"Terminal anorexia nervosa" may not be terminal: An empirical evaluation.

Gaudiani et al. (2022) presented terminal anorexia nervosa (T-AN) as a potential new specifier to the anorexia nervosa (AN) diagnosis, with criteria including (a) AN diagnosis, (b) age > 30 years, (c) previously participated in high-quality care, and (d) the clear, consistent determination by a patient with decision-making capacity that additional treatment would be futile, knowing death will result. This study's purpose was to empirically examine a subgroup of participants with AN who met the first three criteria of T-AN-and a smaller subset who also met a proxy index of the fourth criterion involving death (TD-AN)-and compare them to an adult "not terminal" anorexia nervosa (NT-AN) group and to a "not terminal" subset 30 years of age or older (NTO-AN). Patients at U.S. eating disorder treatment facilities (N = 782; T-AN: n = 51, TD-AN: n = 16, NT-AN: n = 731, NTO-AN: n = 133), all of whom met criteria for a current Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnosis of AN, were compared regarding admission, discharge, and changes from admission to discharge on physiological indices (i.e., white blood cell counts, albumin levels, aspartate aminotransferase levels, and body mass index), as well as self-report measures (i.e., eating disorder, depression, anxiety, and obsessive-compulsive symptoms). In contrast to the tight syndromal symptom interconnections of, and inevitable spiral toward death expected for, a terminal diagnosis, results suggest substantial variability within the T-AN group and TD-AN subset, and an overall trend of improvement across physiological and self-report measures. This study thus provides some empirical evidence against the specification of the T-AN diagnosis. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comparing eating disorder treatment outcomes of transgender and gender diverse adolescents with those of cisgender adolescents.

OBJECTIVE: Eating disorder (ED), depression, and anxiety symptoms at admission and discharge were compared, as were admission-to-discharge changes, for transgender and gender diverse (TGD), and cisgender adolescents receiving intensive treatment for EDs. METHOD: Participants were 44 TGD and 573 cisgender adolescents admitted to a treatment facility. Participants completed the Eating Disorder Examination Questionnaire (EDE-Q), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7) at admission and discharge. RESULTS: Both groups had elevated EDE-Q scores at admission (TGD: M = 3.78, standard deviation [SD] = 1.70; cisgender: M = 3.33, SD = 1.74) that improved by discharge (TGD: M = 2.27, SD = 1.83, Cohen's d = .98; cisgender: M = 2.10, SD = 1.54, Cohen's d = .79); there were no differences in EDE-Q between groups at admission (p = .09; odds ratio [OR] = 1.18, 95% confidence interval [CI] [.98, 1.44]) or discharge (p = .48; OR = 1.07, 95% CI [.88, 1.30]). On admission, TGD adolescents had higher suicidality, measured by PHQ-9, item 9 (p < .001; OR = 1.94, 95% CI [1.51, 2.52]), and depression (p < .001; OR = 1.10, 95% CI [1.05, 1.16]) than cisgender participants. Severity decreased over treatment for all measures. Both groups showed similar improvement on suicidality (p = .93; OR = .98, 95% CI [.70,1.36]), depression (p = .42; OR = 1.02, 95% CI [.97, 1.07]), and anxiety (p = .14; OR = 1.05, 95% CI [.99, 1.12]). However, at discharge, suicidality (p = .02; OR = 1.40, 95% CI [1.04, 1.85]), depression (p < .01; OR = 1.06, 95% CI [1.02, 1.11]), and anxiety (p = .02; OR = 1.06, 95% CI [1.01, 1.12]) were higher for TGD adolescents than their cisgender peers. DISCUSSION: All participants had similar ED symptom severity and improvement. Depression, anxiety, and suicidality remained elevated for TGD adolescents compared to their cisgender peers at discharge, suggesting the need for targeted treatment. PUBLIC SIGNIFICANCE: Transgender and gender diverse (TGD) adolescents have increased risk of eating disorders (EDs); few studies examine how they respond to ED treatment. We examine treatment outcomes of TGD adolescents receiving ED treatment compared to their cisgender peers. We measured ED symptoms along with depression, anxiety, and suicidality at the beginning and end of treatment. While TGD adolescents showed similar improvement in ED symptoms, measures of depression, anxiety, and suicidality remained elevated at the time of discharge.

Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate conditioned Fanconi anemia mice.

Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, and leukemia and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a mainstay treatment, is limited by conditioning regimen-related toxicity and graft-versus-host disease (GVHD). Antibody-drug-conjugates (ADCs) targeting hematopoietic stem cells (HSCs) can open marrow niches permitting donor stem cell alloengraftment. Here, we report that single dose anti-mouse CD45-targeted-ADC (CD45-ADC) facilitated stable, multilineage chimerism in 3 distinct FA mouse models representing 90% of FA complementation groups. CD45-ADC profoundly depleted host stem cell enriched LineageSca1+cKit+ cells within 48 hours. Fanca-/- recipients of minor-mismatched BM and single dose CD45-ADC had peripheral blood (PB) mean donor chimerism >90%; donor HSCs alloengraftment was verified in secondary recipients. In Fancc-/- and Fancg-/- recipients of fully allogeneic grafts, PB mean donor chimerism was 60-80% and 70-80%, respectively. The mean percent donor chimerism in BM and spleen mirrored PB results. CD45-ADC conditioned mice did not have clinical toxicity. A transient <2.5-fold increase in hepatocellular enzymes and mild-to-moderate histopathological changes were seen. Under GVHD allo-HSCT conditions, wildtype and Fanca-/- recipients of CD45-ADC had markedly reduced GVHD lethality compared to lethal irradiation. Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable FA patients.

An examination of adults with atypical anorexia nervosa at admission to treatment at higher levels of care: An attempt to increase diagnostic clarity.

OBJECTIVE: Anorexia nervosa (AN) is a serious illness with a high mortality rate and multiple physiological complications. The vague definition of atypical AN allows for subjective interpretation. This retrospective study aimed to focus future research on the operational definition of atypical AN by examining four factors associated with atypical AN at admission to higher level of care treatment. METHODS: Adults with atypical AN (n = 69) were examined within sample analyses among four groups: (1) >10% versus ≤10% weight loss; (2) weight loss within the previous 3 months versus >3 months; (3) engaging in purging behaviors versus absence of purging behaviors; and (4) endorsing versus not endorsing significant cognitive aspects of AN. RESULTS: Patients with atypical AN endorsed elevated ED cognitions on the Eating Disorder Examination-Questionnaire and depressive symptoms; a lack of association was found between weight loss severity and weight loss time frame with depressive symptoms, eating concern, and restraint. Purging behavior was associated with a higher expected body weight percentage (%EBW) and dietary restraint, while greater AN cognitions were associated with a higher EBW and weight loss percentage. Few patients demonstrated bradycardia, hypophosphatemia, or amenorrhea. DISCUSSION: This study demonstrated the severity of ED cognitions and depressive symptoms in this atypical AN sample and provided directions for future studies in the nosology of atypical AN. It may be important to distinguish between individuals with atypical AN who are purging and those who are not. Atypical AN was associated with a low frequency of physiological disturbances. PUBLIC SIGNIFICANCE: This study provides further clarification regarding the operational definition of atypical AN; currently, a constellation of symptoms under Other Specified Feeding or Eating Disorders. This study was consistent with previous research in reporting severe eating disorder cognitions in adults with atypical AN, and noted the potential importance of distinguishing a purging distinction. A minority of patients in this study had physiological impairments.

Accelerated Aging and Microsatellite Instability in Recessive Dystrophic Epidermolysis Bullosa-Associated Cutaneous Squamous Cell Carcinoma.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severely debilitating disorder caused by mutations in COL7A1 and is characterized by extreme skin fragility, chronic inflammation and fibrosis. A majority of RDEB patients develop squamous cell carcinoma (SCC), a highly aggressive skin cancer with limited treatment options currently available. In this study, we utilized an approach leveraging WGS and RNA-seq across three different tissues in a single RDEB patient to gain insight into possible mechanisms of RDEB-associated SCC progression and to identify potential therapeutic options. As a result, we identified PLK-1 as a possible candidate for targeted therapy and discovered microsatellite instability and accelerated aging as factors potentially contributing to the aggressive nature and early onset of RDEB SCC. By integrating multi-tissue genomic and transcriptomic analyses in a single patient, we demonstrate the promise of bridging the gap between genomic research and clinical applications for developing tailored therapies for patients with rare genetic disorders such as RDEB.

Prevention of acute GVHD using an orthogonal IL-2/IL-2Rß system to selectively expand regulatory T cells in vivo.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor ß (oIL-2Rß) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex-disparate GVHD model of lethally irradiated BALB/c mice given T cell-depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rß-transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rß Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rß Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rß system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.

Medical considerations in the care of transgender and gender diverse patients with eating disorders.

