Charge state-dependent symmetry breaking of atomic defects in transition metal dichalcogenides.

The functionality of atomic quantum emitters is intrinsically linked to their host lattice coordination. Structural distortions that spontaneously break the lattice symmetry strongly impact their optical emission properties and spin-photon interface. Here we report on the direct imaging of charge state-dependent symmetry breaking of two prototypical atomic quantum emitters in mono- and bilayer MoS2 by scanning tunneling microscopy (STM) and non-contact atomic force microscopy (nc-AFM). By changing the built-in substrate chemical potential, different charge states of sulfur vacancies (VacS) and substitutional rhenium dopants (ReMo) can be stabilized. Vac S - 1 as well as Re Mo 0 and Re Mo - 1 exhibit local lattice distortions and symmetry-broken defect orbitals attributed to a Jahn-Teller effect (JTE) and pseudo-JTE, respectively. By mapping the electronic and geometric structure of single point defects, we disentangle the effects of spatial averaging, charge multistability, configurational dynamics, and external perturbations that often mask the presence of local symmetry breaking.

Heterogenous thinning of peripapillary tissues occurs early during high myopia development in juvenile tree shrews.

Myopia is an independent risk factor for glaucoma, but the link between both conditions remains unknown. Both conditions induce connective tissue remodeling at the optic nerve head (ONH), including the peripapillary tissues. The purpose of this study was to investigate the thickness changes of the peripapillary tissues during experimental high myopia development in juvenile tree shrews. Six juvenile tree shrews experienced binocular normal vision, while nine received monocular -10D lens treatment starting at 24 days of visual experience (DVE) to induce high myopia in one eye and the other eye served as control. Daily refractive and biometric measurements and weekly optical coherence tomography scans of the ONH were obtained for five weeks. Peripapillary sclera (Scl), choroid-retinal pigment epithelium complex (Ch-RPE), retinal nerve fiber layer (RNFL), and remaining retinal layers (RRL) were auto-segmented using a deep learning algorithm after nonlinear distortion correction. Peripapillary thickness values were quantified from 3D reconstructed segmentations. All lens-treated eyes developed high myopia (-9.8 ± 1.5 D), significantly different (P < 0.001) from normal (0.69 ± 0.45 D) and control eyes (0.76 ± 1.44 D). Myopic eyes showed significant thinning of all peripapillary tissues compared to both, normal and control eyes (P < 0.001). At the experimental end point, the relative thinning from baseline was heterogeneous across tissues and significantly more pronounced in the Scl (-8.95 ± 3.1%) and Ch-RPE (-16.8 ± 5.8%) when compared to the RNFL (-5.5 ± 1.6%) and RRL (-6.7 ± 1.8%). Furthermore, while axial length increased significantly throughout the five weeks of lens wear, significant peripapillary tissue thinning occurred only during the first week of the experiment (until a refraction of -2.5 ± 1.9 D was reached) and ceased thereafter. A sectorial analysis revealed no clear pattern. In conclusion, our data show that in juvenile tree shrews, experimental high myopia induces significant and heterogeneous thinning of the peripapillary tissues, where the retina seems to be protected from profound thickness changes as seen in Ch-RPE and Scl. Peripapillary tissue thinning occurs early during high myopia development despite continued progression of axial elongation. The observed heterogeneous thinning may contribute to the increased risk for pathological optic nerve head remodeling and glaucoma later in life.

The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.

Mutations in the tyrosine phosphatase SHP2 are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting auto-inhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that, while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8-10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.

Intra-host Trypanosoma cruzi strain dynamics shape disease progression: the missing link in Chagas disease pathogenesis.

