Predicting 35-Cl electric field gradient tensors in crystalline solids using cluster and fragment-corrected planewave density functional theory.

Planewave-corrected methods have proven effective for accurately modeling nuclear magnetic resonance (NMR) parameters in crystalline systems. Recent work extended the application of planewave-corrected calculations beyond the second row, predicting EFG tensor parameters for 35Cl using a simple molecular correction to projector augmented-wave (PAW) density functional theory (DFT). Here we extend this work using fragment and cluster-based calculations coupled with polarizable continuum (PCM) methods to improve further the accuracy of planewave-corrected 35Cl EFG tensor calculations. Benchmark data from a test set comprised of 105 individual 35Cl EFG tensor principal components for chlorine-containing molecular crystals and crystalline chloride salts shows fragment-corrected planewave calculations using the PBE0 hybrid density functional improve the accuracy of predicted EFG tensor components by 30 % relative to traditional planewave calculations. We compare the influence of different geometry optimization methods and density functionals on the accuracy of predicted 35Cl EFG tensor parameters. Four cases of spectral assignment are presented to demonstrate the utility of improving the accuracy of predicted 35Cl EFG tensor parameters.

Testosterone, cortisol, and psychopathy: Further evidence with the Levenson self-report psychopathy scale and the inventory of callous unemotional traits.

The current study explored associations between testosterone, cortisol, and both the Levenson Self-Report Psychopathy Scale (LSRPS) and the Inventory of Callous Unemotional (ICU) traits. Data were gathered from a relatively large sample of university students (n = 522) and analyses considered direct and interactive associations between hormones and psychopathic traits, as well as interactions between these associations and the time of day at which samples were gathered and the sex of participants. Baseline cortisol had a negative association with LSRPS primary psychopathy scores. In addition, baseline cortisol interacted with the time of day in association with LSRPS total scores. Simple slopes analyses indicated cortisol had a negative association with LSRPS total scores in the morning but not the afternoon. Interactions among hormone measures were not statistically significant. There was also no evidence for the moderation of associations between hormones and psychopathic traits by sex.

Primary Cell Culture as a Model System for Evolutionary Molecular Physiology.

Primary cell culture is a powerful model system to address fundamental questions about organismal physiology at the cellular level, especially for species that are difficult, or impossible, to study under natural or semi-natural conditions. Due to their ease of use, primary fibroblast cultures are the dominant model system, but studies using both somatic and germ cells are also common. Using these models, genome evolution and phylogenetic relationships, the molecular and biochemical basis of differential longevities among species, and the physiological consequences of life history evolution have been studied in depth. With the advent of new technologies such as gene editing and the generation of induced pluripotent stem cells (iPSC), the field of molecular evolutionary physiology will continue to expand using both descriptive and experimental approaches.

Distinguishing between COOH, COO- , and hydrogen disordered COOH sites in solids with 13 C chemical shift anisotropy and T1 measurements.

Since 1993, it has been known that 13 C chemical shift tensor (i.e., δ11 , δ22 , and δ33 ) provides information sufficient to distinguish between COOH and COO- sites. Herein, four previously unreported metrics are proposed for differentiating COOH/COO- moieties. A new relationship is also introduced that correlates the asymmetry (i.e., δ11 -δ22 ) of COOH sites to the proximity of hydrogen bond donating partners within 2.6 Å with high accuracy (±0.05 Å). Conversely, a limitation to all proposed metrics is that they fail to distinguish between COO- and hydrogen disordered COOH sites. To reconcile this omission, a new approach is proposed based on T1 measurements of both 1 H and 13 C. The 13 C T1 values are particularly sensitive with the T1 for hydrogen disordered COOH moieties found to be nearly six times smaller than T1 's from COO- sites.

Quantitative T1 brain mapping in early relapsing-remitting multiple sclerosis: longitudinal changes, lesion heterogeneity and disability.

OBJECTIVES: To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability. METHODS: Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). RESULTS: Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p < .001), and were associated with EDSS score at baseline (p < .05) and follow-up (supramedian: p < .01; prolonged: p < .05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p < .05). CONCLUSION: T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability. CLINICAL RELEVANCE STATEMENT: MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. KEY POINTS: • Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis.

Exploring the role of primary fibroblast cells in comparative physiology: a historical and contemporary overview.