Transgender and gender diverse (TGD) individuals are at increased risk for the development of eating disorders, but very little has been published with regards to the unique aspects of their medical care in eating disorder treatment. Providing gender affirming care is a critical component of culturally competent eating disorder treatment. This includes knowledge of gender affirming medical and surgical interventions and how such interventions may be impacted by eating disordered behaviors, as well as the role of such interventions in eating disorder treatment and recovery. TGD individuals face barriers to care, and one of these can be provider knowledge. By better understanding these needs, clinicians can actively reduce barriers and ensure TGD individuals are provided with appropriate care. This review synthesizes the available literature regarding the medical care of TGD patients and those of patients with eating disorders and highlights areas for further research.

Transgender and gender diverse (TGD) people are at increased risk for developing eating disorders, but very little is known about their unique medical needs while in eating disorder treatment. TGD refers to individuals whose sex reported at birth does not align with their gender identity. This review examines the existing literature on TGD medical care and integrates this with the eating disorder literature. Improved knowledge of the medical needs to TGD individuals can help decrease barriers to care. This review aims to better understand the medical needs of TGD individuals in eating disorder treatment and highlights areas for further research.

Accumulation of senescence observed in spinocerebellar ataxia type 7 mouse model.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by a trinucleotide CAG repeat. SCA7 predominantly causes a loss of photoreceptors in the retina and Purkinje cells of the cerebellum. Severe infantile-onset SCA7 also causes renal and cardiac irregularities. Previous reports have shown that SCA7 results in increased susceptibility to DNA damage. Since DNA damage can lead to accumulation of senescent cells, we hypothesized that SCA7 causes an accumulation of senescent cells over the course of disease. A 140-CAG repeat SCA7 mouse model was evaluated for signs of disease-specific involvement in the kidney, heart, and cerebellum, tissues that are commonly affected in the infantile form. We found evidence of significant renal abnormality that coincided with an accumulation of senescent cells in the kidneys of SCA7140Q/5Q mice, based on histology findings in addition to RT-qPCR for the cell cycle inhibitors p16Ink4a and p21Cip1 and senescence-associated ß-galactosidase (SA-ßgal) staining, respectively. The Purkinje layer in the cerebellum of SCA7140Q/5Q mice also displayed SA-ßgal+ cells. These novel findings offer evidence that senescent cells accumulate in affected tissues and may possibly contribute to SCA7's specific phenotype.

Comparing eating disorder treatment outcomes of transgender and nonbinary individuals with cisgender individuals.

OBJECTIVE: The purpose of this study was to compare symptom severity of eating disorders (EDs), depression and anxiety at admission and discharge for transgender and nonbinary (TNB) individuals and cisgender adult individuals receiving treatment for EDs at higher levels of care (HLOC), adding to the limited research in this area. METHOD: Participants were 25 TNB individuals and 376 cisgender individuals admitted to a HLOC ED treatment facility. Participants completed the Eating Disorder Examination Questionnaire (EDE-Q), Patient Health Questionnaire-9, and Beck Anxiety Inventory at admission and discharge. RESULTS: TNB individuals showed significant improvements on EDE-Q global scores between admission and discharge (Cohen's d = 1.27), and showed similar improvements on the EDE-Q over the course of treatment (Cohen's d = 0.06) when compared to cisgender individuals. TNB individuals had more severe depression at admission (Cohen's d = 0.61). Although depression improved over the course of treatment for both groups, TNB individuals showed less improvement (Cohen's d = 0.59). Suicidality was higher for TNB individuals on admission and discharge and did not improve significantly over the course of treatment (Cohen's d = 0.38). DISCUSSION: This study provides preliminary evidence that TNB and cisgender individuals show similar improvement in ED symptoms during HLOC treatment. However, TNB individuals have more severe depression and less improvement in depression compared to cisgender individuals, without improvement in suicidality. TNB individuals may benefit from care targeting depression and suicidality during ED treatment. PUBLIC SIGNIFICANCE STATEMENT: TNB individuals have increased risk of EDs. Little research addresses how TNB individuals respond to ED treatment, which was traditionally created for cisgender individuals. We present one of the first studies examining ED treatment outcomes for TNB adults. TNB individuals showed improved ED symptoms with treatment, but less improvement in depression and their suicidality remained elevated. This suggests the need for targeted treatment.

Eating disorder behaviors as predictors of suicidal ideation among people with an eating disorder.