Chronic Chagasic cardiomyopathy develops years after infection in 20-40% of patients, but disease progression is poorly understood. Here, we assessed Trypanosoma cruzi parasite dynamics and pathogenesis over a 2.5-year period in naturally infected rhesus macaques. Individuals with better control of parasitemia were infected with a greater diversity of parasite strains compared to those with increasing parasitemia over time. Also, the in vivo parasite multiplication rate decreased with increasing parasite diversity, suggesting competition among strains or a stronger immune response in multiple infections. Significant differences in electrocardiographic (ECG) profiles were observed in Chagasic macaques compared to uninfected controls, suggesting early conduction defects, and changes in ECG patterns over time were observed only in macaques with increasing parasitemia and lower parasite diversity. Disease progression was also associated with plasma fibronectin degradation, which may serve as a biomarker. These data provide a novel framework for the understanding of Chagas disease pathogenesis, with parasite diversity shaping disease progression.IMPORTANCEChagas disease progression remains poorly understood, and patients at increased risk of developing severe cardiac disease cannot be distinguished from those who may remain asymptomatic. Monitoring of Trypanosoma cruzi strain dynamics and pathogenesis over 2-3 years in naturally infected macaques shows that increasing parasite diversity in hosts is detrimental to parasite multiplication and Chagasic cardiomyopathy disease progression. This provides a novel framework for the understanding of Chagas disease pathogenesis.

Lipopolysaccharide structure modulates cationic biocide susceptibility and crystalline biofilm formation in Proteus mirabilis.

Chlorhexidine (CHD) is a cationic biocide used ubiquitously in healthcare settings. Proteus mirabilis, an important pathogen of the catheterized urinary tract, and isolates of this species are often described as "resistant" to CHD-containing products used for catheter infection control. To identify the mechanisms underlying reduced CHD susceptibility in P. mirabilis, we subjected the CHD tolerant clinical isolate RS47 to random transposon mutagenesis and screened for mutants with reduced CHD minimum inhibitory concentrations (MICs). One mutant recovered from these screens (designated RS47-2) exhibited ~ 8-fold reduction in CHD MIC. Complete genome sequencing of RS47-2 showed a single mini-Tn5 insert in the waaC gene involved in lipopolysaccharide (LPS) inner core biosynthesis. Phenotypic screening of RS47-2 revealed a significant increase in cell surface hydrophobicity and serum susceptibility compared to the wildtype, and confirmed defects in LPS production congruent with waaC inactivation. Disruption of waaC was also associated with increased susceptibility to a range of other cationic biocides but did not affect susceptibility to antibiotics tested. Complementation studies showed that repression of smvA efflux activity in RS47-2 further increased susceptibility to CHD and other cationic biocides, reducing CHD MICs to values comparable with the most CHD susceptible isolates characterized. The formation of crystalline biofilms and blockage of urethral catheters was also significantly attenuated in RS47-2. Taken together, these data show that aspects of LPS structure and upregulation of the smvA efflux system function in synergy to modulate susceptibility to CHD and other cationic biocides, and that LPS structure is also an important factor in P. mirabilis crystalline biofilm formation.

Longitudinal Changes of Bruch's Membrane Opening, Anterior Scleral Canal Opening, and Border Tissue in Experimental Juvenile High Myopia.

Purpose: To investigate the relative positional changes between the Bruch's membrane opening (BMO) and the anterior scleral canal opening (ASCO), and border tissue configuration changes during experimental high myopia development in juvenile tree shrews. Methods: Juvenile tree shrews were assigned randomly to two groups: binocular normal vision (n = 9) and monocular -10 D lens treatment starting at 24 days of visual experience to induce high myopia in one eye while the other eye served as control (n = 12). Refractive and biometric measurements were obtained daily, and 48 radial optical coherence tomography B-scans through the center of the optic nerve head were obtained weekly for 6 weeks. ASCO and BMO were segmented manually after nonlinear distortion correction. Results: Lens-treated eyes developed high degree of axial myopia (-9.76 ± 1.19 D), significantly different (P < 0.001) from normal (0.34 ± 0.97 D) and control eyes (0.39 ± 0.88 D). ASCO-BMO centroid offset gradually increased and became significantly larger in the experimental high myopia group compared with normal and control eyes (P < 0.0001) with an inferonasal directional preference. The border tissue showed a significantly higher tendency of change from internally to externally oblique configuration in the experimental high myopic eyes in four sectors: nasal, inferonasal, inferior, and inferotemporal (P < 0.005). Conclusions: During experimental high myopia development, progressive relative deformations of ASCO and BMO occur simultaneously with changes in border tissue configuration from internally to externally oblique in sectors that are close to the posterior pole (nasal in tree shrews). These asymmetric changes may contribute to pathologic optic nerve head remodeling and an increased risk of glaucoma later in life.

