Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.

Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.

From Gut Microbiota to Brain Waves: The Potential of the Microbiome and EEG as Biomarkers for Cognitive Impairment.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder and a leading cause of dementia. Aging is a significant risk factor for AD, emphasizing the importance of early detection since symptoms cannot be reversed once the advanced stage is reached. Currently, there is no established method for early AD diagnosis. However, emerging evidence suggests that the microbiome has an impact on cognitive function. The gut microbiome and the brain communicate bidirectionally through the gut-brain axis, with systemic inflammation identified as a key connection that may contribute to AD. Gut dysbiosis is more prevalent in individuals with AD compared to their cognitively healthy counterparts, leading to increased gut permeability and subsequent systemic inflammation, potentially causing neuroinflammation. Detecting brain activity traditionally involves invasive and expensive methods, but electroencephalography (EEG) poses as a non-invasive alternative. EEG measures brain activity and multiple studies indicate distinct patterns in individuals with AD. Furthermore, EEG patterns in individuals with mild cognitive impairment differ from those in the advanced stage of AD, suggesting its potential as a method for early indication of AD. This review aims to consolidate existing knowledge on the microbiome and EEG as potential biomarkers for early-stage AD, highlighting the current state of research and suggesting avenues for further investigation.

Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: a meta-analysis.

AIMS: Benefits of pharmacologic omega-3 fatty acid administration in cardiovascular prevention are controversial. Particularly, effects on coronary revascularization are unclear; also debated are specific benefits of eicosapentaenoic acid (EPA). We investigated incident coronary revascularizations, myocardial infarction (MI), stroke, heart failure (HF), unstable angina, and cardiovascular death, in subjects randomized to receive EPA or EPA + docosahexaenoic acid (EPA + DHA) vs. control. METHODS AND RESULTS: Meta-analysis of randomized controlled trials (RCTs) was conducted after MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library search. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed for abstracting data and assessing data quality and validity. Data were pooled using a random effects model. Eighteen RCTs with 134 144 participants (primary and secondary cardiovascular prevention) receiving DHA + EPA (n = 52 498), EPA alone (n = 14 640), or control/placebo (n = 67 006) were included. Follow-up ranged from 4.5 months to 7.4 years. Overall, compared with controls, omega-3 supplementation reduced the risk of revascularization [0.90, 95% confidence interval (CI) 0.84-0.98; P = 0.001; P-heterogeneity = 0.0002; I2 = 68%], MI (0.89, 95% CI 0.81-0.98; P = 0.02; P-heterogeneity = 0.06; I2 = 41%), and cardiovascular death (0.92, 95% CI 0.85-0.99; P = 0.02; P-heterogeneity = 0.13; I2 = 33%). Lower risk was still observed in trials where most participants (≥60%) were on statin therapy. Compared with DHA + EPA, EPA alone showed a further significant risk reduction of revascularizations (0.76, 95% CI 0.65-0.88; P = 0.0002; P-interaction = 0.005) and all outcomes except HF. CONCLUSION: Omega-3 fatty acid supplementation reduced the risk of cardiovascular events and coronary revascularization, regardless of background statin use. Eicosapentaenoic acid alone produced greater benefits. The role of specific omega-3 molecules in primary vs. secondary prevention and the potential benefits of reduced revascularizations on overall health status and cost savings warrant further research.

It is debated whether pharmacologic administration of omega-3 fatty acids reduces cardiac events. In particular, it is unclear whether benefits are actually restricted to the use of eicosapentaenoic acid (EPA), or whether combined administration of EPA + docosahexaenoic acid (DHA) is needed; furthermore, little is known about possible benefits of omega-3 fatty acids in reducing incidence of coronary revascularization procedures. In this meta-analysis of all published evidence of clinical trials comparing EPA alone or EPA + DHA vs. control (134 144 participants), we demonstrate the following: In the overall analysis of all trials, omega-3 supplementation reduced the risk of myocardial infarction and cardiovascular death, to a modest extent. However, when trials administering EPA alone were separately analysed, a further significant risk reduction for cardiovascular outcomes was demonstrated. Importantly, these benefits were also observed in subjects who were already taking statins as part of their chronic therapy.Administration of omega-3 fatty acids, particularly EPA alone, was also associated with a substantial decrease in the risk for subsequent coronary revascularizations. Reduction of revascularization procedures may induce additional benefits on overall health status and associated cost savings.

