectively), as compared to the untreated control, without challenge inoculation by the pathogen. To study the effects of individual or combined application of P. chororaphis ToZa7 and the compatible biocontrol fungus Clonostachys rosea IK726, challenged with the pathogen, the expression patterns of the above three PR genes were monitored, in tomato roots. Expression of PR1-a was noteworthy, especially 48 h after challenge inoculation, when C. rosea IK726 alone or in combination with P. chororaphis, ToZa7 was pre-inoculated on tomato roots (38.53-fold and 53.74-fold, respectively). Expression of PR1-a, 72 h after challenge inoculation, was the highest in P. chororaphis ToZa7, among biocontrol treatments. Expression of CHI3 was much lower, while up-regulation of GLUA was overall not observed. Confocal laser scanning microscopy of intact tomato roots and bacterial counts of superficially disinfected roots revealed, for the first time, that P. chororaphis ToZa7 colonizes the exterior as well as the internal tissues. [ABSTRACT FROM AUTHOR]