Development of human hippocampal subfield microstructure and relation to associative inference.

The hippocampus is a complex brain structure composed of subfields that each have distinct cellular organizations. While the volume of hippocampal subfields displays age-related changes that have been associated with inference and memory functions, the degree to which the cellular organization within each subfield is related to these functions throughout development is not well understood. We employed an explicit model testing approach to characterize the development of tissue microstructure and its relationship to performance on two inference tasks, one that required memory (memory-based inference) and one that required only perceptually available information (perception-based inference). We found that each subfield had a unique relationship with age in terms of its cellular organization. While the subiculum (SUB) displayed a linear relationship with age, the dentate gyrus (DG), cornu ammonis field 1 (CA1), and cornu ammonis subfields 2 and 3 (combined; CA2/3) displayed non-linear trajectories that interacted with sex in CA2/3. We found that the DG was related to memory-based inference performance and that the SUB was related to perception-based inference; neither relationship interacted with age. Results are consistent with the idea that cellular organization within hippocampal subfields might undergo distinct developmental trajectories that support inference and memory performance throughout development.

Safety and preservation of cardiac function following therapeutic vaccination against Trypanosoma cruzi in rhesus macaques.

BACKGROUND: Chronic Chagasic cardiomyopathy is responsible for a large disease burden in the Americas, and a therapeutic vaccine would be highly desirable. We tested the safety and efficacy of a therapeutic DNA vaccine encoding antigens TSA-1 and Tc24 for preventing cardiac alterations in experimentally infected macaques. A secondary objective was to evaluate the feasibility of detecting changes in cardiac alterations in these animals. METHODS: Naïve rhesus macaques were infected with Trypanosoma cruzi and treated with three doses of DNA vaccines. RESULTS: Blood cell counts and chemistry indicated that therapeutic vaccination was safe, as hepatic and renal function appeared unaffected by the vaccination and/or infection with T. cruzi. Electrocardiographic (ECG) recordings indicated that no marked arrhythmias developed up to 7 months post-infection. Univariate analysis of ECG parameters found no significant differences in any of these parameters between vaccinated and control macaques. However, linear discriminant analysis revealed that control macaques presented clear alterations in their ECG patterns at 7 months post-infection, indicative of the onset of conduction defects and cardiac alterations, and these changes were prevented in vaccine treated macaques. CONCLUSIONS: This is the first evidence that therapeutic vaccination against T. cruzi can prevent cardiac alterations in non-human primates, strengthening the rationale for developing a human vaccine against Chagas disease.

Recombinant Simian Varicella Virus-Simian Immunodeficiency Virus Vaccine Induces T and B Cell Functions and Provides Partial Protection against Repeated Mucosal SIV Challenges in Rhesus Macaques.