Spine Involvement and Vertebral Deformity in Patients Diagnosed with Chronic Recurrent Multifocal Osteomyelitis.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder of bone, typically arising adjacent to the physes of long bones but also seen throughout the skeleton. For patients with spinal involvement, CRMO lesions can cause compression deformities with a range of severity from minimal anterior wedging to circumferential height loss, known as vertebra plana. This study examines a large cohort of CRMO patients to determine the prevalence of spine involvement and vertebral deformity. METHODS: This is a retrospective review of all patients with a diagnosis of CRMO seen at our institution between January 2003 and December 2020. These patients were identified through a prospectively maintained database of all CRMO patients seen at the institution. A retrospective review was undertaken to identify all patients with spinal involvement and determine the prevalence of CRMO in the spine and its effects on vertebral height and deformity. RESULTS: Of 170 patients included in this study, 48 (28.2%) were found to have spinal involvement. Among patients with spinal involvement, vertebral body lesions were identified in 27 (56.3%) patients. The remaining lesions were in the sacrum or posterior elements. Radiographic evidence of the vertebral body height loss was noted in 23 of these 27 patients. CONCLUSIONS: This cohort of CRMO patients demonstrates that 28% of patients have spinal involvement, and 48% of those patients have vertebral body height loss. While the ideal treatment for spinal CRMO has yet to be determined, imaging studies, including whole-body MRI and spine-specific MRI, are useful in identifying vertebral lesions and deformities. Identification and surveillance of these lesions are important as the disorder has a relapsing and remitting course, and patients can develop significant vertebral body height loss. Once deformity has developed, we have seen no evidence of reconstitution of the height of the collapsed vertebra. Bisphosphonates have been successful in preventing the progression of vertebral body height loss. LEVEL OF EVIDENCE: Level II: Retrospective study investigating spinal involvement and prevalence of vertebral body deformity in patients diagnosed with CRMO.

US Population Eligibility and Estimated Impact of Tirzepatide Treatment on Obesity Prevalence and Cardiovascular Disease Events.

PURPOSE: Tirzepatide promotes weight loss and reduces risk factors for cardiovascular disease (CVD) in adults with overweight and obesity. We examined the number of US adults eligible for tirzepatide and its impact on obesity and CVD events. METHODS: We identified US adults aged ≥ 18 years from the cross-sectional US National Health and Nutrition Examination Survey (NHANES) 2015-2018 eligible for tirzepatide based on SURMOUNT-1 trial eligibility criteria. Weight changes in SURMOUNT-1 from tirzepatide 15 mg treatment were used to project the impact on weight change and obesity prevalence in the population assuming titration to this dosage. We estimated 10-year CVD risks from BMI-based Framingham CVD risk scores before and after applying tirzepatide 15 mg treatment BMI and risk factor effects from SURMOUNT-1, the differences in estimated risks multiplied by the eligible NHANES weighted population representing the estimated "preventable" CVD events. RESULTS: We identified 4015 US adults (estimated population size of 93.4 million [M]) to fit SURMOUNT-1 eligibility criteria, representing 38% of US adults. When the effects of 15 mg tirzepatide were applied, we estimated 70.6% (65.9 M) and 56.7% (53.0 M) of adults to show ≥ 15% and ≥ 20% reductions in weight, respectively, translating to 58.8% (55.0 M) fewer persons with obesity. Among those without CVD, estimated 10-year CVD risks were 10.1% "before" and 7.7% "after" tirzepatide "treatment" reflecting a 2.4% absolute (and 23.6% relative) risk reduction translating to 2.0 million preventable CVD events over 10 years. CONCLUSION: Tirzepatide treatment in appropriate US adults may substantially reduce obesity prevalence and CVD events, impacting beneficially on associated healthcare costs.

A genome scale transcriptional regulatory model of the human placenta.

Gene regulation is essential to placental function and fetal development. We built a genome-scale transcriptional regulatory network (TRN) of the human placenta using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out-of-sample R2 greater than 0.25 for 73% of target genes. We performed siRNA knockdowns of four TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for three of the four TFs. Our final model contained 113,158 interactions across 391 TFs and 7712 target genes and is publicly available. We identified 29 TFs which were significantly enriched as regulators for genes previously associated with preterm birth, and eight of these TFs were decreased in preterm placentas.

Five Hypotheses on the Origins of Temperature Dependence of 77Se NMR Shifts in Diselenides.

