Applying the Research Domain Criteria to Rodent Studies of Sex Differences in Chronic Stress Susceptibility.

Women have a 2-fold increased rate of stress-associated psychiatric disorders such as depression and anxiety, but the mechanisms that underlie this increased susceptibility remain incompletely understood. Historically, female subjects were excluded from preclinical studies and clinical trials. Additionally, chronic stress paradigms used to study psychiatric pathology in animal models were developed for use in males. However, recent changes in National Institutes of Health policy encourage inclusion of female subjects, and considerable work has been performed in recent years to understand biological sex differences that may underlie differences in susceptibility to chronic stress-associated psychiatric conditions. Here, we review the utility as well as current challenges of using the framework of the National Institute of Mental Health's Research Domain Criteria as a transdiagnostic approach to study sex differences in rodent models of chronic stress including recent progress in the study of sex differences in the neurobehavioral domains of negative valence, positive valence, cognition, social processes, and arousal.

Dynamic regulation of water potential in Juniperus osteosperma mediates ecosystem carbon fluxes.

Some plants exhibit dynamic hydraulic regulation, in which the strictness of hydraulic regulation (i.e. iso/anisohydry) changes in response to environmental conditions. However, the environmental controls over iso/anisohydry and the implications of flexible hydraulic regulation for plant productivity remain unknown. In Juniperus osteosperma, a drought-resistant dryland conifer, we collected a 5-month growing season time series of in situ, high temporal-resolution plant water potential ( Ψ ) and stand gross primary productivity (GPP). We quantified the stringency of hydraulic regulation associated with environmental covariates and evaluated how predawn water potential contributes to empirically predicting carbon uptake. Juniperus osteosperma showed less stringent hydraulic regulation (more anisohydric) after monsoon precipitation pulses, when soil moisture and atmospheric demand were high, and corresponded with GPP pulses. Predawn water potential matched the timing of GPP fluxes and improved estimates of GPP more strongly than soil and/or atmospheric moisture, notably resolving GPP underestimation before vegetation green-up. Flexible hydraulic regulation appears to allow J. osteosperma to prolong soil water extraction and, therefore, the period of high carbon uptake following monsoon precipitation pulses. Water potential and its dynamic regulation may account for why process-based and empirical models commonly underestimate the magnitude and temporal variability of dryland GPP.

Use of Biological Feedback as a Health Behavior Change Technique in Adults: Scoping Review.

BACKGROUND: Recent advancements in personal biosensing technology support the shift from standardized to personalized health interventions, whereby biological data are used to motivate health behavior change. However, the implementation of interventions using biological feedback as a behavior change technique has not been comprehensively explored. OBJECTIVE: The purpose of this review was to (1) map the domains of research where biological feedback has been used as a behavior change technique and (2) describe how it is implemented in behavior change interventions for adults. METHODS: A comprehensive systematic search strategy was used to query 5 electronic databases (Ovid MEDLINE, Elsevier Embase, Cochrane Central Register of Controlled Trials, EBSCOhost PsycINFO, and ProQuest Dissertations & Theses Global) in June 2021. Eligible studies were primary analyses of randomized controlled trials (RCTs) in adults that incorporated biological feedback as a behavior change technique. DistillerSR was used to manage the literature search and review. RESULTS: After removing 49,500 duplicates, 50,287 articles were screened and 767 articles were included. The earliest RCT was published in 1972 with a notable increase in publications after 2000. Biological feedback was most used in RCTs aimed at preventing or managing diabetes (n=233, 30.4%), cardiovascular disease (n=175, 22.8%), and obesity (n=115, 15%). Feedback was often given on multiple biomarkers and targeted multiple health behaviors. The most common biomarkers used were anthropometric measures (n=297, 38.7%), blood pressure (n=238, 31%), and glucose (n=227, 29.6%). The most targeted behaviors were diet (n=472, 61.5%), physical activity (n=417, 54.4%), and smoking reduction (n=154, 20.1%). The frequency and type of communication by which biological feedback was provided varied by the method of biomarker measurement. Of the 493 (64.3%) studies where participants self-measured their biomarker, 476 (96.6%) received feedback multiple times over the intervention and 468 (94.9%) received feedback through a biosensing device. CONCLUSIONS: Biological feedback is increasingly being used to motivate behavior change, particularly where relevant biomarkers can be readily assessed. Yet, the methods by which biological feedback is operationalized in intervention research varied, and its effectiveness remains unclear. This scoping review serves as the foundation for developing a guiding framework for effectively implementing biological feedback as a behavior change technique. TRIAL REGISTRATION: Open Science Framework Registries; https://doi.org/10.17605/OSF.IO/YP5WAd. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/32579.

