Rapid sp3-Enriched Scaffold Generation via a Selective Aziridine Amide Ring-Opening Reaction.

Sp3-enriched small molecules play a critical role in developing drug candidates. While designing analogues with greater sp3 character, a methodology utilizing a less explored cyclic-aziridine amide ring-opening reaction to generate sp3-enriched scaffolds has been developed and reported. This methodology enables rapid access to substructures with higher fsp3 values, attracting greater attention within the past few decades. The reaction exhibits a wide reaction scope, featuring a highly sterically hindered phenolic ether, thiophenolic ethers, protected aniline formations, and aliphatic/heteroaromatic ring-containing aziridine amides as substrates. Additionally, this reaction provides access to congested tertiary ether formations through regioselective transformation, applicable to an extensive range of drug discovery targets, construction of complex small molecules, and natural product syntheses. The scaffolds developed show improved physicochemical properties.

Session Reactions Scale-3: Initial psychometric evidence.

Objective: This study aimed to develop an updated brief self-report post-session measure, suitable for collecting systematic feedback on clients' session reactions in the context of measurement-based care (MBC). Method: The Session Reactions Scale-3 (SRS-3; 33 items) was developed by extending and adjusting the Revised Session Reactions Scale. In Study 1, the psychometric properties of the SRS-3 were tested on N = 242 clients. In Study 2, a brief version of the SRS-3 (SRS-3-B; 15 items) was developed using a combination of conceptual, empirical, and pragmatic criteria. In Study 3, the psychometric properties of the SRS-3-B were tested on a new sample of N = 265 clients. Results: Exploratory factor analysis supported the use of the SRS-3-B as a two-factor (helpful reactions, hindering reactions) or unidimensional (overall session evaluation) instrument. The SRS-3-B was meaningfully related to another process measure (Individual Therapy Process Questionnaire) both on the item and factor levels. Conclusions: The SRS-3-B is a reliable process measure to elicit rich and clinically meaningful feedback from clients within the MBC context and as a research instrument to assess the helpful and hindering aspects of therapy sessions.

The Impact of Different Thematic Apperception Test Administration Methods on Narrative Length and Story Richness as Measured by the Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G).

The Thematic Apperception Test (TAT) is the second most commonly used performance-based task in clinical practice. However, traditional TAT administration is time-consuming and raises accessibility issues. This study examines the effect of administration modifications (i.e., examiner handwriting versus typing, examiner recording versus participant recording, and re-prompting versus no re-prompting) on narrative length and richness as measured by the Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G). A four-card TAT protocol was administered to 150 college students under one of five conditions. The resulting narratives were scored by two trained raters using the SCORS-G. MANOVA procedures showed (a) no significant differences between examiner handwriting versus typing; (b) the shortest, blandest narratives were produced when the examiner recorded the narratives without re-prompting; and (c) the longest, richest narratives were produced when the participant typed the narratives with re-prompts on the computer screen. Clinical and research implications and future directions will be discussed.

Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

Comparative study of different SES neighborhood clinics for health literacy and internet access.

Background: As healthcare services are increasingly dependent on patient utilization of technology to effectively deliver services, the digital divide has the potential to exacerbate health disparities if health literacy and internet access present formidable barriers to patient use of technology. Methods: We examined the differences in health literacy and internet access between lower and upper SES neighborhood primary-care clinics in Northeast Florida. The REALM-SF for health literacy was used to assess health literacy and census survey questions were used to assess internet and technology access, during the Fall, 2020. The clinics were affiliated with a safety-net hospital in a major city in Southeastern U.S. Results: Analysis of key demographic data confirmed that the responding patients from economically disadvantaged neighborhood clinics resided in economically disadvantaged zip codes (307 responding patients lived in lower SES neighborhoods) and did have lower education levels (3% of the patients from Upper SES clinics had 11 grade or lower education, compared to 21%-29% of patients from Lower SES clinics). Patient health literacy significantly differed between clinics located in economically disadvantaged neighborhoods and clinics located in more affluent neighborhoods, with Upper SES clinics being 2.4 times more likely to have 9th grade or higher reading level. Access to internet technology was also higher in the Upper SES clinics, with 59% of respondents from Upper SES clinics versus 32%-40% from Lower SES clinics owning a computer or an IPAD. Conclusion: Results of this study have important implications for patient-engaged use of digital technology for health. Healthcare and public health clinics should be aware of the difference in health literacy and internet access when implementing technology-based services, so that advances in medicine, including precision medicine and telehealth, can be disseminated and implemented with broad populations, including disadvantaged groups.