Notable thermal shifts in diselenides have been documented in 77Se NMR for more than 50 years, but no satisfactory explanation has been found. Here, five hypotheses are considered as possible explanations for the large temperature dependence of the 77Se chemical shifts of diaryl and dialkyl diselenides compared to monoselenides and selenols. Density functional theory calculations are provided to bolster hypotheses and better understand the effects of barrier height and dipole energies. It is proposed that the temperature dependence of diselenide 77Se NMR chemical shifts is due to rotation around the Se-Se bond and sampling of twisted conformers at higher temperatures. The molecular twisting is solvent dependent; here, DMSO-d6 and toluene-d8 were evaluated. No correlation was established between para-substituents on diaryl diselenides and the magnitude of the change in the 77Se NMR shift (Δδ) with temperature.

Cyclometalated luminescent platinum(II) complexes of dissymmetrical 2,2':4',2''-terpyridine and its self-assembled dimer presenting Pt-Ag dative bonds.

A series of cyclometalated (N^C^N) Pt(II)-platinum complexes featuring a terpyridine ligand with a non-coordinating nitrogen atom and a Pt-C bond was synthesized. In the presence of Ag+, the bis(isonitrile)Pt(II) complex formed a remarkable self-assembled helicoidal dimer stabilized by coordination of Ag(I) and metallophilic Pt-Ag interactions. Its assembly was observed in the solid state and maintained in solution. All complexes show strong luminescence and multiple emitting states, which could be rationalized based on solid state X-ray structures and coordinating environment.

A review of prospective studies regarding percutaneous peripheral nerve stimulation treatment in the management of chronic pain.

Conventionally, peripheral nerve stimulation (PNS) for treatment of chronic pain has involved a two-stage process: a short-term (e.g., 7 days) trial and, if significant pain relief is achieved, a permanent PNS system is implanted. A percutaneous PNS treatment is now available where a coiled lead may be implanted for up to 60 days with the goal of producing sustained relief. In the present review, published prospective trials using percutaneous PNS treatment were identified and synthesized. The collected evidence indicates that percutaneous PNS treatment for up to 60 days provides durable clinically significant improvements in pain and pain interference. Similar efficacy across diverse targets and etiologies supports the broad applicability for use within the chronic pain population using this nonopioid technology.

What is this review about? This review looks at a drug-free way to treat chronic pain called percutaneous peripheral nerve stimulation (PNS). Percutaneous means it is placed through the skin. PNS applies small amounts of electricity to the nerves to reduce chronic pain. Most PNS systems involve a two-step process. A short trial is first performed to see if a patient has pain relief. A permanent system is then placed if the person had pain relief. Percutaneous PNS treatments are different. They use a thin wire called a lead placed in the body for up to 60 days. The lead is taken out at the end of the treatment period. Studies have shown that this type of PNS treatment can reduce chronic pain even after the treatment is over. No previous article has collected all these studies of percutaneous PNS in one place.What evidence was gathered? This review found evidence from studies on treatment of chronic pain. Pain types included shoulder pain, neuropathic pain and low back pain. It found that percutaneous PNS treatment for up to 60 days can reduce pain and how pain interferes with daily life.How can these data lead to better care for patients? These findings mean that percutaneous PNS treatments could be a useful, non-drug option for many types of chronic pain.

Evaluation of Nutrition and Performance Parameters in Division 1 Collegiate Athletes.

BACKGROUND: Testing and evaluating athletes is necessary and should include performance, body composition, and nutrition. The purpose of this study was to report assessments of dietary intake, V˙O2max, and body composition in D1 collegiate athletes and examine relationships between these assessments. METHODS: Dietary intake was assessed with 3-day recalls and compared to recommendations, and body composition was assessed via bioelectrical impedance analysis (BIA) (n = 48). V˙O2max was evaluated using a graded exercise test (GXT) with a verification bout (n = 35). Reliability between "true" V˙O2max and verification was determined. Correlations and regressions were performed. RESULTS: Energy, carbohydrate, and micronutrient intake was lower than recommendations. Mean V˙O2max was 47.3 and 47.4 mL·kg-1·min-1 for GXT and verification, respectively. While correlations were apparent among dietary intake, V˙O2max, and body composition, percent fat-free mass (%FFM) predicted 36% of V˙O2max. CONCLUSIONS: Collegiate athletes are not meeting energy and carbohydrate recommendations and exceed fat recommendations. Vitamin D and magnesium were low in all sports, and iron and calcium were low in females. V˙O2max ranged from 35.6 to 63.0 mL·kg-1·min-1, with females below average and males meeting typical values for their designated sport. Assessing D1 athletes can provide guidance for sports dietitians, coaches, and strength and conditioning specialists to track and monitor nutrition in athletes.