Long-Term Complete Remission of a Patient With Double-Hit Diffuse Large B-Cell Lymphoma Treated by Chemoimmunotherapy and Chinese Herbal Medicine.

Double-hit diffuse large B-cell lymphoma (DHL) is an uncommon subtype of lymphoma which poorly responds to current drug therapies and has low rates of long-term survival in the patients. Herein, we report a case of a 73-year-old Caucasian male who was diagnosed with DHL with double-hit mutations of rearrangement of both c-MYC and BCL2 in November 2013. He commenced the standard R-CHOP-14 chemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) but changed to dose-adjusted DA-EPOCH-R protocol (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab) in the second and third cycles due to double-hit mutation. Because of intolerance to the intensive therapy, the patient decided to switch to Chinese medicine intervention. From March 2014 to December 2019, he was prescribed with a classical Chinese herbal formula-Sijunzi Decoction plus Prunella vulgaris based prescriptions. After 2 months of the Chinese herbal medicine intervention, the patient felt his right groin mass disappeared. Imaging follow-up showed no residual masses, and no lymphadenopathy was seen. During the period of Chinese herbal medicine treatment, his adherence and tolerability were well maintained with no adverse events. Imaging surveillances afterward found no evidence of lymphoma recurrence. His regular blood tests indicated that the patient's blood counts were normal and stable; no hematologic toxicity, hepatoxicity, or nephrotoxicity associated with Chinese herbal medicine were found. Follow-up visits until 2020 found that he had been living and enjoying a good quality of life for over 8 years post-diagnosis. This case study illustrates the potential values of Chinese herbal medicine in DHL treatment, alongside chemo-immunotherapy, and in maintaining long-term survival and satisfactory quality of life for DHL patients. The case report provides clinicians with preliminary evidence of the use of Chinese herbal medicine as a therapeutic strategy in the management of DHL.

Contemporary tree growth shows altered climate memory.

Trees are long-lived organisms, exhibiting temporally complex growth arising from strong climatic "memory." But conditions are becoming increasingly arid in the western USA. Using a century-long tree-ring network, we find altered climate memory across the entire range of a widespread western US conifer: growth is supported by precipitation falling further into the past (+15 months), while increasingly impacted by more recent temperature conditions (-8 months). Tree-ring datasets can be biased, so we confirm altered climate memory in a second, ecologically-sampled tree-ring network. Predicted drought responses show trees may have also become more sensitive to repeat drought. Finally, plots near sites with relatively longer precipitation memory and shorter temperature memory had significantly lower recent mortality rates (R2  = 0.61). We argue that increased drought frequency has altered climate memory, demonstrate how non-stationarity may arise from failure to account for memory, and suggest memory length may be predictive of future tree mortality.

The clinical features of juvenile dermatomyositis: A single-centre inception cohort.