With the advent of tissue culture, and eventually the in vitro growth and maintenance of individual cell types, it became possible to ask mechanistic questions about whole organism physiology that are impractical to address within a captive setting or within the whole organism. The earliest studies focused on understanding the wound-healing response while refining cell growth and maintenance protocols from various species. In addition to its extensive use in biomedical research, this approach has been co-opted by comparative physiologists interested in reductionist/mechanistic questions related to how cellular physiology can help explain whole organism function. Here, we provide a historical perspective on the emergence of primary cell culture with an emphasis on fibroblasts followed by an overview of applying this method to ask questions about the role of life-history evolution in shaping organismal physiology at the cellular level, as well as the effect of exogenous factors (i.e., temperature, and oxygen availability) on cellular function. Finally, we propose future uses for primary fibroblasts to address questions in conservation biology and comparative physiology.

The relationship between nutrition, gut dysbiosis, and pediatric sickle cell pain outcomes: A pilot study.

BACKGROUND: Nutritional deficiencies are prevalent in sickle cell disease (SCD) and may be associated with worse pain outcomes. Gut dysbiosis has been reported in patients with SCD and may contribute to both nutritional deficiencies and pain. OBJECTIVES: We tested the association of nutrition, fat-soluble vitamin (FSV) deficiency, and gut microbiome composition on clinical outcomes in SCD. Second, we measured the association between diet and exocrine pancreatic function on FSV levels. METHODS: Using case control design, we enrolled children with SCD (n = 24) and matched healthy controls (HC; n = 17, age, sex, race/ethnicity). Descriptive statistics summarized demographic and clinical data. Wilcoxson-rank tests compared FSV levels between cohorts. Regression modeling tested the association between FSV levels and SCD status. Welch's t-test with Satterthwaite adjustment evaluated associations between microbiota profiles, SCD status, and pain outcomes. RESULTS: Vitamin A and D levels were significantly decreased in participants with HbSS as compared to HC (vitamin A, p = < .0001, vitamin D, p = .014) independent of nutritional status. FSV correlated with dietary intake in SCD and HC cohorts. Gut microbial diversity was reduced in hemoglobin SS (HbSS) compared to hemoglobin SC (HbSC) and HC, p = .037 and .059, respectively. The phyla Erysipelotrichaceae and Betaproteobacteria were higher in SCD children reporting the highest quality-of-life (QoL) scores (p = .008 and .049, respectively), while Clostridia were higher in those with lower QoL scores (p = .03). CONCLUSION: FSV deficiencies and gut dysbiosis are prevalent in children with SCA. Gut microbial composition is significantly different in children with SCD with low QoL scores.

Study design and baseline to evaluate water service provision among peri-urban communities in Kasai Oriental, Democratic Republic of the Congo.

We present a study design and baseline results to establish the impact of interventions on peri-urban water access, security and quality in Kasai Oriental province of the Democratic Republic of the Congo. In standard development practice, program performance is tracked via monitoring and evaluation frameworks of varying sophistication and rigor. Monitoring and evaluation, while usually occurring nearly concurrently with program delivery, may or may not measure parameters that can identify performance with respect to the project's overall goals. Impact evaluations, often using tightly controlled trial designs and conducted over years, challenge iterative program evolution. This study will pilot an implementation science impact evaluation approach in the areas immediately surrounding 14 water service providers, at each surveying 100 randomly-selected households and conducting water quality assessments at 25 randomly-selected households and five water points every three months. We present preliminary point-of-collection and point-of-use baseline data. This study is utilizing a variety of short- and medium-term monitoring and impact evaluation methods to provide feedback at multiple points during the intervention. Rapid feedback monitoring will assess the continuity of water services, point-of-consumption and point-of-collection microbial water quality, household water security, household measures of health status, ability and willingness to pay for water and sanitation service provision, and service performance monitoring. Long-term evaluation will focus on the use of qualitative comparative analysis whereby we will investigate the combination of factors that lead to improved water access, security and quality.

Development and Validation of a Respiratory-Responsive Vocal Biomarker-Based Tool for Generalizable Detection of Respiratory Impairment: Independent Case-Control Studies in Multiple Respiratory Conditions Including Asthma, Chronic Obstructive Pulmonary Disease, and COVID-19.