The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children.

Epidemiologic studies demonstrate an association between early-life respiratory illnesses (RIs) and the development of childhood asthma. However, it remains uncertain whether these children are predisposed to both conditions or if early-life RIs induce alterations in airway function, immune responses, or other human biology that contribute to the development of asthma. Puerto Rican children experience a disproportionate burden of early-life RIs and asthma, making them an important population for investigating this complex interplay. PRIMERO, the Puerto Rican Infant Metagenomics and Epidemiologic Study of Respiratory Outcomes , recruited pregnant women and their newborns to investigate how the airways develop in early life among infants exposed to different viral RIs, and will thus provide a critical understanding of childhood asthma development. As the first asthma birth cohort in Puerto Rico, PRIMERO will prospectively follow 2,100 term healthy infants. Collected samples include post-term maternal peripheral blood, infant cord blood, the child's peripheral blood at the year two visit, and the child's nasal airway epithelium, collected using minimally invasive nasal swabs, at birth, during RIs over the first two years of life, and at annual healthy visits until age five. Herein, we describe the study's design, population, recruitment strategy, study visits and procedures, and primary outcomes.

Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains.

BACKGROUND: Bacterial diversity could contribute to the diversity of tuberculosis infection and treatment outcomes observed clinically, but the biological basis of this association is poorly understood. The aim of this study was to identify associations between phenogenomic variation in Mycobacterium tuberculosis and tuberculosis clinical features. METHODS: We developed a high-throughput platform to define phenotype-genotype relationships in M tuberculosis clinical isolates, which we tested on a set of 158 drug-sensitive M tuberculosis strains sampled from a large tuberculosis clinical study in Ho Chi Minh City, Viet Nam. We tagged the strains with unique genetic barcodes in multiplicate, allowing us to pool the strains for in-vitro competitive fitness assays across 16 host-relevant antibiotic and metabolic conditions. Relative fitness was quantified by deep sequencing, enumerating output barcode read counts relative to input normalised values. We performed a genome-wide association study to identify phylogenetically linked and monogenic mutations associated with the in-vitro fitness phenotypes. These genetic determinants were further associated with relevant clinical outcomes (cavitary disease and treatment failure) by calculating odds ratios (ORs) with binomial logistic regressions. We also assessed the population-level transmission of strains associated with cavitary disease and treatment failure using terminal branch length analysis of the phylogenetic data. FINDINGS: M tuberculosis clinical strains had diverse growth characteristics in host-like metabolic and drug conditions. These fitness phenotypes were highly heritable, and we identified monogenic and phylogenetically linked variants associated with the fitness phenotypes. These data enabled us to define two genetic features that were associated with clinical outcomes. First, mutations in Rv1339, a phosphodiesterase, which were associated with slow growth in glycerol, were further associated with treatment failure (OR 5·34, 95% CI 1·21-23·58, p=0·027). Second, we identified a phenotypically distinct slow-growing subclade of lineage 1 strains (L1.1.1.1) that was associated with cavitary disease (OR 2·49, 1·11-5·59, p=0·027) and treatment failure (OR 4·76, 1·53-14·78, p=0·0069), and which had shorter terminal branch lengths on the phylogenetic tree, suggesting increased transmission. INTERPRETATION: Slow growth under various antibiotic and metabolic conditions served as in-vitro intermediate phenotypes underlying the association between M tuberculosis monogenic and phylogenetically linked mutations and outcomes such as cavitary disease, treatment failure, and transmission potential. These data suggest that M tuberculosis growth regulation is an adaptive advantage for bacterial success in human populations, at least in some circumstances. These data further suggest markers for the underlying bacterial processes that contribute to these clinical outcomes. FUNDING: National Health and Medical Research Council/A∗STAR, National Institutes of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the Wellcome Trust Fellowship in Public Health and Tropical Medicine.

Interpreting an Archaean paleoenvironment through 3D imagery of microbialites.