INTRODUCTION: Juvenile Dermatomyositis (JDM), a severe and rare autoimmune disease, is the most common idiopathic inflammatory myopathy in children. We describe the clinical features of a large single-centre cohort. METHODS: We studied an inception cohort (0-18 years old) referred for diagnosis to the JDM clinic at The Hospital for Sick Children (SickKids), between January 1989 and September 2017. Probable or definite diagnosis of JDM was done according to the 2017 ACR/EULAR Criteria. We excluded children who had treatment started at another hospital. The data were collected retrospectively from clinical charts and the SickKids JDM database. RESULTS: 172/230 (74.8%) patients were included. They were most often female (female:male = 1.8:1); the age at diagnosis was 8.5±4.3 years. There was a positive family history for autoimmune disease in 52%, mainly rheumatoid arthritis. No patient died. The most common signs at inception were muscle weakness (85.5%), nailfold capillary abnormalities (83.4%), Gottron papules (78.5%), heliotrope rash (66.3%), abnormal gait (55.8%), and malar/facial rash (54.7%). The prevalence of Gottron papules, heliotrope rash, facial/malar rash, nailfold capillary abnormalities, Raynaud phenomenon, dysphonia/dysphagia (a frequent cause of hospitalization), mouth ulcers, calcinosis, eye problems, joint involvement, acanthosis nigricans and lipodystrophy increased during follow-up. Muscle enzymes, namely CK, ALT, AST, were often normal or only slightly raised despite active muscle disease; conversely LD was often high. Anti-Nuclear Autoantibodies were positive in 49.7% of patients at diagnosis. The course of the disease was: 29.1% monocyclic, 5.3% polycyclic, 33.1% chronic. The course of 56 patients (32.5%) was not classifiable due to length of follow-up. Corticosteroids were used as treatment in almost all our patients and 30% required intravenous therapy due to the severity of the presentation; methotrexate was added in 64%, more often in recent years. Unresponsive patients were treated mostly with intravenous immunoglobulins (IVIG). CONCLUSIONS: The information obtained from this relatively large number of patients adds to the growing knowledge base of this rare disease. TRIAL REGISTRATION: SickKids Research Ethics Board approved the study.

A 3-D groundwater isoscape of the contiguous USA for forensic and water resource science.

A wide range of hydrological, ecological, environmental, and forensic science applications rely on predictive "isoscape" maps to provide estimates of the hydrogen or oxygen isotopic compositions of environmental water sources. Many water isoscapes have been developed, but few studies have produced isoscapes specifically representing groundwaters. None of these have represented distinct subsurface layers and isotopic variations across them. Here we compiled >6 million well completion records and >27,000 groundwater isotope datapoints to develop a space- and depth-explicit water isoscape for the contiguous United States. This 3-dimensional model shows that vertical isotopic heterogeneity in the subsurface is substantial in some parts of the country and that groundwater isotope delta values often differ from those of coincident precipitation or surface water resources; many of these patterns can be explained by established hydrological and hydrogeological mechanisms. We validate the groundwater isoscape against an independent data set of tap water values and show that the model accurately predicts tap water values in communities known to use groundwater resources. This new approach represents a foundation for further developments and the resulting isoscape should provide improved predictions of water isotope values in systems where groundwater is a known or potential water source.

Temperature memory and non-structural carbohydrates mediate legacies of a hot drought in trees across the southwestern USA.

Trees are long-lived organisms that integrate climate conditions across years or decades to produce secondary growth. This integration process is sometimes referred to as 'climatic memory.' While widely perceived, the physiological processes underlying this temporal integration, such as the storage and remobilization of non-structural carbohydrates (NSC), are rarely explicitly studied. This is perhaps most apparent when considering drought legacies (perturbed post-drought growth responses to climate), and the physiological mechanisms underlying these lagged responses to climatic extremes. Yet, drought legacies are likely to become more common if warming climate brings more frequent drought. To quantify the linkages between drought legacies, climate memory and NSC, we measured tree growth (via tree ring widths) and NSC concentrations in three dominant species across the southwestern USA. We analyzed these data with a hierarchical mixed effects model to evaluate the time-scales of influence of past climate (memory) on tree growth. We then evaluated the role of climate memory and the degree to which variation in NSC concentrations were related to forward-predicted growth during the hot 2011-2012 drought and subsequent 4-year recovery period. Populus tremuloides exhibited longer climatic memory compared to either Pinus edulis or Juniperus osteosperma, but following the 2011-2012 drought, P. tremuloides trees with relatively longer memory of temperature conditions showed larger (more negative) drought legacies. Conversely, Pinus edulis trees with longer temperature memory had smaller (less negative) drought legacies. For both species, higher NSC concentrations followed more negative (larger) drought legacies, though the relevant NSC fraction differed between P. tremuloides and P. edulis. Our results suggest that differences in tree NSC are also imprinted upon tree growth responses to climate across long time scales, which also underlie tree resilience to increasingly frequent drought events under climate change.