Longitudinal measurement invariance of the Behavioral Health Measure in a clinical sample.

The practice of routine outcome monitoring (ROM) has grown in popularity and become a fixture in feedback-supported clinical practice and research. However, if the interpretation of an ROM measure changes over time, treatment outcome scores may be inaccurate and produce erroneous or misguided interpretations of client progress and therapist efficacy. The current study examined whether factorial invariance held when using the Behavioral Health Measure (BHM-20) longitudinally in a clinical sample (n = 12,467). Using multidimensional item response theory-based models for the investigation of the BHM-20 factor structure, at a single time point and then longitudinally. Based on the original factor structure of the BHM-20 a unidimensional model, a three-factor orthogonal model, and a three-factor correlated model were fit to the data, indicating poor model fit with the proposed three-factor or unidimensional models. Next, using exploratory factor analysis and subsequent multidimensional item response theory procedures, a new 4-factor (General Distress, Life Functioning, Anxiety, and Alcohol/Drug Use) model was proposed with improved model-fit statistics. Finally, when testing the longitudinal invariance of the BHM-17 over 10 sessions of treatment, it was found to be fully consistent. The current study proposes the use of a 17-item, 4-factor model for a new understanding of the BHM-17. Implications for use in ROM and limitations are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Risks posed by SARS-CoV-2 to North American bats during winter fieldwork.

The virus that causes COVID-19 likely evolved in a mammalian host, possibly Old-World bats, before adapting to humans, raising the question of whether reverse zoonotic transmission to bats is possible. Wildlife management agencies in North America are concerned that the activities they authorize could lead to transmission of SARS-CoV-2 to bats from humans. A rapid risk assessment conducted in April 2020 suggested that there was a small but significant possibility that SARS-CoV-2 could be transmitted from humans to bats during summer fieldwork, absent precautions. Subsequent challenge studies in a laboratory setting have shed new information on these risks, as has more detailed information on human epidemiology and transmission. This inquiry focuses on the risk to bats from winter fieldwork, specifically surveys of winter roosts and handling of bats to test for white-nose syndrome or other research needs. We use an aerosol transmission model, with parameter estimates both from the literature and from formal expert judgment, to estimate the risk to three species of North American bats, as a function of several factors. We find that risks of transmission are lower than in the previous assessment and are notably affected by chamber volume and local prevalence of COVID-19. Use of facemasks with high filtration efficiency or a negative COVID-19 test before field surveys can reduce zoonotic risk by 65 to 88%.

The scope and severity of white-nose syndrome on hibernating bats in North America.

Assessing the scope and severity of threats is necessary for evaluating impacts on populations to inform conservation planning. Quantitative threat assessment often requires monitoring programs that provide reliable data over relevant spatial and temporal scales, yet such programs can be difficult to justify until there is an apparent stressor. Leveraging efforts of wildlife management agencies to record winter counts of hibernating bats, we collated data for 5 species from over 200 sites across 27 U.S. states and 2 Canadian provinces from 1995 to 2018 to determine the impact of white-nose syndrome (WNS), a deadly disease of hibernating bats. We estimated declines of winter counts of bat colonies at sites where the invasive fungus that causes WNS (Pseudogymnoascus destructans) had been detected to assess the threat impact of WNS. Three species undergoing species status assessment by the U.S. Fish and Wildlife Service (Myotis septentrionalis, Myotis lucifugus, and Perimyotis subflavus) declined by more than 90%, which warrants classifying the severity of the WNS threat as extreme based on criteria used by NatureServe. The scope of the WNS threat as defined by NatureServe criteria was large (36% of Myotis lucifugus range) to pervasive (79% of Myotis septentrionalis range) for these species. Declines for 2 other species (Myotis sodalis and Eptesicus fuscus) were less severe but still qualified as moderate to serious based on NatureServe criteria. Data-sharing across jurisdictions provided a comprehensive evaluation of scope and severity of the threat of WNS and indicated regional differences that can inform response efforts at international, national, and state or provincial jurisdictions. We assessed the threat impact of an emerging infectious disease by uniting monitoring efforts across jurisdictional boundaries and demonstrated the importance of coordinated monitoring programs, such as the North American Bat Monitoring Program (NABat), for data-driven conservation assessments and planning.

Alcance y Severidad del Síndrome de Nariz Blanca en los Murciélagos Hibernando en América del Norte Resumen La evaluación del alcance y la severidad de las amenazas es necesaria para los análisis de impacto sobre las poblaciones que se usan para orientar a la planeación de la conservación. La evaluación cuantitativa de amenazas con frecuencia requiere de programas de monitoreo que proporcionen datos confiables en escalas espaciales y temporales, aunque dichos programas pueden ser difíciles de justificar hasta que exista un estresante aparente. Gracias a una movilización de esfuerzos de las agencias de manejo de fauna para registrar los conteos invernales de murciélagos hibernadores, recopilamos datos para cinco especies en más de 200 sitios a lo largos de 27 estados de EUA y dos provincias canadienses entre 1995 y 2018 para determinar el impacto del síndrome de nariz blanca (SNB), una enfermedad mortal de los murciélagos hibernadores. Estimamos declinaciones en los conteos invernales de las colonias de murciélagos en sitios en donde el hongo invasivo que ocasiona el SNB (Pseudogymnoascus destructans) había sido detectado para evaluar el impacto de amenaza del SNB. Tres especies que se encuentran bajo valoración por parte del Servicio de Pesca y Vida Silvestre de los EUA (Myotis septentrionalis, Myotis lucifugus y Perimyotis subflavus) tuvieron una declinación de más del 90%, lo que justifica la clasificación de la severidad de la amenaza del SNB como extrema con base en el criterio usado por NatureServe. El alcance de la amenaza del SNB definido por el criterio de NatureServe fue desde amplio (36% de la distribución de Myotis lucifugus) hasta dominante (79% de la distribución de Myotis septentrionalis) para estas especies. Las declinaciones de otras dos especies (Myotis sodalis y Eptesicus fuscus) fueron menos severas, pero de igual manera quedaron clasificadas desde moderada hasta seria con base en los criterios de NatureServe. El intercambio de datos entre las jurisdicciones proporcionó una evaluación completa del alcance y la severidad de la amenaza del SNB e indicó las diferencias regionales que pueden guiar a los esfuerzos de respuesta realizados en las jurisdicciones internacionales, nacionales, estatales o provinciales. Evaluamos el impacto de amenaza de una enfermedad infecciosa emergente mediante la combinación de los esfuerzos de monitoreo que sobrepasan fronteras jurisdiccionales y demostramos la importancia que tienen para la planeación y la evaluación basadas en datos de la conservación los programas de monitoreo coordinados, como el Programa de Monitoreo de los Murciélagos Norteamericanos (NABat).

Psychotherapy racial/ethnic disparities in treatment outcomes: The role of university racial/ethnic composition.

OBJECTIVE: Mental health disparities between racial/ethnic minorities (REM) and White individuals are well documented. These disparities extend into psychotherapy and have been observed among clients receiving care at university/college counseling centers. However, less is known about if campus RE composition affects outcomes from psychotherapy for REM and White clients. METHOD: This study examined psychotherapy outcomes from 16,011 clients who engaged in services at 33 university/college counseling centers. Each of these clients completed the Behavioral Health Measure as a of part routine practice. Campus RE composition was coded from publicly available data. RESULTS: The results demonstrated that White clients had better therapy outcomes than REM clients when they were at campuses where there were more White students. For universities 1 SD below the mean percentage of White students, the average difference in therapy outcomes for White and REM clients was Cohen's d = .21 (with White students experiencing more improvement); however, for universities 1 SD above the mean, the between group outcome disparity was greater (Cohen's d = .38). CONCLUSION: Therapists and higher education professionals should consider environmental impacts on counseling services. Implications for higher education, counseling centers, and mental health disparities are provided. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

NABat: A top-down, bottom-up solution to collaborative continental-scale monitoring.

Collaborative monitoring over broad scales and levels of ecological organization can inform conservation efforts necessary to address the contemporary biodiversity crisis. An important challenge to collaborative monitoring is motivating local engagement with enough buy-in from stakeholders while providing adequate top-down direction for scientific rigor, quality control, and coordination. Collaborative monitoring must reconcile this inherent tension between top-down control and bottom-up engagement. Highly mobile and cryptic taxa, such as bats, present a particularly acute challenge. Given their scale of movement, complex life histories, and rapidly expanding threats, understanding population trends of bats requires coordinated broad-scale collaborative monitoring. The North American Bat Monitoring Program (NABat) reconciles top-down, bottom-up tension with a hierarchical master sample survey design, integrated data analysis, dynamic data curation, regional monitoring hubs, and knowledge delivery through web-based infrastructure. NABat supports collaborative monitoring across spatial and organizational scales and the full annual lifecycle of bats.

Addressing racial equity in health psychology research: An application of the multicultural orientation framework.

Health psychology research emphasizes biological and positivist methods, giving less attention to the multifaceted sociocultural and political forces at play in health processes and outcomes. In this article, we present a new sociostructural approach for working toward racial equity in health psychology research, consistent with public psychology goals. This new approach uses the multicultural orientation framework (MCO) to guide health psychologists to consider the sociocultural and political history of their work, systems of oppression and privilege embedded in health research, and a path toward using research to achieve social change, antiracism, and health equity. We identify MCO as a tool for health psychology researchers to engage in ongoing self-reflection, cultivate cultural humility, and act upon opportunities to examine cultural factors at each step of the research process. After describing the MCO's components of cultural humility, cultural opportunities, and cultural comfort, we introduce questions that researchers can use to guide self-reflexivity and the implementation of MCO into health psychology research focused on racial equity. Specifically, we present the issue of Black women's perinatal health to embody the importance of applying MCO to health disparities research. We then walk through how to apply MCO in health research study development, data collection, and data dissemination. As we outline how to apply MCO to promote antiracist health research, we aim to enact social change consistent with the public psychology goals of building and fostering strong community relationships that inform social policy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Possibility for reverse zoonotic transmission of SARS-CoV-2 to free-ranging wildlife: A case study of bats.

The COVID-19 pandemic highlights the substantial public health, economic, and societal consequences of virus spillover from a wildlife reservoir. Widespread human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also presents a new set of challenges when considering viral spillover from people to naïve wildlife and other animal populations. The establishment of new wildlife reservoirs for SARS-CoV-2 would further complicate public health control measures and could lead to wildlife health and conservation impacts. Given the likely bat origin of SARS-CoV-2 and related beta-coronaviruses (ß-CoVs), free-ranging bats are a key group of concern for spillover from humans back to wildlife. Here, we review the diversity and natural host range of ß-CoVs in bats and examine the risk of humans inadvertently infecting free-ranging bats with SARS-CoV-2. Our review of the global distribution and host range of ß-CoV evolutionary lineages suggests that 40+ species of temperate-zone North American bats could be immunologically naïve and susceptible to infection by SARS-CoV-2. We highlight an urgent need to proactively connect the wellbeing of human and wildlife health during the current pandemic and to implement new tools to continue wildlife research while avoiding potentially severe health and conservation impacts of SARS-CoV-2 "spilling back" into free-ranging bat populations.

Multifunctional opioid receptor agonism and antagonism by a novel macrocyclic tetrapeptide prevents reinstatement of morphine-seeking behaviour.

BACKGROUND AND PURPOSE: The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) is a multifunctional µ-opioid receptor and κ-opioid receptor agonist and κ-opioid receptor antagonist that produces antinociception and prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference (CPP). We hypothesized that an analogue of CJ-15,208, cyclo[Pro-Sar-Phe-d-Phe], would demonstrate multifunctional µ-opioid receptor and κ-opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective µ-opioid receptor agonists, while preventing both drug- and stress-induced reinstatement of morphine-induced CPP. EXPERIMENTAL APPROACH: The opioid receptor agonist and antagonist activity of cyclo[Pro-Sar-Phe-d-Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor "knockout" mice using the 55°C warm-water tail-withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo[Pro-Sar-Phe-d-Phe] to block morphine- and stress-induced reinstatement of extinguished CPP was determined. KEY RESULTS: cyclo[Pro-Sar-Phe-d-Phe] demonstrated dose-dependent, short-lasting antinociception, with an ED50 (and 95% confidence interval) of 0.15 (0.05-0.21) nmol i.c.v. and 1.91 (0.40-3.54) mg·kg-1 i.p., mediated by µ- and κ-opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose-dependent κ-opioid receptor antagonist-like activity at 2.5, but not at 4.5, h after administration. cyclo[Pro-Sar-Phe-d-Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ-receptors. Pretreatment with cyclo[Pro-Sar-Phe-d-Phe] prevented stress- and drug-induced reinstatement of extinguished morphine-place preference responses in a time-dependent manner. CONCLUSIONS AND IMPLICATIONS: These data suggest that cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug- and stress-induced relapse in morphine-abstinent subjects.

Design, Synthesis, and Characterization of the Macrocyclic Tetrapeptide cyclo[Pro-Sar-Phe-d-Phe]: A Mixed Opioid Receptor Agonist-Antagonist Following Oral Administration.

Substance abuse remains a serious public health crisis, affecting millions of people worldwide. Macrocyclic tetrapeptides like CJ-15,208 and [d-Trp]CJ-15,208 demonstrate opioid activity shown to attenuate the rewarding effects of cocaine in conditioned place preference assays in mice, making them promising lead compounds for treating substance abuse. In the present study, we report the rational design, synthesis, conformational analysis, and continued pharmacological evaluation of the novel macrocyclic tetrapeptide cyclo[Pro-Sar-Phe-d-Phe] to further explore this unique molecular scaffold. This peptide was rationally designed based on X-ray and NMR structures of related macrocyclic tetrapeptides. Following synthesis, its solution-phase conformations were determined by NMR and molecular modeling. The peptide adopted multiple conformations in polar solvents, but a single conformation in chloroform that is stabilized by intramolecular hydrogen bonding. The peptide is orally bioavailable, producing antinociception and antagonism of kappa opioid receptor (KOR) stimulation following oral administration in a mouse 55 °C warm-water tail-withdrawal assay. Notably, cyclo[Pro-Sar-Phe-d-Phe] blocked both stress- and drug-induced reinstatement of cocaine and morphine conditioned place preference in mice following oral administration, and displayed a decreased side-effect profile compared to morphine. Thus, cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for the treatment of substance abuse.

High body mass index is associated with increased diurnal strains in the articular cartilage of the knee.

OBJECTIVE: Obesity is an important risk factor for osteoarthritis (OA) and is associated with changes in both the biomechanical and inflammatory environments within the joint. However, the relationship between obesity and cartilage deformation is not fully understood. The goal of this study was to determine the effects of body mass index (BMI) on the magnitude of diurnal cartilage strain in the knee. METHODS: Three-dimensional maps of knee cartilage thickness were developed from 3T magnetic resonance images of the knees of asymptomatic age- and sex-matched subjects with normal BMI (18.5-24.9 kg/m2) or high BMI (25-31 kg/m2). Site-specific magnitudes of diurnal cartilage strain were determined using aligned images recorded at 8:00 AM and 4:00 PM on the same day. RESULTS: Subjects with high BMI had significantly thicker cartilage on both the patella and femoral groove, as compared to subjects with normal BMI. Diurnal cartilage strains were dependent on location in the knee joint, as well as BMI. Subjects with high BMI, compared to those with normal BMI, exhibited significantly higher compressive strains in the tibial cartilage. Cartilage thickness on both femoral condyles decreased significantly from the AM to the PM time point; however, there was no significant effect of BMI on diurnal cartilage strain in the femur. CONCLUSION: Increased BMI is associated with increased diurnal strains in articular cartilage of both the medial and lateral compartments of the knee. The increased cartilage strains observed in individuals with high BMI may, in part, explain the elevated risk of OA associated with obesity or may reflect alterations in the cartilage mechanical properties in subjects with high BMI.

Diurnal variations in articular cartilage thickness and strain in the human knee.

Due to the biphasic viscoelastic nature of cartilage, joint loading may result in deformations that require times on the order of hours to fully recover. Thus, cartilaginous tissues may exhibit cumulative strain over the course of each day. The goal of this study was to assess the magnitude and spatial distribution of strain in the articular cartilage of the knee with daily activity. Magnetic resonance (MR) images of 10 asymptomatic subjects (six males and four females) with mean age of 29 years were obtained at 8:00 AM and 4:00 PM on the same day using a 3T magnet. These images were used to create 3D models of the femur, tibia, and patella from which cartilage thickness distributions were quantified. Cartilage thickness generally decreased from AM to PM in all areas except the patellofemoral groove and was associated with significant compressive strains in the medial condyle and tibial plateau. From AM to PM, cartilage of the medial tibial plateau exhibited a compressive strain of -5.1±1.0% (mean±SEM) averaged over all locations, while strains in the lateral plateau were slightly lower (-3.1±0.6%). Femoral cartilage showed an average strain of -1.9±0.6%. The findings of this study show that human knee cartilage undergoes diurnal changes in strain that vary with site in the joint. Since abnormal joint loading can be detrimental to cartilage homeostasis, these data provide a baseline for future studies investigating the effects of altered biomechanics on diurnal cartilage strains and cartilage physiology.

Experimental infection of bats with Geomyces destructans causes white-nose syndrome.

White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease.