DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity.

Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology. The core advance is optimized cellular specificity-up to 3,000-fold in 15 min-enabling the targeted delivery of even epileptogenic drugs without off-target effects. Additionally, we introduce brain-wide dosing methods as an alternative to local cannulation and tracer reagents for brain-wide dose quantification. We describe four pharmaceuticals-two that antagonize excitatory and inhibitory postsynaptic receptors, and two that allosterically potentiate these receptors. Their versatility is showcased across multiple mouse-brain regions, including cerebellum, striatum, visual cortex and retina. Finally, in the ventral tegmental area, we find that blocking inhibitory inputs to dopamine neurons accelerates locomotion, contrasting with previous optogenetic and pharmacological findings. Beyond enabling the bidirectional perturbation of chemical synapses, these reagents offer intersectional precision-between genetically defined postsynaptic cells and neurotransmitter-defined presynaptic partners.

Harnessing Immunomodulatory Polymers for Treatment of Autoimmunity, Allergy, and Transplant Rejection.

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection.

Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Sexual Identity Disclosure and Alcohol Experiences Among LGBTQ+ Adolescents.

Sexual and gender minority youth (SGMY) report greater alcohol use in comparison to their heterosexual counterparts. Prior research has found that elevated alcohol use among SGMY can be explained by minority stress experiences. Sexual identity outness may be another factor that drives alcohol use among SGMY, given that outness is associated with alcohol use among older sexual and gender minority samples. We examined how patterns of sexual identity outness were associated with lifetime alcohol use, past-30-day alcohol use, and past-30-day heavy episodic drinking. Data were drawn from the LGBTQ National Teen Survey (N = 8884). Participants were SGMY aged 13 to 17 (mean age = 15.59) years living in the US. Latent class analysis was used to identify sexual identity outness patterns. Multinomial regressions were used to examine the probability of class membership by alcohol use. Six outness classes were identified: out to all but teachers (n = 1033), out to siblings and peers (n = 1808), out to siblings and LGBTQ+ peers (n = 1707), out to LGBTQ+ peers (n = 1376), mostly not out (n = 1653), and very much not out (n = 1307). SGMY in classes characterized by greater outness to peers, friends, and family had greater odds of lifetime alcohol use compared with SGMY in classes characterized by lower outness. These findings suggest that SGMY with greater sexual identity outness may be a target for alcohol use prevention programming. Differences in sexual identity outness may be explained by minority stress factors.

Amide- and bis-amide-linked highly potent and broadly active antifungal agents for the treatment of invasive fungal infections- towards the discovery of pre-clinical development candidate FC12406.

Most fungal infections are common, localized to skin or mucosal surfaces and can be treated effectively with topical antifungal agents. However, while invasive fungal infections (IFIs) are uncommon, they are very difficult to control medically, and are associated with high mortality rates. We have previously described highly potent bis-guanidine-containing heteroaryl-linked antifungal agents, and were interested in expanding the range of agents to novel series so as to reduce the degree of aromaticity (with a view to making the compounds more drug-like), and provide broadly active high potency derivatives. We have investigated the replacement of the central aryl ring from our original series by both amide and a bis-amide moieties, and have found particular structure-activity relationships (SAR) for both series', resulting in highly active antifungal agents against both mold and yeast pathogens. In particular, we describe the in vitro antifungal activity, absorption, distribution, metabolism and elimination (ADME) properties, and off-target properties of FC12406 (34), which was selected as a pre-clinical development candidate.

The effect of a reduction in irrational beliefs on Posttraumatic Stress Disorder (PTSD), depression, and anxiety symptoms in a group treatment for post-9/11 Veterans.

Previous research has indicated that a Rational Emotive Behavior Therapy (REBT)-Informed Group focused on changing irrational beliefs to address comorbid depression and anxiety (as well as anger and guilt) in a combat Veteran population diagnosed with Posttraumatic Stress Disorder (PTSD) demonstrated significant reductions in depression and PTSD symptoms at posttreatment. However, mechanisms of change associated with improvement have not been evaluated. REBT theory suggests that a decline in irrational beliefs predicts a decrease in PTSD, depression, and anxiety symptoms. This study aimed to test this tenet of REBT theory in a naturalistic treatment setting. Participants (N = 86) were post-9/11 combat Veterans, engaged in the REBT-Informed Group between October 2016 and February 2020. Results of hierarchical multiple regression analyses indicated that a reduction in irrational beliefs predicted notable decreases in PTSD, depression, and anxiety symptoms controlling for several covariates. This study extends previous research demonstrating the success of the REBT-Informed Group with combat Veterans and gives support to REBT theory regarding the effect of a decline in irrational beliefs. Future directions include replication of findings with Veterans who experienced military sexual trauma (MST), pre-9/11 Veterans, those at other military or Veterans Affairs (VA) medical centers, and civilians to determine generalizability.