BACKGROUND: Vocal biomarker-based machine learning approaches have shown promising results in the detection of various health conditions, including respiratory diseases, such as asthma. OBJECTIVE: This study aimed to determine whether a respiratory-responsive vocal biomarker (RRVB) model platform initially trained on an asthma and healthy volunteer (HV) data set can differentiate patients with active COVID-19 infection from asymptomatic HVs by assessing its sensitivity, specificity, and odds ratio (OR). METHODS: A logistic regression model using a weighted sum of voice acoustic features was previously trained and validated on a data set of approximately 1700 patients with a confirmed asthma diagnosis and a similar number of healthy controls. The same model has shown generalizability to patients with chronic obstructive pulmonary disease, interstitial lung disease, and cough. In this study, 497 participants (female: n=268, 53.9%; <65 years old: n=467, 94%; Marathi speakers: n=253, 50.9%; English speakers: n=223, 44.9%; Spanish speakers: n=25, 5%) were enrolled across 4 clinical sites in the United States and India and provided voice samples and symptom reports on their personal smartphones. The participants included patients who are symptomatic COVID-19 positive and negative as well as asymptomatic HVs. The RRVB model performance was assessed by comparing it with the clinical diagnosis of COVID-19 confirmed by reverse transcriptase-polymerase chain reaction. RESULTS: The ability of the RRVB model to differentiate patients with respiratory conditions from healthy controls was previously demonstrated on validation data in asthma, chronic obstructive pulmonary disease, interstitial lung disease, and cough, with ORs of 4.3, 9.1, 3.1, and 3.9, respectively. The same RRVB model in this study in COVID-19 performed with a sensitivity of 73.2%, specificity of 62.9%, and OR of 4.64 (P<.001). Patients who experienced respiratory symptoms were detected more frequently than those who did not experience respiratory symptoms and completely asymptomatic patients (sensitivity: 78.4% vs 67.4% vs 68%, respectively). CONCLUSIONS: The RRVB model has shown good generalizability across respiratory conditions, geographies, and languages. Results using data set of patients with COVID-19 demonstrate its meaningful potential to serve as a prescreening tool for identifying individuals at risk for COVID-19 infection in combination with temperature and symptom reports. Although not a COVID-19 test, these results suggest that the RRVB model can encourage targeted testing. Moreover, the generalizability of this model for detecting respiratory symptoms across different linguistic and geographic contexts suggests a potential path for the development and validation of voice-based tools for broader disease surveillance and monitoring applications in the future.

Synergistic Steric and Electronic Effects on the Photoredox Catalysis by a Multivariate Library of Titania Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) that display photoredox activity are attractive materials for sustainable photocatalysis. The ability to tune both their pore sizes and electronic structures based solely on the choice of the building blocks makes them amenable for systematic studies based on physical organic and reticular chemistry principles with high degrees of synthetic control. Here, we present a library of eleven isoreticular and multivariate (MTV) photoredox-active MOFs, UCFMOF-n, and UCFMTV-n-x% with a formula Ti6O9[links]3, where the links are linear oligo-p-arylene dicarboxylates with n number of p-arylene rings and x mol% of multivariate links containing electron-donating groups (EDGs). The average and local structures of UCFMOFs were elucidated from advanced powder X-ray diffraction (XRD) and total scattering tools, consisting of parallel arrangements of one-dimensional (1D) [Ti6O9(CO2)6]∞ nanowires connected through the oligo-arylene links with the topology of the edge-2-transitive rod-packed hex net. Preparation of an MTV library of UCFMOFs with varying link sizes and amine EDG functionalization enabled us to study both their steric (pore size) and electronic (highest occupied molecular orbital-lowest unoccupied molecular orbital, HOMO-LUMO, gap) effects on the substrate adsorption and photoredox transformation of benzyl alcohol. The observed relationship between the substrate uptake and reaction kinetics with the molecular traits of the links indicates that longer links, as well as increased EDG functionalization, exhibit impressive photocatalytic rates, outperforming MIL-125 by almost 20-fold. Our studies relating photocatalytic activity with pore size and electronic functionalization demonstrate how these are important parameters to consider when designing new MOF photocatalysts.

A new depsidone from the neotricone-rich chemotype of the lichenised fungus Usnea fulvoreagens.