HIV vaccine mediated efficacy, using an expanded live attenuated recombinant varicella virus-vectored SIV rSVV-SIVgag/env vaccine prime with adjuvanted SIV-Env and SIV-Gag protein boosts, was evaluated in a female rhesus macaques (RM) model against repeated intravaginal SIV challenges. Vaccination induced anti-SIV IgG responses and neutralizing antibodies were found in all vaccinated RMs. Three of the eight vaccinated RM remained uninfected (vaccinated and protected, VP) after 13 repeated challenges with the pathogenic SIVmac251-CX-1. The remaining five vaccinated and infected (VI) macaques had significantly reduced plasma viral loads compared with the infected controls (IC). A significant increase in systemic central memory CD4+ T cells and mucosal CD8+ effector memory T-cell responses was detected in vaccinated RMs compared to controls. Variability in lymph node SIV-Gag and Env specific CD4+ and CD8+ T cell cytokine responses were detected in the VI RMs while all three VP RMs had more durable cytokine responses following vaccination and prior to challenge. VI RMs demonstrated predominately SIV-specific monofunctional cytokine responses while the VP RMs generated polyfunctional cytokine responses. This study demonstrates that varicella virus-vectored SIV vaccination with protein boosts induces a 37.5% efficacy rate against pathogenic SIV challenge by generating mucosal memory, virus specific neutralizing antibodies, binding antibodies, and polyfunctional T-cell responses.

Veterans Affairs Health Care Provider Perceptions of Virtual Reality: Brief Exploratory Survey.

BACKGROUND: Virtual reality (VR), a simulated experience that can be similar to or completely different from the real world, has become increasingly useful within the psychiatric and medical fields. This VR technology has been applied in medical school trainings, exposure therapy for individuals with posttraumatic stress disorder (PTSD), and reminiscence therapy associated with mood disorders for older adults. Perceptions of VR through the lens of the health care provider require further exploration. VR has grown in popularity; however, this modality continues to be underused in most Veterans Affairs (VA) hospitals. OBJECTIVE: A web-based survey was used to explore health care provider perceptions of immersive VR availability and use for older adults and identify potential barriers for immersive VR use in older adults with cognitive impairment. METHODS: An 8-item web-based survey was developed to obtain health care provider feedback. This survey was disseminated throughout a single Veterans Integrated Services Network (VISN). The VR survey was developed via the Survey Monkey platform and distributed through the secure VA email network. Providers were asked to voluntarily participate in the brief, anonymous survey and offer their perceptions of immersive VR use within their patient population. Survey data were reviewed and interpreted using descriptive statistics. RESULTS: A total of 49 respondents completed the survey over a 15-day period. Of them, 36 respondents (73%) had heard of a VR device, though the majority (n=44, 90%) had never used or prescribed a VR device. Respondents identified several potential barriers to immersive VR use in older adults with cognitive impairment (eg, hearing difficulties, perceptions of technology, cognitive concerns, access to resources, and visual impairment). Despite the barriers identified, providers (n=48, 98%) still reported that they would feel comfortable prescribing immersive VR as an intervention for their patient population. CONCLUSIONS: Survey findings revealed that health care providers within this VISN for VAs have heard of VR, although they may not have actively engaged in its use. Most of the providers reported that they would prescribe the use of an immersive VR intervention for their older adult patients. This key point highlights the desire to implement VR strategies for patient use by their providers. If underlying barriers can be addressed and relatively resolved, this technological intervention has the potential to create substantial breakthroughs in clinical care.

Predictors of children's emotion regulation outcomes during COVID-19: Role of conflict within the family.

Objective: This work aimed to analyze the role of family conflict on children's emotion regulation and stress outcomes during the COVID-19 pandemic. Background: The COVID-19 pandemic brought novel stress to families. The stress experienced could impact family relationships-specifically, perceptions of closeness and patterns of conflict. Positive family environment and high-quality family relationships are associated with adaptive coping and lower levels of stress among children. Method: Data were collected online from 110 participants at baseline and again 30 days later. Associations between parent-child relationship, sibling relationships, and child stress and emotion regulation outcomes 30 days later were tested through multiple stepwise regression. Results: Both significant regression models suggest that parent-child conflict is the strongest predictor of child stress and negativity over the 30-day assessment period. Sibling conflict predicted child stress but not negativity. Conclusion: Family conflict during the COVID-19 pandemic influenced children's emotion regulation outcomes as seen through significant associations between child-parent conflict, sibling conflict, perceived child stress, and children's negativity. Implications: Family scientists and practitioners should consider interventions that help parents teach their children how to cope with their own stresses and emotions after conflict.