While stromatolites, and to a lesser extent thrombolites, have been extensively studied in order to unravel Precambrian (>539 Ma) biological evolution, studies of clastic-dominated microbially induced sedimentary structures (MISS) are relatively scarce. The lack of a consolidated record of clastic microbialites creates questions about how much (and what) information on depositional and taphonomic settings can be gleaned from these fossils. We used µCT scanning, a non-destructive X-ray-based 3D imaging method, to reconstruct morphologies of ancient MISS and mat textures in two previously described coastal Archaean samples from the ~3.48 Ga Dresser Formation, Pilbara, Western Australia. The aim of this study was to test the ability of µCT scanning to visualize and make 3D measurements that can be used to interpret the biotic-environmental interactions. Fossil MISS including mat laminae with carpet-like textures in one sample and mat rip-up chips in the second sample were investigated. Compiled δ13C and δ34S analyses of specimens from the Dresser Fm. are consistent with a taxonomically diverse community that could be capable of forming such MISS. 3D measurements of fossil microbial mat chips indicate significant biostabilization and suggest formation in flow velocities >25 cm s-1. Given the stratigraphic location of these chips in a low-flow lagoonal layer, we conclude that these chips formed due to tidal influence, as these assumed velocities are consistent with recent modeling of Archaean tides. The success of µCT scanning in documenting these microbialite features validates this technique both as a first step analysis for rare samples prior to the use of more destructive techniques and as a valuable tool for gaining insight into microbialite taphonomy.

Impact of cardiorespiratory fitness and diabetes status on cardiovascular disease and all-cause mortality: An NHANES retrospective cohort study.

High cardiorespiratory fitness (CRF) is associated with decreased mortality in people with pre-diabetes (pre-DM) and diabetes mellitus (DM); however, the degree to which CRF attenuates the risk of cardiovascular disease (CVD)-related and all-cause mortality is unclear. Study objective: We examined the impact of CRF status on CVD-related morbidity and all-cause mortality in non-DM, Pre-DM, and DM populations. Design and setting: 13,968 adults from the Third US National Health and Nutrition Examination Survey (NHANES III) were stratified into non-DM, pre-DM, or DM groups based on HbA1c levels. VO2Max was calculated using the Fitness Registry and Importance of Exercise: A National Database (FRIEND) equation. Participants: Participants were categorized into tertiles of VO2Max; first VO2Max tertile was the lowest VO2Max and third VO2Max tertile was the highest. Main outcome measures: Cox regression was used to analyze the relationship between glycemic levels, VO2Max, and CVD-related and all-cause mortality. Results: Those with DM in the highest fitness tertile had CVD (HR 0.13; 95 % CI 0.06, 0.27; p < 0.0001) and all cause (HR 0.28; 95 % CI 0.21, 0.38; p < 0.0001) mortality rates as low or lower than those with pre-DM (CVD HR 1.02; 95 % CI 0.78, 1.33 p < 0.892; all cause HR 0.96; 95 % CI 0.83, 1.12; p < 0.5496) or non-DM (CVD HR 0.65; 95 % CI 0.52, 0.80; p < 0.0001; all cause HR 0.61; 95 % CI 0.55, 0.68; p < 0.0001) at lower fitness levels. Regardless of DM status, there was lower all-cause mortality with higher CRF levels. Conclusions: Higher fitness levels in DM individuals are associated with total and CVD mortality rates as low or lower than those without DM with lower fitness.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Culicoides Midge Abundance across Years: Modeling Inter-Annual Variation for an Avian Feeder and a Candidate Vector of Hemorrhagic Diseases in Farmed Wildlife.

(1) Background: Epizootic hemorrhagic disease virus (EHDV) and bluetongue virus (BTV) are orbiviruses that cause hemorrhagic disease (HD) with significant economic and population health impacts on domestic livestock and wildlife. In the United States, white-tailed deer (Odocoileus virginianus) are particularly susceptible to these viruses and are a frequent blood meal host for various species of Culicoides biting midges (Diptera: Ceratopogonidae) that transmit orbiviruses. The species of Culicoides that transmit EHDV and BTV vary between regions, and larval habitats can differ widely between vector species. Understanding how midges are distributed across landscapes can inform HD virus transmission risk on a local scale, allowing for improved animal management plans to avoid suspected high-risk areas or target these areas for insecticide control. (2) Methods: We used occupancy modeling to estimate the abundance of gravid (egg-laden) and parous (most likely to transmit the virus) females of two putative vector species, C. stellifer and C. venustus, and one species, C. haematopotus, that was not considered a putative vector. We developed a universal model to determine habitat preferences, then mapped a predicted weekly midge abundance during the HD transmission seasons in 2015 (July-October) and 2016 (May-October) in Florida. (3) Results: We found differences in habitat preferences and spatial distribution between the parous and gravid states for C. haematopotus and C. stellifer. Gravid midges preferred areas close to water on the border of well and poorly drained soil. They also preferred mixed bottomland hardwood habitats, whereas parous midges appeared less selective of habitat. (4) Conclusions: If C. stellifer is confirmed as an EHDV vector in this region, the distinct spatial and abundance patterns between species and physiological states suggest that the HD risk is non-random across the study area.