Temporal controls on crown nonstructural carbohydrates in southwestern US tree species.

In trees, large uncertainties remain in how nonstructural carbohydrates (NSCs) respond to variation in water availability in natural, intact ecosystems. Variation in NSC pools reflects temporal fluctuations in supply and demand, as well as physiological coordination across tree organs in ways that differ across species and NSC fractions (e.g., soluble sugars vs starch). Using landscape-scale crown (leaves and twigs) NSC concentration measurements in three foundation tree species (Populus tremuloides, Pinus edulis, Juniperus osteosperma), we evaluated in situ, seasonal variation in NSC responses to moisture stress on three timescales: short-term (via predawn water potential), seasonal (via leaf δ13C) and annual (via current year's ring width index). Crown NSC responses to moisture stress appeared to depend on hydraulic strategy, where J. osteosperma appears to regulate osmotic potentials (via higher sugar concentrations), P. edulis NSC responses suggest respiratory depletion and P. tremuloides responses were consistent with direct sink limitations. We also show that overly simplistic models can mask seasonal and tissue variation in NSC responses, as well as strong interactions among moisture stress at different timescales. In general, our results suggest large seasonal variation in crown NSC concentrations reflecting the multiple cofunctions of NSCs in plant tissues, including storage, growth and osmotic regulation of hydraulically vulnerable leaves. We emphasize that crown NSC pool size cannot be viewed as a simple physiological metric of stress; in situ NSC dynamics are complex, varying temporally, across species, among NSC fractions and among tissue types.

Non-structural carbohydrate dynamics associated with antecedent stem water potential and air temperature in a dominant desert shrub.

Non-structural carbohydrates (NSCs) are necessary for plant growth and affected by plant water status, but the temporal dynamics of water stress impacts on NSC are not well understood. We evaluated how seasonal NSC concentrations varied with plant water status (predawn xylem water potential, Ψ) and air temperature (T) in the evergreen desert shrub Larrea tridentata. Aboveground sugar and starch concentrations were measured weekly or monthly for ~1.5 years on 6-12 shrubs simultaneously instrumented with automated stem psychrometers; leaf photosynthesis (Anet ) was measured monthly for 1 year. Leaf sugar increased during the dry, premonsoon period, associated with lower Ψ (greater water stress) and high T. Leaf sugar accumulation coincided with declines in leaf starch and stem sugar, suggesting the prioritization of leaf sugar during low photosynthetic uptake. Leaf starch was strongly correlated with Anet and peaked during the spring and monsoon seasons, while stem starch remained relatively constant except for depletion during the monsoon. Recent photosynthate appeared sufficient to support spring growth, while monsoon growth required the remobilization of stem starch reserves. The coordinated responses of different NSC fractions to water status, photosynthesis, and growth demands suggest that NSCs serve multiple functions under extreme environmental conditions, including severe drought.

Switchable resolution in soft x-ray tomography of single cells.

The diversity of living cells, in both size and internal complexity, calls for imaging methods with adaptable spatial resolution. Soft x-ray tomography (SXT) is a three-dimensional imaging technique ideally suited to visualizing and quantifying the internal organization of single cells of varying sizes in a near-native state. The achievable resolution of the soft x-ray microscope is largely determined by the objective lens, but switching between objectives is extremely time-consuming and typically undertaken only during microscope maintenance procedures. Since the resolution of the optic is inversely proportional to the depth of focus, an optic capable of imaging the thickest cells is routinely selected. This unnecessarily limits the achievable resolution in smaller cells and eliminates the ability to obtain high-resolution images of regions of interest in larger cells. Here, we describe developments to overcome this shortfall and allow selection of microscope optics best suited to the specimen characteristics and data requirements. We demonstrate that switchable objective capability advances the flexibility of SXT to enable imaging cells ranging in size from bacteria to yeast and mammalian cells without physically modifying the microscope, and we demonstrate the use of this technology to image the same specimen with both optics.

Temporal shifts in iso/anisohydry revealed from daily observations of plant water potential in a dominant desert shrub.

Plant species are characterized along a spectrum of isohydry to anisohydry depending on their regulation of water potential (Ψ), but the plasticity of hydraulic strategies is largely unknown. The role of environmental drivers was evaluated in the hydraulic behavior of Larrea tridentata, a drought-tolerant desert shrub that withstands a wide range of environmental conditions. With a 1.5 yr time-series of 2324 in situ measurements of daily predawn and midday Ψ, the temporal variability of hydraulic behavior was explored in relation to soil water supply, atmospheric demand and temperature. Hydraulic behavior in Larrea was highly dynamic, ranging from partial isohydry to extreme anisohydry. Larrea exhibited extreme anisohydry under wet soil conditions corresponding to periods of high productivity, whereas partial isohydry was exhibited after prolonged dry or cold conditions, when productivity was low. Environmental conditions can strongly influence plant hydraulic behavior at relatively fast timescales, which enhances our understanding of plant drought responses. Although species may exhibit a dominant hydraulic behavior, variable environmental conditions can prompt plasticity in Ψ regulation, particularly for species in seasonally dry climates.

Soft X-ray tomography: virtual sculptures from cell cultures.

Cellular complexity is represented best in high-spatial resolution, three-dimensional (3D) reconstructions. Soft X-ray tomography (SXT) generates detailed volumetric reconstructions of cells preserved in a near-to-native, frozen-hydrated state. SXT is broadly applicable and can image specimens ranging from bacteria to large mammalian cells. As a reference, we summarize light and electron microscopic methods. We then present an overview of SXT and discuss its role in cellular imaging. We detail the methods used to image biological specimens and present recent highlights that illustrate the capabilities of the technique. We conclude by discussing correlative imaging, specifically the combination of SXT and fluorescence microscopy performed on the same specimen. This correlated approach combines the structural morphology of a cell with its physiological characteristics to build a deeply informative composite view.

Antecedent soil water content and vapor pressure deficit interactively control water potential in Larrea tridentata.

Plant water potential Ψ is regulated by stomatal responses to atmospheric moisture demand D and soil water availability W, but the timescales of influence and interactions between these drivers of plant Ψ are poorly understood. Here, we quantify the effects of antecedent D and W on plant Ψ in the desert shrub Larrea tridentata. Repeated measurements of plant baseline water potential ΨB and diurnal water potential ΨD were analyzed in a Bayesian framework to evaluate the influence of antecedent D and W at daily and subdaily timescales. Both ΨB and ΨD exhibited negative, 2- to 4-d lagged responses to daily-scale D; conversely, plant ΨD responded almost instantaneously to subdaily D, though the direction of this response depended on antecedent moisture conditions. Plant ΨB and ΨD responded positively and immediately (no lag) to shallow W, which contrasts the negative, lagged (6-7 d) response to deep W. The changing sensitivity of ΨD to subdaily D highlights shifting modes of plant Ψ regulation: D effects on ΨD range from negative to neutral to positive depending on past conditions and time of day. Explicit consideration of antecedent conditions across multiple timescales can reveal important complexities in plant responses.

Mesoscale imaging with cryo-light and X-rays: Larger than molecular machines, smaller than a cell.