The COVID misinfodemic: not new, never more lethal.

'Infodemia' is a portmanteau between 'information' and 'epidemics', referring to wide and rapid accumulation and dissemination of information, misinformation, and disinformation about a given subject, such as a disease. As facts, rumors and fears mix and disperse, the misinfodemic creates loud background noise, preventing the general public from discerning between accurate and false information. We compared and contrasted key elements of the AIDS and COVID-19 misinfodemics, to identify common features, and, based on experience with the AIDS pandemic, recommend actions to control and reverse the SARS-CoV-2 misinfodemic that contributed to erode the trust between the public and scientists and governments and has created barriers to control of COVID-19. As pandemics emerge and evolve, providing robust responses to future misinfodemics must be a priority for society and public health.

Stress, anxiety, and health-related quality of life in BRCA1/2-positive women with and without cancer: A comparison of four US female samples.

Introduction: Women with BRCA1/2 mutations have a 11-72% increased risk of breast/ovarian cancers throughout their lifetime. The current study examines psychosocial differences between the current sample of BRCA1/2-positive women with and without cancer histories and three comparable United States (US) female samples without BRCA1/2 mutations. Methods: Sixty BRCA1/2-positive women (with and without cancer histories) were recruited through multiple private online support groups in the US. Participants completed an online survey outlining sociodemographic and genetic counseling information, and anxiety, stress, and health-related quality of life (HRQoL) outcomes. Outcomes were compared to three similar US female normative samples via independent samples t-test analyses. Results: State and trait anxiety (p = 0.00) and stress (p = 0.001) were significantly worse in the current sample of BRCA1/2-positive women compared comparable US female samples. All HRQoL domains were significantly better in the current sample except energy/vitality, which was significantly lower (p = 0.02) in the current sample. Results were stratified by cancer and recurrence status. Conclusions: This study provides insight into how a sample of BRCA1/2-positive women both with and without cancer fare post-genetic counseling as compared to three normative female populations. Results infer the need for additional education, patient-provider training, and mental health referrals to support this population in order to circumvent unintended consequences and to improve psychosocial health in those being tested for, and those who test positive for, BRCA1/2 genetic mutations.

Effects of Parental Acceptance-Rejection on Children's Internalizing and Externalizing Behaviors: A Longitudinal, Multicultural Study.

Background: Grounded in interpersonal acceptance-rejection theory, this study assessed children's (N=1,315) perceptions of maternal and paternal acceptance-rejection in nine countries (China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States) as predictors of children's externalizing and internalizing behaviors across ages 7-14 years. Methods: Parenting behaviors were measured using children's reports on the Parental Acceptance-Rejection Questionnaire. Child externalizing and internalizing behaviors were measured using mother, father, and child reports on the Achenbach System of Empirically-Based Assessment. Results: Using a multilevel modeling framework, we found that in cultures where both maternal and paternal indifference/neglect scores were higher than average-compared to other cultures -children's internalizing problems were more persistent. At the within-culture level, all four forms of maternal and paternal rejection (i.e., coldness/lack of affection, hostility/aggression, indifference/neglect, and undifferentiated rejection) were independently associated with both externalizing and internalizing problems across ages 7-14 even after controlling for child gender, parent education, and each of the four forms of parental rejection. Conclusions: Results demonstrate that the effects of perceived parental acceptance-rejection are panculturally similar.

Perceptions and care Recommendations from Previvors: Qualitative analysis of female BRCA1/2 mutation Carriers' experience with genetic testing and counseling.

Introduction: It is estimated that 12.5% of women will be diagnosed with breast cancer and 1.10% with ovarian cancer during their lifetime. Although less common, women with these mutations have a 11-72% increased risk of breast/ovarian cancers and are hereditary. Genetic testing/counseling presents the opportunity to identify carriers of BRCA1/2 genetic mutations before a cancer diagnosis. Methods: Thirty-four BRCA1/2-positive women (with and without histories of breast/ovarian cancers) were recruited through online national support groups to gain a better understanding of their genetic testing/counseling perceptions and experiences. After confirming eligibility, they were invited to participate in either a telephone or webcam interview. Interview transcripts were analyzed using qualitative thematic text analysis and descriptive coding techniques. Results: Six major themes emerged, capturing the perceptions and experiences of genetic testing/counseling for these women: 1) Emotional Reactions to Results and Genetic Counseling, 2) Future Recommendations, 3) Family Solidarity and Support, 4) Experiences with the Healthcare System, 5) Preventive Concerns and Decisions, and 6) Sources Affecting Perceived Risk. Two subthemes also emerged within the first theme, which are termed "Pre-vivor," and "Testing Intuition." Conclusions: Participants indicated that genetic testing/counseling improvements would be helpful for women in this population surrounding quality care, including sensitivity training for healthcare professionals involved in testing/counseling, additional educational resources, and increased emotional and financial support. Although these recommendations may be beneficial, more widespread research with greater generalizability to disparate groups may be necessary prior to implementation.

Nonlinear distortion correction for posterior eye segment optical coherence tomography with application to tree shrews.

We propose an empirical distortion correction approach for optical coherence tomography (OCT) devices that use a fan-scanning pattern to image the posterior eye segment. Two types of reference markers were used to empirically estimate the distortion correction approach in tree shrew eyes: retinal curvature from MRI images and implanted glass beads of known diameter. Performance was tested by correcting distorted images of the optic nerve head. In small animal eyes, our purposed method effectively reduced nonlinear distortions compared to a linear scaling method. No commercial posterior segment OCT provides anatomically correct images, which may bias the 3D interpretation of these scans. Our method can effectively reduce such bias.

Defeated No More: Meaning-Making After Military Sexual Trauma.

INTRODUCTION: Military sexual trauma (MST) has been a concern within our U.S. military for many years. Many interventions have been found to benefit this population, although meaning-based interventions are still lacking in this area. The purpose of this phenomenological study is to understand the meaning-making process and themes that arise for female military veterans as they narrate their experience(s) of MST. MATERIALS AND METHODS: The qualitative study consisted of six female participants, from different areas across the nation, who all reported experiencing MST during their time in service. Their experiences of MST included both sexual harassment and sexual assault. Participants completed a semi-structured interview that was analyzed using an axial coding method to discover the major themes of each participant's interview. The participants discussed the positive and negative aspects of their journey following their MST experience(s). This study's procedures were approved by Adler University's Institutional Review Board. RESULTS: Many found the interview to be a healing experience on their path of post-traumatic growth (PTG). There were eight major themes that arose from the data analysis under the three main domains of (1) creating a work or doing a deed, (2) experiencing something or encountering someone in a way to produce PTG, and (3) altering one's attitude toward unavoidable suffering. The eight themes were as follows: advocacy, adaptive coping, sense of family unit, psychological clarity, meaningful mantra, survivor mentality code, view of self in the world, and resiliency. CONCLUSIONS: All participants endorsed engagement in some type of activity that fell into one of the three major domains identified above. This finding helped highlight the PTG that participants were able to experience through their meaning-making journey. There were several recommendations and study implications that were derived from this research study. With the themes introduced from this study, future treatment planning for individual survivors of MST can be better informed by the utilization of meaning-making techniques. Family and group meaning-based interventions would also be an area of continued exploration for this population. Future implications for practice are also included within this article. Significant limitations of the study include amount of participants, lack of diversity in sample population, qualitative study results, and lack of a more-personal interviewing process.

Hif1α and Wnt are required for posterior gene expression during Xenopus tropicalis tail regeneration.

Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1α, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1α is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1α and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1α is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate that Hif1α has regulatory roles in Wnt target gene expression across multiple tissue contexts.