Microsecretory Adenocarcinoma of the Ear Canal: Novel Cutaneous Analog of a Salivary Gland Neoplasm.

ABSTRACT: Microsecretory adenocarcinoma (MSA) of the salivary gland is a new entity recently added to the World Health Organization Classification of Head and Neck Tumors. This tumor is characterized by a recurrent MEF2C-SS18 translocation. We present a nodular tumor confined to the dermis of the ear canal of a 44-year-old patient, which demonstrated classic histopathologic features and molecular alteration of MSA. Specifically, the tumor was composed of numerous tubules and microcysts filled with abundant basophilic mucinous secretion and associated with a fibromyxoid stroma. The tumor cells were diffusely positive for CK7 and SOX10 and variably positive for S100 and p63. Breakapart fluorescence in situ hybridization for SS18 confirmed rearrangement of this gene. Together, these findings support a primary cutaneous MSA, presumably arising from ceruminous glands of the ear canal. Based on current knowledge of its salivary gland counterpart, cutaneous MSA is expected to be locally invasive but unlikely to recur or metastasize on complete excision.

Complex Outness Patterns Among Sexual Minority Youth: A Latent Class Analysis.

Prior scholarship has documented health-relevant consequences of sexual minority youth (SMY) sexual identity disclosure (i.e., "outness"), yet most of the extant work focuses on one social context at a time and/or measures outness as dichotomous: out or not out. However, SMY are out in some contexts (e.g., family, friends) and not in others, and to varying degrees (e.g., to some friends, but not to all). Using a national sample of 8884 SMY ages 13-17 (45% cisgender female, 67% White, 38% gay/lesbian and 34% bisexual, and 36% from the U.S. South), this study used latent class analysis to identify complex patterns of outness among SMY, as well differences in class membership by demographics, depression, family rejection, and bullying. The results indicated six distinct classes: out to all but teachers (n = 1033), out to siblings and peers (n = 1808), out to siblings and LGBTQ peers (n = 1707), out to LGBTQ peers (n = 1376), mostly not out (n = 1653), and very much not out (n = 1307). The findings reveal significant differences in class membership by age, sexual identity, gender identity, race and ethnicity, geography, and well-being outcomes. Moreover, these findings underscore the complex role of outness across social contexts in shaping health and well-being.

Compound FC-10696 Inhibits Egress of Marburg Virus.

Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW domain-containing proteins via its conserved PPxY late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small-molecule compounds targeting the viral PPxY/host WW domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure-activity relationship (SAR) of a previously described series of PPxY inhibitors. We show that FC-10696 inhibits egress of mVP40 virus-like particles (VLPs) and egress of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated-mice displayed delayed onset of weight loss and clinical signs and significantly lower viral loads compared to controls, with 14% of animals surviving 21 days following a lethal MARV challenge. Thus, FC-10696 represents a first-in-class, host-oriented inhibitor effectively targeting late stages of the MARV life cycle.

Maternal care boosted by paternal imprinting in mammals.

In mammals, mothers are the primary caregiver, programmed, in part, by hormones produced during pregnancy. High-quality maternal care is essential for the survival and lifelong health of offspring. We previously showed that the paternally silenced imprinted gene pleckstrin homology-like domain family A member 2 (Phlda2) functions to negatively regulate a single lineage in the mouse placenta called the spongiotrophoblast, a major source of hormones in pregnancy. Consequently, the offspring's Phlda2 gene dosage may influence the quality of care provided by the mother. Here, we show that wild-type (WT) female mice exposed to offspring with three different doses of the maternally expressed Phlda2 gene-two active alleles, one active allele (the extant state), and loss of function-show changes in the maternal hypothalamus and hippocampus during pregnancy, regions important for maternal-care behaviour. After birth, WT dams exposed in utero to offspring with the highest Phlda2 dose exhibit decreased nursing and grooming of pups and increased focus on nest building. Conversely, 'paternalised' dams, exposed to the lowest Phlda2 dose, showed increased nurturing of their pups, increased self-directed behaviour, and a decreased focus on nest building, behaviour that was robustly maintained in the absence of genetically modified pups. This work raises the intriguing possibility that imprinting of Phlda2 contributed to increased maternal care during the evolution of mammals.

Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase.

Here we report the first small-molecule inhibitors of human sulfide:quinone oxidoreductase (SQOR) that decrease the rate of breakdown of hydrogen sulfide (H2S), a potent cardioprotective signaling molecule. SQOR is a mitochondrial membrane-bound protein that catalyzes a two-electron oxidation of H2S to sulfane sulfur (S0), using glutathione (or sulfite) and coenzyme Q (CoQ) as S0 and electron acceptor, respectively. Inhibition of SQOR may constitute a new approach for the treatment of heart failure with reduced ejection fraction. Starting from top hits identified in a high-throughput screen, we conducted SAR development guided by docking of lead candidates into our crystal structure of SQOR. We identified potent SQOR inhibitors such as 19 which has an IC50 of 29 nM for SQOR inhibition and favorable pharmacokinetic and ADME properties required for in vivo efficacy testing.

Highly potent, broadly active antifungal agents for the treatment of invasive fungal infections.

Invasive fungal infections have become an important healthcare issue due in large part to high mortality rates under standard of care (SOC) therapies creating an urgent need for new and effective anti-fungal agents. We have developed a series of non-peptide, structurally-constrained analogs of host defence proteins that have distinct advantages over peptides for pharmaceutical uses. Here we report the chemical optimization of bis-guanidine analogs focused on alterations of the central aryl core and the connection of it to the terminal guanidines. This effort resulted in the production of highly potent, broadly active compounds with low mammalian cell cytotoxicity that have comparable or improved antifungal activities over SOC agents. One optimal compound was also found to possess favourable in vitro pharmaceutical and off-target properties suitable for further development.

Endothelial HIF-2α as a Key Endogenous Mediator Preventing Emphysema.

Rationale: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of HIF-2α (hypoxia-inducible factor-2α)-regulated genes, and tobacco smoke decreases pulmonary HIF-2α concentrations. These findings suggest that decreased HIF-2α expression is important in the development of emphysema.Objectives: The objective of this study was to evaluate the roles of endothelial-cell (EC) HIF-2α in the pathogenesis of emphysema in mice.Methods: Mouse lungs were examined for emphysema after either the loss or the overexpression of EC Hif-2α. In addition, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for HGF (hepatocyte growth factor), a protein involved in alveolar development and homeostasis. Lungs from patients with emphysema were measured for endothelial HIF-2α expression.Measurements and Main Results: EC Hif-2α deletion resulted in emphysema in association with fewer ECs and pericytes. After SU5416 exposure, EC Hif-2α-knockout mice developed more severe emphysema, whereas EC Hif-2α-overexpressing mice were protected. EC Hif-2α-knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2α expression.Conclusions: Here, we demonstrate a unique protective role for pulmonary endothelial HIF-2α and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2α may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2α may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.

Intersections of Racial Discrimination and LGB Victimization for Mental Health: A Prospective Study of Sexual Minority Youth of Color.

Sexual minority youth (i.e., lesbian, gay, and bisexual youth; LGB) of color have multiple minoritized identities, and few studies examine the implications of intersectional minority stressors for their prospective mental health. The current study tested three intersectional hypotheses: the additive hypothesis-racial discrimination and LGB victimization are independently associated with mental health; the multiplicative hypothesis-racial discrimination and LGB victimization interact in to exacerbate their negative association with mental health, and the inuring hypothesis-only racial discrimination or LGB victimization is associated with mental health. Data come from a sample of lesbian, gay, and bisexual youth of color (36% Black, 30% Latino, 26% Multi-racial, 4% Native American, and 3% Asian, Hawaiian, and Pacific Islander) from two U.S. cities, one in the Northeast (77%) and one in the Southwest, who were between ages 15-24 (M = 19) and surveyed four times over three years spaced nine months apart (N = 476; 38% bisexual; 67% free and reduced lunch; and 49% assigned female at birth). The multiplicative hypothesis was supported for depression symptoms, and the additive hypothesis was supported for suicidal ideation. Intersectional minority stressors undermine the mental health of sexual minority youth of color and warrant further investigation.

Endothelial Hypoxia-Inducible Factor-2α Is Required for the Maintenance of Airway Microvasculature.

BACKGROUND: Hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents. METHODS: The tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1α or HIF-2α, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells. RESULTS: The genetic deletion of Hif-2α but not Hif-1α caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2α promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2α deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2α or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2α in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation. CONCLUSIONS: Our findings reveal that the constitutive expression of endothelial HIF-2α is required for airway microvascular health.

Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation.

BACKGROUND: Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4, are candidates for the second hit. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. METHODS: Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2-mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes. RESULTS: Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated leukotriene B4 biosynthesis. Bmpr2-mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-ß) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-ß antagonism suggests that TGF-ß is critical for neointimal transformation. CONCLUSIONS: In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-ß signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.

Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension.

RATIONALE: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. OBJECTIVE: To evaluate whether and how Treg deficiency differentially affects male and female rats in experimental PH. METHODS AND RESULTS: Male and female athymic rnu/rnu rats, lacking Tregs, were treated with the VEGFR2 (vascular endothelial growth factor receptor 2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution before SU5416 administration. Plasma PGI2 (prostacyclin) levels were measured. Lung and right ventricles were assessed for the expression of the vasoprotective proteins COX-2 (cyclooxygenase 2), PTGIS (prostacyclin synthase), PDL-1 (programmed death ligand 1), and HO-1 (heme oxygenase 1). Inhibitors of these pathways were administered to athymic rats undergoing Treg immune reconstitution. Finally, human cardiac microvascular endothelial cells cocultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and ER (estrogen receptor) expression, and culture supernatants were assayed for PGI2 and IL (interleukin)-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented right ventricular fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1, and PDL-1 expression and reduced right ventricular PDL-1 levels. In both sexes, Treg immune reconstitution protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and PD-1 (programmed death 1)/PDL-1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL-1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10. CONCLUSIONS: In 2 animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on the normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

Irrigation Scheduling Based on Wireless Sensors Output and Soil-Water Characteristic Curve in Two Soils.

Data-driven irrigation planning can optimize crop yield and reduce adverse impacts on surface and ground water quality. We evaluated an irrigation scheduling strategy based on soil matric potentials recorded by wireless Watermark (WM) sensors installed in sandy loam and clay loam soils and soil-water characteristic curve data. Five wireless WM nodes (IRROmesh) were installed at each location, where each node consisted of three WM sensors that were installed at 15, 30, and 60 cm depths in the crop rows. Soil moisture contents, at field capacity and permanent wilting points, were determined from soil-water characteristic curves and were approximately 23% and 11% for a sandy loam, and 35% and 17% for a clay loam, respectively. The field capacity level which occurs shortly after an irrigation event was considered the upper point of soil moisture content, and the lower point was the maximum soil water depletion level at 50% of plant available water capacity in the root zone, depending on crop type, root depth, growth stage and soil type. The lower thresholds of soil moisture content to trigger an irrigation event were 17% and 26% in the sandy loam and clay loam soils, respectively. The corresponding soil water potential readings from the WM sensors to initiate irrigation events were approximately 60 kPa and 105 kPa for sandy loam, and clay loam soils, respectively. Watermark sensors can be successfully used for irrigation scheduling by simply setting two levels of moisture content using soil-water characteristic curve data. Further, the wireless system can help farmers and irrigators monitor real-time moisture content in the soil root zone of their crops and determine irrigation scheduling remotely without time consuming, manual data logging and frequent visits to the field.

Reduced genetic potential for butyrate fermentation in the gut microbiome of infants who develop allergic sensitization.

BACKGROUND: Allergic disease is the most frequent chronic health issue in children and has been linked to early-life gut microbiome dysbiosis. Many lines of evidence suggest that microbially derived short-chain fatty acids, and particularly butyrate, can promote immune tolerance. OBJECTIVE: We sought to determine whether bacterial butyrate production in the gut during early infancy is protective against the development of atopic disease in children. METHODS: We used shotgun metagenomic analysis to determine whether dysbiosis in butyrate fermentation could be identified in human infants, before their developing allergic disease. RESULTS: We found that the microbiome of infants who went on to develop allergic sensitization later in childhood lacked genes encoding key enzymes for carbohydrate breakdown and butyrate production. CONCLUSIONS: Our findings support the importance of microbial carbohydrate metabolism during early infancy in protecting against the development of allergies.

Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA.

The human gamma-herpesviruses Epstein-Barr virus (EBV) (HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein-Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)-NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins.