Effects of Harmful Algal Blooms on Amphibians and Reptiles are Under-Reported and Under-Represented.

Harmful algal blooms (HABs) are a persistent and increasing problem globally, yet we still have limited knowledge about how they affect wildlife. Although semi-aquatic and aquatic amphibians and reptiles have experienced large declines and occupy environments where HABs are increasingly problematic, their vulnerability to HABs remains unclear. To inform monitoring, management, and future research, we conducted a literature review, synthesized the studies, and report on the mortality events describing effects of cyanotoxins from HABs on freshwater herpetofauna. Our review identified 37 unique studies and 71 endpoints (no-observed-effect and lowest-observed-effect concentrations) involving 11 amphibian and 3 reptile species worldwide. Responses varied widely among studies, species, and exposure concentrations used in experiments. Concentrations causing lethal and sublethal effects in laboratory experiments were generally 1 to 100 µg/L, which contains the mean value of reported HAB events but is 70 times less than the maximum cyanotoxin concentrations reported in the environment. However, one species of amphibian was tolerant to concentrations of 10,000 µg/L, demonstrating potentially immense differences in sensitivities. Most studies focused on microcystin-LR (MC-LR), which can increase systemic inflammation and harm the digestive system, reproductive organs, liver, kidneys, and development. The few studies on other cyanotoxins illustrated that effects resembled those of MC-LR at similar concentrations, but more research is needed to describe effects of other cyanotoxins and mixtures of cyanotoxins that commonly occur in the environment. All experimental studies were on larval and adult amphibians; there were no such studies on reptiles. Experimental work with reptiles and adult amphibians is needed to clarify thresholds of tolerance. Only nine mortality events were reported, mostly for reptiles. Given that amphibians likely decay faster than reptiles, which have tissues that resist decomposition, mass amphibian mortality events from HABs have likely been under-reported. We propose that future efforts should be focused on seven major areas, to enhance our understanding of effects and monitoring of HABs on herpetofauna that fill important roles in freshwater and terrestrial environments. Environ Toxicol Chem 2024;00:1-14. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Targeting a microbiota Wolbachian aminoacyl-tRNA synthetase to block its pathogenic host.

The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, Wolbachia, a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt Wolbachia's symbiosis with pathogens using boron-based compounds targeting an unprecedented Wolbachia enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti-Wolbachia efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind Wolbachia LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.

Self-reported food liking and wanting: A factor analytic study of ratings across 49 consecutive days.

Reward responses to food are thought to play an important role in highly palatable food overconsumption. In animal models, food reward responses can be decoupled into unique "liking" (in the moment enjoyment) and "wanting" (motivation/craving) components. However, research on liking and wanting has been hampered by uncertainty regarding whether liking and wanting can be reliably separated in humans. We used factor analysis to test whether ratings of liking and wanting could be empirically separated in women assessed across 49 consecutive days. Female participants (N = 688; ages 15-30) from the Michigan State University Twin Registry reported liking and wanting of foods consumed that day, and wanting of foods not consumed that day, separately for sweets (e.g., cookies), fast food (e.g., French fries), carbohydrates (e.g., bread), and whole foods (fruit, plain chicken) each evening for 49 consecutive days. We examined both average levels and daily levels of liking/wanting across the 49-day period that captured individual differences in liking/wanting over time. Across both types of analyses, liking and wanting for foods that were eaten formed a single factor rather than separate, dissociable factors, while wanting of foods not eaten formed an independent factor. At the daily level, a liking/wanting factor emerged for each individual food category (e.g., liking/wanting sweets), whereas in average analyses, a single factor emerged that collapsed across all food types (i.e., liking/wanting of all foods). Results suggest individuals have difficulty distinguishing between liking and wanting of foods they have eaten on that day but may be able to more reliably separate wanting of foods they have not consumed.

Transient inhibition of type I interferon enhances CD8 + T cell stemness and vaccine protection.

Developing vaccines that promote CD8 + T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1 + stem cell-like memory T (T SCM ) cells are important determinants of long-lived memory. Yet, the developmental requirements for T SCM formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive T SCM cell generation. T SCM cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (T PEX ) cellular state concomitant with viral clearance. T SCM differentiation correlated with T cell retention within the lymph node paracortex, due to increased CXCR3 chemokine abundance which disrupted gradient formation. These affects were due a counterintuitive increase in IFNψ, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific T SCM differentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function. HIGHLIGHTS: Early, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (T SCM ) cell differentiation without establishing chronic infection. T SCM and precursor of exhausted (T PEX ) cellular states are distinguished transcriptionally and by cell surface markers. Developmentally, T SCM cell differentiation occurs via a transition from a T PEX state coinciding with viral clearance. Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple T SCM differentiation to cell retention within the T cell paracortex of the lymph node. Specific promotion of T SCM cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.

Epigenetic regulation of the oxytocin system as an indicator of adaptation to over-controlling parenting and psychosocial functioning in adulthood.

The oxytocin system plays a role in social stress adaptation, and this role is likely to be particularly important in adolescence. One method of regulating the oxytocin system is through DNA methylation in the promoter of the oxytocin receptor gene (OXTRm), which reduces the gene's expression. This multi-method, longitudinal study, using a diverse community sample of 184 adolescents followed from age 13-28, examined the links between OXTRm and exposure to over-controlling parenting in adolescence and conflict with romantic partners and internalizing symptoms in adulthood. Female, but not male, adolescents who were exposed to psychologically controlling parenting at age 13 had lower levels of OXTRm at site -924 at age 28. Reduced OXTRm at site -924 was associated with greater romantic partner-reported relationship conflict at age 27, and reduced OXTRm at site -934 was marginally associated with greater participant-reported conflict for males. Reduced OXTRm at site -924 was also associated with fewer internalizing symptoms at ages 24-25. These results in adulthood are consistent with an upregulated oxytocin system reducing the salience of negative socioemotional stimuli. Overall, findings are consistent with oxytocin playing a role in the stress response system, and more specifically, by helping us to adapt to social environments like parenting and romantic relationships, reducing the salience of negativity, and reducing risk for common emotional problems.

Structural and Molecular Imaging-based Characterization of Soft Tissue and Vascular Calcification in Hyperphosphatemic Familial Tumoral Calcinosis.

Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. In this study, we systematically characterized and quantified macro- and micro-calcification in an HFTC cohort using computed tomography (CT) and 18F-sodium fluoride positron emission tomography/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on four phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (e.g., total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of metabolic activity (e.g., mean standardized uptake values). Microcalcification scores (mCSs) were calculated for the vasculature of six patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs. quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the distal aorta, carotid, and coronaries in 50%, 70%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of macro- and micro-calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride positron emission tomography/computed tomography scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. 82% of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active versus stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment.

Perspectives of Gender-Diverse Youth and Caregivers Facing Gender-Affirming Medical Intervention Bans.

Purpose: In the past 2 years, nearly all 50 states have debated bills seeking to ban minors' access to gender-affirming medical interventions, with many being passed into law. This study documents gender-diverse youths' (GDY) and their caregivers' experiences as they grapple with how such laws impact their families. Methods: Sixteen GDY and 16 caregivers participating in a longitudinal study of the impact of gender-affirming care on GDYs' well-being were interviewed about how the legal and social discourse was impacting them and their families. When interviewed, some participants had completed only the initial intake, others had completed the intake and an initial medical consultation, and a few had recently started gender-affirming hormones. Thematic analysis was used to identify common threads in the youths' and caregivers' experiences. Results: Four main themes were identified: Direct effects of losing access to gender-affirming medical interventions, reflecting how losing access to care would impact well-being; growing hostility toward the gender-diverse community, noting increasing social negativity; personal and social upheaval, reflecting the many aspects of families' lives affected; and galvanization into social action, documenting drives to effect social change. Conclusion: Laws banning gender-affirming medical interventions impact GDY and their families beyond limiting access to medical care. They increase the social stressors, cause social network disruptions, increase hostility toward the gender-diverse community, and lead some GDY and caregivers to engage more politically to protect their community. Gender-affirming health care providers need to recognize how the social and political environment impact GDY and their families to provide high-quality, person-centered care.

Virus-like particles displaying the mature C-terminal domain of filamentous hemagglutinin are immunogenic and protective against Bordetella pertussis respiratory infection in mice.

Bordetella pertussis, the bacterium responsible for whooping cough, remains a significant public health challenge despite the existing licensed pertussis vaccines. Current acellular pertussis vaccines, though having favorable reactogenicity and efficacy profiles, involve complex and costly production processes. In addition, acellular vaccines have functional challenges such as short-lasting duration of immunity and limited antigen coverage. Filamentous hemagglutinin (FHA) is an adhesin of B. pertussis that is included in all multivalent pertussis vaccine formulations. Antibodies to FHA have been shown to prevent bacterial attachment to respiratory epithelial cells, and T cell responses to FHA facilitate cell-mediated immunity. In this study, FHA's mature C-terminal domain (MCD) was evaluated as a novel vaccine antigen. MCD was conjugated to virus-like particles via SpyTag-SpyCatcher technology. Prime-boost vaccine studies were performed in mice to characterize immunogenicity and protection against the intranasal B. pertussis challenge. MCD-SpyVLP was more immunogenic than SpyTag-MCD antigen alone, and in Tohama I strain challenge studies, improved protection against challenge was observed in the lungs at day 3 and in the trachea and nasal wash at day 7 post-challenge. Furthermore, a B. pertussis strain encoding genetically inactivated pertussis toxin was used to evaluate MCD-SpyVLP vaccine immunity. Mice vaccinated with MCD-SpyVLP had significantly lower respiratory bacterial burden at both days 3 and 7 post-challenge compared to mock-vaccinated animals. Overall, these data support the use of SpyTag-SpyCatcher VLPs as a platform for use in vaccine development against B. pertussis and other pathogens.

Tire-derived contaminants 6PPD and 6PPD-Q: Analysis, sample handling, and reconnaissance of United States stream exposures.

The environmental ubiquity of tire and road wear particles (TRWP) underscores the need to understand the occurrence, persistence, and environmental effects of tire-related chemicals in aquatic ecosystems. One such chemical is 6PPD-quinone (6PPD-Q), a transformation product of the tire antioxidant 6PPD. In urban stormwater runoff 6PPD-Q can exceed acute toxicity thresholds for several salmonid species and is being implicated in significant coho salmon losses in the Pacific Northwest. There is a critical need to understand the prevalence of 6PPD-Q across watersheds to identify habitats heavily affected by TRWPs. We conducted a reconnaissance of 6PPD and 6PPD-Q in surface waters across the United States from sites (N = 94) with varying land use (urban, agricultural, and forested) and streamflow to better understand stream exposures. A rapid, low-volume direct-inject, liquid chromatography mass spectrometry method was developed for the quantitation of 6PPD-Q and screening for 6PPD. Laboratory holding times, bottle material, headspace, and filter materials were investigated to inform best practices for 6PPD-Q sampling and analysis. Glass bottles with PTFE-lined caps minimized sorption and borosilicate glass fiber filters provided the highest recovery. 6PPD-Q was stable for at least 5 months in pure laboratory solutions and for 75 days at 5 °C with minimal headspace in the investigated surface water and stormwaters. Results also indicated samples can be frozen to extend holding times. 6PPD was not detected in any of the 526 analyzed samples and there were no detections of 6PPD-Q at agricultural or forested sites. 6PPD-Q was frequently detected in stormwater (57%, N = 90) and from urban impacted sites (45%, N = 276) with concentrations ranging from 0.002 to 0.29 µg/L. The highest concentrations, above the lethal level for coho salmon, occurred during stormwater runoff events. This highlights the importance of capturing episodic runoff events in urban areas near ecologically relevant habitat or nursery grounds for sensitive species.

Treponema pallidum genetic diversity and its implications for targeted vaccine development: A cross-sectional study of early syphilis cases in Southwestern Colombia.