Amelioration of Anxiety Associated with Opioid Withdrawal by Activation of Spinal Mechanoreceptors Via Novel Heterodyned Whole Body Vibration.

Objectives: Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide. An important driving force for relapse is anxiety associated with opioid withdrawal. We hypothesized that our new technology, termed heterodyned whole-body vibration (HWBV) would ameliorate anxiety associated with OUD. Methods: Using a randomized, placebo (sham)-controlled, double-blind study design in an NIH-sponsored Phase 1 trial, we evaluated 60 male and 26 female participants diagnosed with OUD and undergoing treatment at pain and rehabilitation clinics. We utilized the Hamilton Anxiety Scale (HAM-A) and a daily visual analog scale anxiety rating (1-10) to evaluate anxiety. Subjects were treated for 10 min 5X/week for 4 weeks with either sham vibration (no interferential beat or harmonics) or HWBV (beats and harmonics). The participants also completed a neuropsychological test battery at intake and discharge. Results: In OUD subjects with moderate anxiety, there was a significant improvement in daily anxiety scores in the HWBV group compared to the sham treatment group (p=3.41 × 10-7). HAM-A scores in OUD participants at intake showed moderate levels of anxiety in OUD participants (HWBV group: 15.9 ± 1.6; Sham group: 17.8 ± 1.6) and progressively improved in both groups at discharge, but improvement was greater in the HWBV group (p=1.37 × 10-3). Furthermore, three indices of neuropsychological testing (mental rotations, spatial planning, and response inhibition) were significantly improved by HWBV treatment. Conclusions: These findings support HWBV as a novel, non-invasive, non-pharmacological treatment for anxiety associated with OUD.

QTL for the Kinematic Traits That Define the Arabidopsis Root Elongation Zone and Their Relationship to Gravitropism.

Cell expansion in a discrete region called the elongation zone drives root elongation. Analyzing time lapse images can quantify the expansion in kinematic terms as if it were fluid flow. We used horizontal microscopes to collect images from which custom software extracted the length of the elongation zone, the peak relative elemental growth rate (REGR) within it, the axial position of the REGR peak, and the root elongation rate. Automation enabled these kinematic traits to be measured in 1575 Arabidopsis seedlings representing 162 recombinant inbred lines (RILs) derived from a cross of Cvi and Ler ecotypes. We mapped ten quantitative trait loci (QTL), affecting the four kinematic traits. Three QTL affected two or more traits in these vertically oriented seedlings. We compared this genetic architecture with that previously determined for gravitropism using the same RIL population. The major QTL peaks for the kinematic traits did not overlap with the gravitropism QTL. Furthermore, no single kinematic trait correlated with quantitative descriptors of the gravitropism response curve across this population. In addition to mapping QTL for growth zone traits, this study showed that the size and shape of the elongation zone may vary widely without affecting the differential growth induced by gravity.

Impact of Aging on Cardiovascular Diseases: From Chronological Observation to Biological Insights: JACC Family Series.

Cardiovascular disease (CVD) has increasing challenges for human health with an increasingly aging population worldwide, imposing a significant obstacle to the goal of healthy aging. Rapid advancements in our understanding of biological aging process have shed new light on some important insights to aging-related diseases. Although numerous reviews delved into the mechanisms through which biological aging affects CVD and age-related diseases, most of these reviews relied heavily on research related to cellular and molecular processes often observed from animal experiments. Few reviews have provided insights that connect hypotheses regarding the biological aging process with the observed patterns of chronological aging-related impacts on CVD in human populations. The purpose of this review is to highlight some of the major questions in studies of aging-related CVD and provide our perspectives in the context of real-world patterns of CVD with multidimensional information and potential biological insights.