In the context of cell biology, the term mesoscale describes length scales ranging from that of an individual cell, down to the size of the molecular machines. In this spatial regime, small building blocks self-organise to form large, functional structures. A comprehensive set of rules governing mesoscale self-organisation has not been established, making the prediction of many cell behaviours difficult, if not impossible. Our knowledge of mesoscale biology comes from experimental data, in particular, imaging. Here, we explore the application of soft X-ray tomography (SXT) to imaging the mesoscale, and describe the structural insights this technology can generate. We also discuss how SXT imaging is complemented by the addition of correlative fluorescence data measured from the same cell. This combination of two discrete imaging modalities produces a 3D view of the cell that blends high-resolution structural information with precise molecular localisation data.

Structural equation modeling of the associations between the home environment and obesity-related cardiovascular fitness and insulin resistance among Hispanic children.

Hispanic children are disproportionally affected by obesity-related risk of metabolic disease. We used the structural equation modeling to examine the associations between specific diet and physical activity (PA) behaviors at home and Hispanic children's metabolic health. A total of 187 Hispanic children and their parents from an urban community in Wisconsin participated in the study. Exposure variables included, children's daily intake of sugar-sweetened beverages (SSB) and PA; home availability of SSB and PA areas/equipment; and parents' intake of SSB and PA, assessed through self-administered questionnaires. Outcome variables for children's metabolic health included, measured anthropometrics; cardiovascular fitness assessed using the Progressive Aerobic Cardiovascular Endurance Run (PACER); and insulin resistance determined with the homeostasis model assessment of insulin resistance (HOMAIR). We found that children's daily intake of SSB was positively associated with BMI z-score, which in turn, was positively associated with HOMAIR (P < 0.05). Specific diet behaviors at home associated with children's intake of SSB, included home availability of SSB, which mediated the association between parents' and children's intake of SSB (P < 0.05). Children's PA was positively associated with PACER z-score, which in turn, was inversely associated with HOMAIR (P < 0.05). Specific PA behaviors at home associated with children's PA, included home availability of PA areas/equipment, which mediated the association between parents' and children's PA (P < 0.05). The structural equation model indices suggested a satisfactory model fit (Chi-square, X(2) = 53.1, comparative fix index = 0.92, root-mean-squared error associated = 0.04). The findings confirm the need for interventions at the family level that promotes healthier home environments by targeting poor diet and low levels of PA in all family members.

Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A.

The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound 11, of which the ethynyl group was replaced by its' bioisostere-the triazole via click chemistry, showed a high binding affinity to α4ß2 subtype (Ki=1.3 nM) and better selectivity to the α4ß2 subtype over α3ß4 subtype with that of Sazetidine-A. The azide compound 15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog 17 exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a 'long tail' side chain for α4ß2 nAChR binding.

An economic evaluation of health-promotive built environment changes.

OBJECTIVES: This study aimed to help public investment decision makers see the greatest return on their built environment investments by developing an analysis framework for identifying the most promising improvement strategies and assessing the attainable return on investment. METHODS: The 2001 National Household Travel Survey sample (N=4974) from Dane County, Wisconsin, was used to develop a Spatial Seemingly Unrelated Regression model of daily vehicle miles traveled and miles walked or biked. The empirical model was used to analyze the travel impacts of hypothetical built environment changes. These travel impacts were translated into health impacts and monetary values using cost-benefit analysis. RESULTS: Two win-win built environment strategies were found: increased regional retail accessibility and increased prevalence of sidewalks. Based on the present analyses, an investment of $450 million to make sidewalks available to all Dane County residents was estimated to yield a cost-benefit ratio of 1.87 over a 10-year life cycle. CONCLUSION: Certain built environment measures could be predicted to be effective strategies for exerting a positive influence on people's travel behavior and the health of the community. Quantifiable public health benefits gained by better air quality and increased physical activity were shown to outweigh the cost of implementing the built environment measure of adding sidewalks to all roads.