BACKGROUND: Venereal syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (TPA), is surging worldwide, underscoring the need for a vaccine with global efficacy. Vaccine development requires an understanding of syphilis epidemiology and clinical presentation as well as genomic characterization of TPA strains circulating within at-risk populations. The aim of this study was to describe the clinical, demographic, and molecular features of early syphilis cases in Cali, Colombia. METHODS AND FINDINGS: We conducted a cross-sectional study to identify individuals with early syphilis (ES) in Cali, Colombia through a city-wide network of public health centers, private sector HIV clinics and laboratory databases from public health institutions. Whole blood (WB), skin biopsies (SB), and genital and oral lesion swabs were obtained for measurement of treponemal burdens by polA quantitative polymerase chain reaction (qPCR) and for whole-genome sequencing (WGS). Among 1,966 individuals screened, 128 participants met enrollment criteria: 112 (87%) with secondary (SS), 15 (12%) with primary (PS) and one with early latent syphilis; 66/128 (52%) self-reported as heterosexual, while 48 (38%) were men who have sex with men (MSM). Genital ulcer swabs had the highest polA copy numbers (67 copies/µl) by qPCR with a positivity rate (PR) of 73%, while SS lesions had 42 polA copies/µl with PR of 62%. WB polA positivity was more frequent in SS than PS (42% vs 7%, respectively; p = 0.009). Isolation of TPA from WB by rabbit infectivity testing (RIT) was achieved in 5 (56%) of 9 ES WB samples tested. WGS from 33 Cali patient samples, along with 10 other genomic sequences from South America (9 from Peru, 1 from Argentina) used as comparators, confirmed that SS14 was the predominant clade, and that half of all samples had mutations associated with macrolide (i.e., azithromycin) resistance. Variability in the outer membrane protein (OMP) and vaccine candidate BamA (TP0326) was mapped onto the protein's predicted structure from AlphaFold. Despite the presence of mutations in several extracellular loops (ECLs), ECL4, an immunodominant loop and proven opsonic target, was highly conserved in this group of Colombian and South American TPA isolates. CONCLUSIONS: This study offers new insights into the sociodemographic and clinical features of venereal syphilis in a highly endemic area of Colombia and illustrates how genomic sequencing of regionally prevalent TPA strains can inform vaccine development.

New Pathways in Syphilis Vaccine Development.

ABSTRACT: The New Pathways in Syphilis Vaccine Development meeting was held prior to the start of the STI & HIV 2023 World Congress as a pre-meeting symposium to highlight recent advances in the development of an effective syphilis vaccine and discuss the challenges still faced by investigators. Internationally renowned public health officials, clinical investigators, and basic researchers from academia, government, and community-based organizations met on the 24th of July 2023 in Chicago, Illinois. Four speakers discussed key research findings in syphilis vaccine development, which included antigen selection, identification of epitopes associated with protective immunity, and delivery platforms, with great emphasis on development of chimeric antigens. Significant progress was also shown on the elucidation of Treponema pallidum genomes from virtually all continents to assess the diversity in vaccine candidates of the syphilis spirochete.

Atrial Fibrillation and Older Age Predict Serum Brain-Derived Neurotrophic Factor Levels Among Patients With Heart Failure.

BACKGROUND: Predictors have not been determined of serum brain-derived neurotrophic factor (BDNF) levels among patients with heart failure (HF). OBJECTIVE: The primary purpose was to evaluate history of atrial fibrillation, age, gender, and left ventricular ejection fraction as predictors of serum BDNF levels at baseline, 10 weeks, and 4 and 8 months after baseline among patients with HF. METHODS: This study was a retrospective cohort analyses of 241 patients with HF. Data were retrieved from the patients' health records (coded history of atrial fibrillation, left ventricular ejection fraction), self-report (age, gender), and serum BDNF. Linear multiple regression analyses were conducted. RESULTS: One hundred three patients (42.7%) had a history of atrial fibrillation. History of atrial fibrillation was a significant predictor of serum BDNF levels at baseline (ß = -0.16, P = .016), 4 months (ß = -0.21, P = .005), and 8 months (ß = -0.19, P = .015). Older age was a significant predictor at 10 weeks (ß = -0.17, P = .017) and 4 months (ß = -0.15, P = .046). CONCLUSIONS: Prospective studies are needed to validate these results. Clinicians need to assess patients with HF for atrial fibrillation and include treatment of it in management plans.

Predictive utility of ANCA positivity and antigen specificity in the assessment of kidney disease in paediatric-onset small vessel vasculitis.

OBJECTIVES: The objective of this study is to evaluate whether anti-neutrophil cytoplasmic antibody (ANCA) seropositivity and antigen specificity at diagnosis have predictive utility in paediatric-onset small vessel vasculitis. METHODS: Children and adolescents with small vessel vasculitis (n=406) stratified according to the absence (n=41) or presence of ANCA for myeloperoxidase (MPO) (n=129) and proteinase-3 (PR3) (n=236) were compared for overall and kidney-specific disease activity at diagnosis and outcomes between 1 and 2 years using retrospective clinical data from the ARChiVe/Paediatric Vasculitis Initiative registry to fit generalised linear models. RESULTS: Overall disease activity at diagnosis was higher in PR3-ANCA and MPO-ANCA-seropositive individuals compared with ANCA-negative vasculitis. By 1 year, there were no significant differences, based on ANCA positivity or specificity, in the likelihood of achieving inactive disease (~68%), experiencing improvement (≥87%) or acquiring damage (~58%). Similarly, and in contrast to adult-onset ANCA-associated vasculitis, there were no significant differences in the likelihood of having a relapse (~11%) between 1 and 2 years after diagnosis. Relative to PR3-ANCA, MPO-ANCA seropositivity was associated with a higher likelihood of kidney involvement (OR 2.4, 95% CI 1.3 to 4.7, p=0.008) and severe kidney dysfunction (Kidney Disease Improving Global Outcomes (KDIGO) stages 4-5; OR 6.04, 95% CI 2.77 to 13.57, p<0.001) at onset. Nonetheless, MPO-ANCA seropositive individuals were more likely to demonstrate improvement in kidney function (improved KDIGO category) within 1 year of diagnosis than PR3-ANCA seropositive individuals with similarly severe kidney disease at onset (p<0.001). CONCLUSIONS: The results of this study suggest important paediatric-specific differences in the predictive value of ANCA compared with adult patients that should be considered when making treatment decisions in this population.

LAIR1 prevents excess inflammatory tissue damage in S. aureus skin infection and Cutaneous T-cell Lymphoma.

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the causative immune defect is unclear. We previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice do not have a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably, Lair1 KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalent S. aureus phagocytosis compared to WT. These findings support a model in which lack of LAIR1 signaling causes an excessive inflammatory response that does not improve infection control. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection.

Exploring the Application of SiteMap and Site Finder for Focused Cryptic Pocket Identification.

The characterization of cryptic pockets has been elusive, despite substantial efforts. Computational modeling approaches, such as molecular dynamics (MD) simulations, can provide atomic-level details of binding site motions and binding pathways. However, the time scale that MD can achieve at a reasonable cost often limits its application for cryptic pocket identification. Enhanced sampling techniques can improve the efficiency of MD simulations by focused sampling of important regions of the protein, but prior knowledge of the simulated system is required to define the appropriate coordinates. In the case of a novel, unknown cryptic pocket, such information is not available, limiting the application of enhanced sampling techniques for cryptic pocket identification. In this work, we explore the ability of SiteMap and Site Finder, widely used commercial packages for pocket identification, to detect focus points on the protein and further apply other advanced computational methods. The information gained from this analysis enables the use of computational modeling, including enhanced MD sampling techniques, to explore potential cryptic binding pockets suggested by SiteMap and Site Finder. Here, we examined SiteMap and Site Finder results on 136 known cryptic pockets from a combination of the PocketMiner dataset (a recently curated set of cryptic pockets), the Cryptosite Set (a classic set of cryptic pockets), and Natural killer group 2D (NKG2D, a protein target where a cryptic pocket is confirmed). Our findings demonstrate the application of existing, well-studied tools in efficiently mapping potential regions harboring cryptic pockets.

Transcranial Direct Current Stimulation to Ameliorate Post-Stroke Cognitive Impairment.

Post-stroke cognitive impairment is a common and disabling condition with few effective therapeutic options. After stroke, neural reorganization and other neuroplastic processes occur in response to ischemic injury, which can result in clinical improvement through spontaneous recovery. Neuromodulation through transcranial direct current stimulation (tDCS) is a promising intervention to augment underlying neuroplasticity in order to improve cognitive function. This form of neuromodulation leverages mechanisms of neuroplasticity post-stroke to optimize neural reorganization and improve function. In this review, we summarize the current state of cognitive neurorehabilitation post-stroke, the practical features of tDCS, its uses in stroke-related cognitive impairment across cognitive domains, and special considerations for the use of tDCS in the post-stroke patient population.

Antibody-mediated immunological memory correlates with long-term Lyme veterinary vaccine protection in mice.

Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne illness in the United States. Despite the rise in Lyme disease incidence, there is no vaccine against B. burgdorferi approved for human use. Little is known about the immune correlates of protection needed to prevent Lyme disease. In this work, a mouse model was used to characterize the immune response and compare the protection provided by two USDA-approved vaccines for use in canines: Duramune (bacterin vaccine) and Vanguard crLyme (subunit vaccine composed of two outer surface proteins, OspA and OspC). C3H/HeNCrl mice were immunized with two doses of either Duramune or Vanguard, and immune responses and protection against B. burgdorferi were assessed in short (35 days) and long-term (120 days) studies. Flow cytometry, ELISPOT detection of antibody-producing cells, and antibody affinity studies were performed to identify correlates of vaccine-mediated protection. Both vaccines induced humoral responses, with high IgG titers against B. burgdorferi. However, the levels of anti-B. burgdorferi antibodies decayed over time in Vanguard-vaccinated mice. While both vaccines triggered the production of antibodies against both OspA and OspC, antibody levels against these proteins were also lower in Vanguard-vaccinated mice 120 days post-vaccination. Both vaccines only provided partial protection against B. burgdorferi at the dose used in this model. The protection provided by Duramune was superior to Vanguard 120 days post-vaccination, and was characterized by higher antibody titers, higher abundance of long-lived plasma cells, and higher avidity antibodies than Vanguard. Overall, these studies provide insights into the importance of the humoral memory response to veterinary vaccines against Lyme disease and will help inform the development of future human vaccines.

Null models confirm nest site fidelity by male smallmouth bass, Micropterus dolomieu.

BACKGROUND: Many animals appear to preferentially renest in proximity to a site they previously occupied. Evidence of nest fidelity is often inferred from a right skewed distribution of distances between the nests of individuals that breed in two consecutive reproduction episodes, where many individuals nest some arbitrarily close distance to their prior nest and others, in the extended right tail of the distribution, nest far from the nest they previously occupied. Because right skewed distributions of inter-nest distances can arise even when individuals choose nest locations randomly, however, such inferences are prone to error. The importance of null models-used to generate patterns of individual inter-nest distances by processes that do not involve site attachment-for inferences about site fidelity has been known for decades but is still often unappreciated or ignored. METHODS: The right skewed distributions of inter-nest distances observed in two earlier studies of male smallmouth bass (Micropterus dolomieu) suggest prima facie that males exhibit nest site fidelity between annual reproduction episodes, but patterns of inter-nest distances have yet to be compared to an adequate null model. Here, we evaluate the nest site fidelity of marked male M. dolomieu in a decade-long dataset, where we apply a randomization procedure based on the rencontre probability problem to generate null models. Eight observed distributions of individual, annual inter-nest distances are compared to a year-specific null model to determine whether random processes are sufficient to explain the observed distributions of inter-nest distances. RESULTS: Through contrasts between observed annual inter-nest distances and results derived from null models that imposed realistic constraints on behavior, we show that some males were undoubtedly nest-site faithful. To reinforce the utility of null models and to make these kinds of models more accessible, we also provide a supplemental tutorial. The tutorial illustrates how random site choices, subject to common ecological and behavioral constraints, and even how distance is measured, can produce patterns of inter-nest distances that falsely imply nest site fidelity, or a lack of fidelity. The R code needed to reproduce these null models is included. The inference errors evident in our examples generalize to other forms of site fidelity, such as the apparent patch fidelity of certain sea bird foragers. CONCLUSIONS: The comparisons of observed distributions of inter-nest distances with those generated by null models imply that, as suggested in prior studies, male M. dolomieu indeed exhibit annual nest site fidelity. Procedures like those we apply are necessary first steps in analyses when distributions of distances between the nests of individuals in consecutive reproduction episodes are used to infer nest-site fidelity. Why male M. dolomieu are site faithful is a question yet to be answered.