Individuals of Usnea fulvoreagens (Parmeliaceae, lichenised Ascomycota), a shrubby corticolous species that is widespread in Europe, East Asia and North America, produce medullary lichen acids in several distinct chemotypic patterns. One such chemotype reportedly contains an unidentified substance as the major secondary metabolite. We isolated this compound from Californian specimens of U. fulvoreagens and identified it as the rare depsidone neotricone. A co-occurring compound, conneotricone, was identified as 4,10-dihydroxy-5-(hydroxymethyl)-8-methyl-3,7-dioxo-1,3-dihydro-7H-isobenzofuro[4,5-b][1,4]benzodioxepine-11-carboxylic acid by NMR and HPLC-UV-MSn comparison with the material synthesised from salazinic acid.

Benchmark accuracy of predicted NMR observables for quadrupolar 14 N and 17 O nuclei in molecular crystals.

Nuclear quadrupole resonances for 14 N and 17 O nuclei are exquisitely sensitive to interactions with surrounding atoms. As a result, nitrogen and oxygen solid-state nuclear magnetic resonance (ssNMR) provides a powerful tool for investigating structure and dynamics in complex systems. First-principles calculations are increasingly used to facilitate spectral assignment and to evaluate and adjust crystal structures. Recent work combining the strengths of planewave density functional theory (DFT) calculations with a single molecule correction obtained using a higher level of theory has proven successful in improving the accuracy of predicted chemical shielding (CS) tensors and 17 O quadrupolar coupling constants ( C q ). Here we extend this work by examining the accuracy of predicted 14 N and 17 O electric field gradient (EFG) tensor components obtained using alternative planewave-corrections involving cluster and two-body fragment-based calculations. We benchmark the accuracy of CS and EFG tensor predictions for both nitrogen and oxygen using planewave, two-body fragment, and enhanced planewave-corrected techniques. Combining planewave and two-body fragment calculations reduces the error in predicted 17 O C q values by 35% relative to traditional planewave calculations. These enhanced planewave-correction methods improve the accuracy of 17 O and 14 N EFG tensor components by 15% relative to planewave DFT but yield minimal improvement relative to a simple molecular correction. However, in structural environments involving either high symmetry or strong intermolecular interactions, enhanced planewave-corrected methods provide a distinct advantage.

Improving the accuracy of GIPAW chemical shielding calculations with cluster and fragment corrections.

Ab initio methods for predicting NMR parameters in the solid state are an essential tool for assigning experimental spectra and play an increasingly important role in structural characterizations. Recently, a molecular correction (MC) technique has been developed which combines the strengths of plane-wave methods (GIPAW) with single molecule calculations employing Gaussian basis sets. The GIPAW + MC method relies on a periodic calculation performed at a lower level of theory to model the crystalline environment. The GIPAW result is then corrected using a single molecule calculation performed at a higher level of theory. The success of the GIPAW + MC method in predicting a range of NMR parameters is a result of the highly local character of the tensors underlying the NMR observable. However, in applications involving strong intermolecular interactions we find that expanding the region treated at the higher level of theory more accurately captures local many-body contributions to the N15 NMR chemical shielding (CS) tensor. We propose alternative corrections to GIPAW which capture interactions between adjacent molecules at a higher level of theory using either fragment or cluster-based calculations. Benchmark calculations performed on N15 and C13 data sets show that these advanced GIPAW-corrected calculations improve the accuracy of chemical shielding tensor predictions relative to existing methods. Specifically, cluster-based N15 corrections show a 24% and 17% reduction in RMS error relative to GIPAW and GIPAW + MC calculations, respectively. Comparing the benchmark data sets using multiple computational models demonstrates that N15 CS tensor calculations are significantly more sensitive to intermolecular interactions relative to C13. However, fragment and cluster-based corrections that include direct hydrogen bond partners are sufficient for optimizing the accuracy of GIPAW-corrected methods. Finally, GIPAW-corrected methods are applied to the particularly challenging NMR spectral assignment of guanosine dihydrate which contains two guanosine molecules in the asymmetric unit.

Evaluation for Bleeding Disorders in Suspected Child Abuse.