OBJECTIVE: Suicidality is known to be elevated among people with an eating disorder. The aim of the current study was to examine whether any of three specific behavioral facets of eating disorders (i.e., purging, binge eating, restricting) would be the strongest predictors of suicidal ideation, controlling for one another, in longitudinal analyses from admission to discharge. We hypothesized that purging, above and beyond restricting or binge eating, would be the most important predictor of suicidal ideation. METHOD: In the present study, patients with an eating disorder (N = 936), the majority of whom met criteria for a current DSM-5 diagnosis of Anorexia Nervosa (n = 560), completed the Eating Pathology Symptoms Inventory (EPSI) and the Beck Depression Inventory II-Item 9 suicidal ideation index, at admission and again at discharge. The settings were eating disorder treatment facilities offering inpatient, residential, partial hospitalization program (PHP), and intensive outpatient (IOP) levels of care. We pitted EPSI purging, EPSI restriction, and EPSI binge eating against one another in a regression framework predicting discharge suicidal ideation controlling for suicidal ideation at admission. RESULTS: EPSI Purging significantly predicted both presence/absence of suicidal ideation (ß = .22, t = 2.48, p = .01; OR = 1.25, 95% CI [1.05, 1.49]) and intensity of suicidal ideation (ß = .04, t = 2.31, p = .02) at discharge, whereas neither EPSI Restricting nor EPSI Binge Eating did (p > .30). DISCUSSION: Study results suggest that purging may have particular relevance in estimating suicide risk in patients with an eating disorder.

First, do no harm: the proposed definition of "terminal anorexia" is fraught with danger for vulnerable individuals.

A recent article in the Journal of Eating Disorders (10:23, 2022) proposed criteria for "terminal anorexia" with a cited goal of improving access to end-of-life care (Gaudiani et al. in J Eat Disord 10(1):23, 2022). The authors presented three cases in which patients received end-of-life care, including the prescription of medical assistance in dying (MAID), also known as physician-assisted suicide (PAS). The proposed criteria lack the evidence base for adoption and do not acknowledge the compelling evidence that exists surrounding possible prolonged timelines to recovery for some individuals and the nuances of assessing capacity in this population.

Engineering CRISPR/Cas9 for Multiplexed Recombinant Coagulation Factor Production.

Current hemostatic agents are obtained from pooled plasma from multiple donors requiring costly pathogen screening and processing. Recombinant DNA-based production represents an engineering solution that could improve supply, uniformity, and safety. Current approaches are typically for single gene candidate peptides and often employ non-human cells. We devised an approach where multiple gene products could be produced from a single population of cells. We identified gene specific Synergistic Activation Mediators (SAM) from the CRISPR/Cas9 system for targeted overexpression of coagulation factors II, VII, IX, X, and fibrinogen. The components of the CRISPR-SAM system were expressed in Human Embryonic Kidney Cells (HEK293), and single (singleplex) or multi-gene (multiplex) upregulation was assessed by quantitative RT-PCR (qRT-PCR) and protein expression by ELISA analysis. Factor II, VII, IX, and X singleplex and multiplex activation resulted in 120-4700-fold and 60-680-fold increases in gene expression, respectively. Fibrinogen sub-unit gene activation resulted in a 1700-92,000-fold increases and 80-5500-fold increases in singleplex or multiplex approaches, respectively. ELISA analysis showed a concomitant upregulation of candidate gene products. Our findings demonstrate the capability of CRISPR/Cas9 SAMs for single or multi-agent production in human cells and represent an engineering advance that augments current recombinant peptide production techniques.

Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease.

Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%-70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.

Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts.

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplantation and subsequent epidermal allografting from the bone marrow transplant donor. Epidermal allografting of these patients has decreased wound surface area for up to 3 years after treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes coexpressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered proinflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing profibrotic gene POSTN, which may have implications in the development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights into and targets for future RDEB studies and treatments.

Genes and compounds that increase type VII collagen expression as potential treatments for dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is a skin-blistering disease caused by mutations in COL7A1, which encodes type VII collagen (C7). There is no cure for DEB, but previous work has shown potential therapeutic benefit of increased production of even partially functional C7. Genome-wide screens using CRISPR-Cas9 have enabled the identification of genes involved in cancer development, drug resistance and other genetic diseases, suggesting that they could be used to identify drivers of C7 production. A keratinocyte C7 reporter cell line was created and used in a genome-wide CRISPR activation (CRISPRa) screen to identify genes and pathways that increase C7 expression. The CRISPRa screen results were used to develop a targeted drug screen to identify compounds that upregulate C7 expression. The C7_tdTomato cell line was validated as an effective reporter for detection of C7 upregulation. The CRISPRa screen identified DENND4B and TYROBP as top gene hits plus pathways related to calcium uptake and immune signalling in C7 regulation. The targeted drug screen identified several compounds that increase C7 expression in keratinocytes, of which kaempferol, a plant flavonoid, also significantly increased C7 mRNA and protein in DEB patient cells.

A CD45-targeted antibody-drug conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation in mice.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting the use of this potentially curative treatment beyond malignant disorders. Minimizing systemic nontargeted conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. We report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multilineage donor cell engraftment. Conditioning with CD45-ADC (3 mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pretransplant CD45-ADC (3 mg/kg) combined with low-dose TBI (150 cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pretransplant TBI (50 cGy) and posttransplant rapamycin, cyclophosphamide (Cytoxan), or a JAK inhibitor, 90% to 100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5 mg/kg), CD45-ADC as a single agent was sufficient for rapid, high-level multilineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has the potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced-intensity conditioning.

Doublesex regulates male-specific differentiation during distinct developmental time windows in a parasitoid wasp.

Sexually dimorphic traits in insects are subject to sexual selection, but our knowledge of the underlying molecular mechanisms is still scarce. Here we investigate how the highly conserved gene, Doublesex (Dsx), is involved in shaping sexual dimorphism in the model parasitoid wasp Nasonia vitripennis (Hymenoptera: Pteromalidae). First, we present the revised Dsx gene structure including an alternative transcription start, and two additional male NvDsx transcript isoforms. We show sex-specific NvDsx expression and splicing throughout development, and demonstrate that transient NvDsx silencing in different male developmental stages shifts two sexually dimorphic traits from male to female morphology, with the effect being dependent on the timing of silencing. In addition, we determined the effect of NvDsx on the development of reproductive organs. Transient silencing of NvDsx in early male larvae affects the growth and differentiation of the internal and external reproductive tissues. We did not observe phenotypic changes in females after NvDsx silencing. Our results indicate that male NvDsx is required to suppress female-specific traits and/or to promote male-specific traits during distinct developmental windows. This provides new insights into the regulatory activity of Dsx during male wasp development in the Hymenoptera.

P63 targeted deletion under the FOXN1 promoter disrupts pre-and post-natal thymus development, function and maintenance as well as induces severe hair loss.

Progressive immune deficiency of aging is characterized by severe thymic atrophy, contracted T cell repertoire, and poor immune function. p63 is critical for the proliferative potential of embryonic and adult stem cells, as well as thymic epithelial cells (TECs). Because p63 null mice experience rapid post-natal lethality due to epidermal and limb morphogenesis defects, studies to define a role for p63 expression in TEC biology focused on embryonic thymus development and in vitro experiments. Since post-natal thymic stromal development and function differs from that of the embryo, we assessed the impact of lineage-restricted p63 loss on pre- and post-natal murine TEC function by generating mice with a loss of p63 function targeted to TEC, termed p63TECko mice. In adult p63TECko mice, severe thymic hypoplasia was observed with a lack in a discernable segregation into medullary and cortical compartments and peripheral T cell lymphopenia. This profound thymic defect was seen in both neonatal as well as embryonic p63TECko mice. In addition to TECs, p63 also plays in important role in the development of stratified epithelium of the skin; lack of p63 results in defects in skin epidermal stratification and differentiation. Interestingly, all adult p63TECko mice lacked hair follicles despite having normal p63 expression in the skin. Together our results show a critical role of TEC p63 in thymic development and maintenance and show that p63 expression is critical for hair follicle formation.

Avoidant restrictive food intake disorder and suicidal ideation.

Most DSM-5 eating disorder diagnoses are associated with elevated suicide risk; however, little is known about the relationship between Avoidant/Restrictive Food Intake Disorder (ARFID) and suicidal ideation. The aim of the current study was to examine suicidal ideation within an adult ARFID sample. Patients with eating disorders (N = 936), some of whom met criteria for a current DSM-5 diagnosis of ARFID (n = 79), completed the Beck Depression Inventory II Item 9, regarding suicidal ideation. The study was conducted within an eating disorder treatment facility that offers inpatient, residential, partial hospitalization program, and intensive outpatient levels of care. Findings suggest no significant pairwise differences in suicidal ideation prevalence between participants with ARFID and those with any other ED diagnosis. Thorough screening for suicidal thoughts and risk among those with ARFID is warranted at all levels of care. We suggest that future research expand upon this work in a larger adult ARFID sample.