Bruising or bleeding in a child can raise the concern for child abuse. Assessing whether the findings are the result of trauma and/or whether the child has a bleeding disorder is critical. Many bleeding disorders are rare, and not every child with bruising/bleeding that may raise a concern for abuse requires an evaluation for bleeding disorders. However, in some instances, bleeding disorders can present in a manner similar to child abuse. Bleeding disorders cannot be ruled out solely on the basis of patient and family history, no matter how extensive. The history and clinical evaluation can be used to determine the necessity of an evaluation for a possible bleeding disorder, and prevalence and known clinical presentations of individual bleeding disorders can be used to guide the extent of laboratory testing. This clinical report provides guidance to pediatricians and other clinicians regarding the evaluation for bleeding disorders when child abuse is suspected.

Testosterone, cortisol, and criminal behavior in men and women.

Only two studies to date have considered the joint effects of testosterone and cortisol on direct measures of criminal behavior. The current study extends this earlier work by incorporating the direct and interactive effects of baseline hormone measures and hormone change scores in response to social stress. The current study also extends prior work by considering distinct measures of different criminal behavior types and sex differences. Analyses based on a large sample of undergraduates indicated that testosterone had a positive and statistically significant association with impulsive and violent criminal behavior. The interaction of testosterone with cortisol had a negative association with income generating crime. Simple slopes analyses of this interaction indicated testosterone had a positive association with income generating crime when cortisol was low (-1 SD). Associations between hormones and criminal behavior were not moderated by sex.

Cancer-Associated Fibroblasts Suppress CD8+ T-cell Infiltration and Confer Resistance to Immune-Checkpoint Blockade.

Immune-checkpoint blockade (ICB) promotes antitumor immune responses and can result in durable patient benefit. However, response rates in breast cancer patients remain modest, stimulating efforts to discover novel treatment options. Cancer-associated fibroblasts (CAF) represent a major component of the breast tumor microenvironment and have known immunosuppressive functions in addition to their well-established roles in directly promoting tumor growth and metastasis. Here we utilized paired syngeneic mouse mammary carcinoma models to show that CAF abundance is associated with insensitivity to combination αCTLA4 and αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold tumor microenvironment, with transcriptomic, flow cytometric, and quantitative histopathologic analyses demonstrating a relationship between CAF density and a CD8+ T-cell-excluded tumor phenotype. The CAF receptor Endo180 (Mrc2) is predominantly expressed on myofibroblastic CAFs, and its genetic deletion depleted a subset of αSMA-expressing CAFs and impaired tumor progression in vivo. The addition of wild-type, but not Endo180-deficient, CAFs in coimplantation studies restricted CD8+ T-cell intratumoral infiltration, and tumors in Endo180 knockout mice exhibited increased CD8+ T-cell infiltration and enhanced sensitivity to ICB compared with tumors in wild-type mice. Clinically, in a trial of melanoma patients, high MRC2 mRNA levels in tumors were associated with a poor response to αPD-1 therapy, highlighting the potential benefits of therapeutically targeting a specific CAF subpopulation in breast and other CAF-rich cancers to improve clinical responses to immunotherapy. SIGNIFICANCE: Paired syngeneic models help unravel the interplay between CAF and tumor immune evasion, highlighting the benefits of targeting fibroblast subpopulations to improve clinical responses to immunotherapy.

Rapid, Quantitative Nuclear Magnetic Resonance Test for Oxygen-17 Enrichment in Water.

Nuclear magnetic resonance (NMR) studies involving 17O are increasingly important in molecular biology, material science, and other disciplines. A large number of these studies employ H217O as a source of 17O, and this reliance can be limiting because the high cost of H217O. To overcome this constraint, a recent study proposed a distillation scheme capable of producing significant quantities of H217O at a low cost. Although this method is reported to be effective, the reactions proposed to quantify percent of 17O enrichment are either time intensive or have a risk of errors due to the isotope effect. Here, an alternative reaction scheme is described to measure 17O water that ultimately creates methyl benzoate as the sole 17O-containing product. The proposed reaction is completed in a matter of minutes at room temperature, produces only one 17O product, and requires no clean-up step. The large isotope shift observed in solution NMR between the 13C═16O and 13C═17O resonances allows for integration of the individual peaks. This 13C NMR analysis is found to be highly accurate over a wide enrichment range and is accessible to most NMR spectroscopists.