Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Strategies to strengthen COVID-19 vaccine uptake and improve vaccine equity in U.S. Territories and Freely Associated States during the first six months of vaccine rollout.

The eight U.S. territories and freely associated states (TFAS) have historically faced unique social and structural barriers in the implementation of vaccination programs due to geographic remoteness, a high prevalence of socioeconomic disparities, increasing prevalence of natural disasters, limited vaccine providers and clinics, difficulties with procurement and shipping, and difficulty tracking highly mobile populations. In the months leading up to emergency authorizations for the use of COVID-19 vaccines, the TFAS developed tailored vaccination strategies to ensure that key at-risk populations received timely vaccination, and successfully implemented these strategies during the first six months of the vaccine rollout. Subject matter experts supporting the Centers for Disease Control and Prevention's COVID-19 Response recognized the unique historical, geographic, social, and cultural dynamics for residents in the TFAS and worked with partners to prevent, detect, and respond to the pandemic in these jurisdictions. As a result of innovative partnerships and vaccine distribution strategies, vaccine equity was improved in the TFAS during the COVID-19 vaccine rollout.

A neuropsychological profile for high-grade primary central nervous system neuroendocrine tumor (CNS NET): a single-case study.

Objective: Neuroendocrine tumors (NETs) are neoplasms that primarily occur in the lungs, appendix, small intestine, pancreas, and rectum, and typically metastasize to the liver or lymph nodes. However, in rare cases NETs can originate in the central nervous system (CNS). Understanding primary CNS NET neuropsychological manifestations aids in recommendations for neurocognitive follow-up, treatment and lifestyle planning, and future research. Method: Given the dearth of neuropsychological research for CNS NETs, we present a case seen in a 43-year-old woman. Results: Initial and 8-month follow-up neuropsychological evaluations of the patient revealed a Major Neurocognitive Disorder where the pattern of findings was consistent with tumor location and additional treatment-related factors. Reliable change indices at her re-evaluation revealed declines in verbal and visual memory, with statistical, yet not clinical, improvements in different domains. Follow-up monitoring of comprehensive care continued to occur after neuropsychological evaluations. Conclusions: This case study assists in the characterization of initial and follow-up neuropsychological presentation of a primary CNS NET, where evaluations helped inform clinical care and functional recommendations. This case demonstrates the importance for neuropsychologists to have awareness of various conditions, even rare conditions, which can inform a systematic approach to research and clinical care with neuro-oncological populations.

Larger spleens and greater splenic contraction during exercise may be an adaptive characteristic of Nepali Sherpa at high-altitude.

OBJECTIVES: The Sherpa ethnic group living at altitude in Nepal may have experienced natural selection in response to chronic hypoxia. We have previously shown that Sherpa in Kathmandu (1400 m) possess larger spleens and a greater apnea-induced splenic contraction compared to lowland Nepalis. This may be significant for exercise capacity at altitude as the human spleen responds to stress-induced catecholamine secretion by an immediate contraction, which results in transiently elevated hemoglobin concentration ([Hb]). METHODS: To investigate splenic contraction in response to exercise at high-altitude (4300 m; Pb = ~450 Torr), we recruited 63 acclimatized Sherpa (29F) and 14 Nepali non-Sherpa (7F). Spleen volume was measured before and after maximal exercise on a cycle ergometer by ultrasonography, along with [Hb] and oxygen saturation (SpO2). RESULTS: Resting spleen volume was larger in the Sherpa compared with Nepali non-Sherpa (237 ± 62 vs. 165 ± 34 mL, p < .001), as was the exercise-induced splenic contraction (Δspleen volume, 91 ± 40 vs. 38 ± 32 mL, p < .001). From rest to exercise, [Hb] increased (1.2 to 1.4 g.dl-1), SpO2 decreased (~9%) and calculated arterial oxygen content (CaO2) remained stable, but there were no significant differences between groups. In Sherpa, both resting spleen volume and the Δspleen volume were modest positive predictors of the change (Δ) in [Hb] and CaO2 with exercise (p-values from .026 to .037 and R2 values from 0.059 to 0.067 for the predictor variable). CONCLUSIONS: Larger spleens and greater splenic contraction may be an adaptive characteristic of Nepali Sherpa to increase CaO2 during exercise at altitude, but the direct link between spleen size/function and hypoxia tolerance remains unclear.

An autoantibody signature predictive for multiple sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Comparison of minimally invasive to standard temporal lobectomy approaches to epilepsy surgery: Seizure relief and visual confrontation naming outcomes.

The purpose of this study was to systematically examine three different surgical approaches in treating left medial temporal lobe epilepsy (mTLE) (viz., subtemporal selective amygdalohippocampectomy [subSAH], stereotactic laser amygdalohippocampotomy [SLAH], and anterior temporal lobectomy [ATL]), to determine which procedures are most favorable in terms of visual confrontation naming and seizure relief outcome. This was a retrospective study of 33 adults with intractable mTLE who underwent left temporal lobe surgery at three different epilepsy surgery centers who also underwent pre-, and at least 6-month post-surgical neuropsychological testing. Measures included the Boston Naming Test (BNT) and the Engel Epilepsy Surgery Outcome Scale. Fisher's exact tests revealed a statistically significant decline in naming in ATLs compared to SLAHs, but no other significant group differences. 82% of ATL and 36% of subSAH patients showed a significant naming decline whereas no SLAH patient (0%) had a significant naming decline. Significant postoperative naming improvement was seen in 36% of SLAH patients in contrast to 9% improvement in subSAH patients and 0% improvement in ATLs. Finally, there were no statistically significant differences between surgical approaches with regard to seizure freedom outcome, although there was a trend towards better seizure relief outcome among the ATL patients. Results support a possible benefit of SLAH in preserving visual confrontation naming after left TLE surgery. While result interpretation is limited by the small sample size, findings suggest outcome is likely to differ by surgical approach, and that further research on cognitive and seizure freedom outcomes is needed to inform patients and providers of potential risks and benefits with each.

A LTB4/CD11b self-amplifying loop drives pyogranuloma formation in chronic granulomatous disease.

Sterile pyogranulomas and heightened cytokine production are hyperinflammatory hallmarks of Chronic Granulomatous Disease (CGD). Using peritoneal cells of zymosan-treated CGD (gp91phox-/-) versus wild-type (WT) mice, an ex vivo system of pyogranuloma formation was developed to determine factors involved in and consequences of recruitment of neutrophils and monocyte-derived macrophages (MoMacs). Whereas WT cells failed to aggregate, CGD cells formed aggregates containing neutrophils initially, and MoMacs recruited secondarily. LTB4 was key, as antagonizing BLT1 blocked neutrophil aggregation, but acted only indirectly on MoMac recruitment. LTB4 upregulated CD11b expression on CGD neutrophils, and the absence/blockade of CD11b inhibited LTB4 production and cell aggregation. Neutrophil-dependent MoMac recruitment was independent of MoMac Nox2 status, BLT1, CCR1, CCR2, CCR5, CXCR2, and CXCR6. As proof of concept, CD11b-deficient CGD mice developed disrupted pyogranulomas with poorly organized neutrophils and diminished recruitment of MoMacs. Importantly, the disruption of cell aggregation and pyogranuloma formation markedly reduced proinflammatory cytokine production.

Black and White Adults' Racial and Gender Stereotypes of Psychopathology Symptoms in Black and White Children.

Adults' judgments of children's behaviors play a critical role in assessment and treatment of childhood psychopathology. Judgments of children's psychiatric symptoms are likely influenced by racial biases, but little is known about the specific racial biases adults hold about children's psychiatric symptoms, which could play a critical role in childhood mental health disparities. This study examined one form of such biases, racial stereotypes, to determine if White and Black adults hold implicit and explicit racial stereotypes about common childhood psychopathology symptoms, and if these stereotypes vary by child gender and disorder type. Participants included 82 self-identified Black men, 84 Black woman, 1 Black transgender individual, 1 Black genderfluid individual, 81 White men, and 85 White women. Analyses of implicit stereotypes revealed that White adults associated psychopathology symptoms more strongly with Black children than did Black adults (p < .001). All adults held stronger implicit racial stereotypes for oppositional defiant disorder, anxiety, and depression than for attention-deficit/hyperactivity disorder (p < .001). For explicit stereotypes, White adults generally associated psychopathology symptoms more with Black children than did Black adults but effects varied across child gender and disorder type. As the first study to examine racial and gender stereotypes across common childhood psychopathology symptoms, these findings point to a need for further investigation of the presence and impact of racial biases in the mental healthcare system for Black youth and to identify interventions to mitigate the impacts of racial biases to inform racial equity in mental healthcare in the United States.

"Toward Breast Reinnervation- What is our Endpoint" A systematic review of normal breast sensibility.

BACKGROUND: To restore breast sensibility, some centers are offering nerve reconstruction as a component of implant and flap-based breast reconstruction. To interpret and contextualize the results of these procedures, it is necessary to understand the normal range of breast sensibility, the factors that affect it, and the best methods for its objective measurement. METHODS: We conducted systematic and comprehensive searches across PubMed, Web of Science, and Cochrane Library databases using keywords and controlled vocabulary for the concepts of the breast, nipple, areola, and measurement. The search results were imported into Rayyan QCRI for a blinded screening of titles and abstracts. Studies were evaluated for bias using RevMan 5 software. The results of sensory measurements were pooled, and a quantitative summary of breast sensibility was generated. RESULTS: A total of 36 articles were identified, including retrospective, cross-sectional, and prospective studies. Although there were some consistent findings across studies, such that breast sensibility is inversely related to breast volume, there was wide variability in the following parameters: population, breast condition, measurement modality, anatomic areas of measurement, and sensibility findings. This heterogeneity precluded the generation of normative breast sensibility measurements. Furthermore, we detected a high degree of bias in most studies, due to self-selection of participants and failure to record patient characteristics that may alter sensibility. CONCLUSIONS: The literature lacks consistent data delineating normative values for breast sensibility. Standardized measurements of healthy volunteers with various breast characteristics are necessary to elucidate normative values and interpret efforts to restore sensibility in breast reconstruction.

The Montreal Cognitive Assessment: Norms and Reliable Change Indices for Standard and MoCA-22 Administrations.

OBJECTIVE: The Montreal Cognitive Assessment (MoCA) is among the most frequently administered cognitive screening tests, yet demographically diverse normative data are needed for repeated administrations. METHOD: Data were obtained from 18,410 participants using the National Alzheimer's Coordinating Center Uniform Data Set. We developed regression-based norms using Tobit regression to account for ceiling effects, explored test-retest reliability of total scores and by domain stratified by age and diagnosis with Cronbach's alpha, and reported the cumulative change frequencies for individuals with serial MoCA administrations to gage expected change. RESULTS: Strong ceiling effects and negative skew were observed at the total score, domain, and item levels for the cognitively normal group, and performances became more normally distributed as the degree of cognitive impairment increased. In regression models, years of education was associated with higher MoCA scores, whereas older age, male sex, Black and American Indian or Alaska Native race, and Hispanic ethnicity were associated with lower predicted scores. Temporal stability was adequate and good at the total score level for the cognitively normal and cognitive disorders groups, respectively, but fell short of reliability standards at the domain level. CONCLUSIONS: MoCA total scores are adequately reproducible among those with cognitive diagnoses, but domain scores are unstable. Robust regression-based norms should be used to adjust for demographic performance differences, and the limited reliability, along with the ceiling effects and negative skew, should be considered when interpreting MoCA scores.

Aging differentially alters the transcriptome and landscape of chromatin accessibility in the male and female mouse hippocampus.

Aging-related memory impairment and pathological memory disorders such as Alzheimer's disease differ between males and females, and yet little is known about how aging-related changes in the transcriptome and chromatin environment differ between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus in both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response and synaptic function and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic function. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE-1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Sex differences in gene expression and chromatin accessibility were amplified with aging, findings that may shed light on sex differences in aging-related and pathological memory loss.

TNFα: TNFR1 signaling inhibits maturation and maintains the pro-inflammatory programming of monocyte-derived macrophages in murine chronic granulomatous disease.

Introduction: Loss of NADPH oxidase activity results in proinflammatory macrophages that contribute to hyperinflammation in Chronic Granulomatous Disease (CGD). Previously, it was shown in a zymosan-induced peritonitis model that gp91phox-/- (CGD) monocyte-derived macrophages (MoMacs) fail to phenotypically mature into pro-resolving MoMacs characteristic of wild type (WT) but retain the ability to do so when placed in the WT milieu. Accordingly, it was hypothesized that soluble factor(s) in the CGD milieu thwart appropriate programming. Methods: We sought to identify key constituents using ex vivo culture of peritoneal inflammatory leukocytes and their conditioned media. MoMac phenotyping was performed via flow cytometry, measurement of efferocytic capacity and multiplex analysis of secreted cytokines. Addition of exogenous TNFα, TNFα neutralizing antibody and TNFR1-/- MoMacs were used to study the role of TNFα: TNFR1 signaling in MoMac maturation. Results: More extensive phenotyping defined normal MoMac maturation and demonstrated failure of maturation of CGD MoMacs both ex vivo and in vivo. Protein components, and specifically TNFα, produced and released by CGD neutrophils and MoMacs into conditioned media was identified as critical to preventing maturation. Exogenous addition of TNFα inhibited WT MoMac maturation, and its neutralization allowed maturation of cultured CGD MoMacs. TNFα neutralization also reduced production of IL-1ß, IL-6 and CXCL1 by CGD cells though these cytokines played no role in MoMac programming. MoMacs lacking TNFR1 matured more normally in the CGD milieu both ex vivo and following adoptive transfer in vivo. Discussion: These data lend mechanistic insights into the utility of TNFα blockade in CGD and to other diseases where such therapy has been shown to be beneficial.

Use of Tocilizumab Followed by Rituximab Desensitization on Relapsing Myelin Oligodendrocyte Antibody Disease: A Case Report.

Myelin oligodendrocyte antibody disease is a demyelinating disorder that usually presents with a monophasic course. Relapse in this demyelinating disorder is rare, and those who relapse have a weaker response to standard therapy. In this case report, we report a three-year follow-up on a case of a female patient who was diagnosed with myelin oligodendrocyte antibody disease at 21 years old. The patient initially presented with transverse myelitis followed by optic neuritis five months after the onset of transverse myelitis. On relapse, the patient was initially treated with rituximab only to present with type 1 hypersensitivity reaction. Due to the hypersensitivity reaction, the treatment regimen was shifted to tocilizumab, for which she completed a total of five cycles. With tocilizumab treatment, she was noted to have one relapse of symptoms triggered by COVID-19 infection. However, due to tocilizumab-associated alopecia, the patient was shifted to rituximab infusion with desensitization. She then underwent four cycles of rituximab with desensitization, which she tolerated well, and is now in full remission after the fourth cycle of rituximab with no residual deficits. As relapse in myelin oligodendrocyte antibody disease is rare, studies regarding the use of tocilizumab and rituximab as second-line treatment for this disorder are limited. Literature regarding treatment with rituximab infusion with desensitization is even more limited. This case report highlights the potential use of tocilizumab and rituximab in relapsing cases of myelin oligodendrocyte antibody disease, as well as the need for additional literature regarding the use of tocilizumab and rituximab with or without desensitization in relapse in myelin oligodendrocyte antibody disease.

Detection of lymphoproliferative disease virus in Iowa Wild Turkeys (Meleagris gallopavo): Comparison of two sections of the proviral genome.

An accurate diagnostic test is an essential aspect of successfully monitoring and managing wildlife diseases. Lymphoproliferative Disease Virus (LPDV) is an avian retrovirus that was first identified in domestic turkeys in Europe and was first reported in a Wild Turkey (Meleagris gallopavo) in the United States in 2009. It has since been found to be widely distributed throughout North America. The majority of studies have utilized bone marrow and PCR primers targeting a 413-nucleotide sequence of the gag gene of the provirus to detect infection. While prior studies have evaluated the viability of other tissues for LPDV detection (whole blood, spleen, liver, cloacal swabs) none to date have studied differences in detection rates when utilizing different genomic regions of the provirus. This study examined the effectiveness of another section of the provirus, a 335-nucleotide sequence starting in the U3 region of the LTR (Long Terminal Repeat) and extending into the Matrix of the gag region (henceforth LTR), for detecting LPDV. Bone marrow samples from hunter-harvested Wild Turkeys (n = 925) were tested for LPDV with the gag gene and a subset (n = 417) including both those testing positive and those where LPDV was not detected was re-tested with LTR. The positive percent agreement (PPA) was 97.1% (68 of 70 gag positive samples tested positive with LTR) while the negative percent agreement (NPA) was only 68.0% (236 of 347 gag negative samples tested negative with LTR). Cohen's Kappa (κ = 0.402, Z = 10.26, p<0.0001) and the McNemar test (OR = 55.5, p<0.0001) indicated weak agreement between the two gene regions. We found that in Iowa Wild Turkeys use of the LTR region identified LPDV in many samples in which we failed to detect LPDV using the gag region and that LTR may be more appropriate for LPDV surveillance and monitoring. However, neither region of the provirus resulted in perfect detection and additional work is necessary to determine if LTR is more reliable in other geographic regions where LPDV occurs.

Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma.

PURPOSE: There are no effective treatment strategies for children with highest-risk posterior fossa group A ependymoma (PFA). Chromosome 1q gains (1q+) are present in approximately 25% of newly diagnosed PFA tumors, and this number doubles at recurrence. Seventy percent of children with chromosome 1q+ PFA will die because of the tumor, highlighting the urgent need to develop new therapeutic strategies for this population. EXPERIMENTAL DESIGN: In this study, we utilize 1q+ PFA in vitro and in vivo models to test the efficacy of combination radiation and chemotherapy in a preclinical setting. RESULTS: 5-fluorouracil (5FU) enhances radiotherapy in 1q+ PFA cell lines. Specifically, 5FU increases p53 activity mediated by the extra copy of UCK2 located on chromosome 1q in 1q+ PFA. Experimental downregulation of UCK2 resulted in decreased 5FU sensitivity in 1q+ PFA cells. In in vitro studies, a combination of 5FU, retinoid tretinoin (ATRA), and radiation provided the greatest reduction in cellular proliferation and greatest increase in markers of apoptosis in 1q+ PFA cell lines compared with other treatment arms. Similarly, in vivo experiments demonstrated significant enhancement of survival in mice treated with combination radiation and 5FU and ATRA. CONCLUSIONS: These results are the first to identify a chromosome 1q+ specific therapy approach in 1q+ PFA. Existing phase I studies have already established single-agent pediatric safety and dosages of 5FU and ATRA, allowing for expedited clinical application as phase II trials for children with high-risk PFA.

Differential splenic responses to hyperoxic breathing at high altitude in Sherpa and lowlanders.

The human spleen contracts in response to stress-induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non-Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = âˆ¼430 torr; P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$  = âˆ¼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non-Sherpa (165 ± 34 mL; P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3-1.6). In response to hyperoxia, non-Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7-48.9; P < 0.001; ES = 1.8, 95% CI: 0.93-2.66), while spleen size remained unchanged in Sherpa (-2 ± 13 mL, 95% CI: -2.4 to 7.3; P = 0.640; ES = 0.18, 95% CI: -0.10 to 0.47). Our findings suggest that Sherpa and non-Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude-related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non-Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb].

Cis-regulatory modes of Ultrabithorax inactivation in butterfly forewings.

Hox gene clusters encode transcription factors that drive regional specialization during animal development: for example the Hox factor Ubx is expressed in the insect metathoracic (T3) wing appendages and differentiates them from T2 mesothoracic identities. Hox transcriptional regulation requires silencing activities that prevent spurious activation and regulatory crosstalks in the wrong tissues, but this has seldom been studied in insects other than Drosophila, which shows a derived Hox dislocation into two genomic clusters that disjoined Antennapedia (Antp) and Ultrabithorax (Ubx). Here, we investigated how Ubx is restricted to the hindwing in butterflies, amidst a contiguous Hox cluster. By analysing Hi-C and ATAC-seq data in the butterfly Junonia coenia, we show that a Topologically Associated Domain (TAD) maintains a hindwing-enriched profile of chromatin opening around Ubx. This TAD is bordered by a Boundary Element (BE) that separates it from a region of joined wing activity around the Antp locus. CRISPR mutational perturbation of this BE releases ectopic Ubx expression in forewings, inducing homeotic clones with hindwing identities. Further mutational interrogation of two non-coding RNA encoding regions and one putative cis-regulatory module within the Ubx TAD cause rare homeotic transformations in both directions, indicating the presence of both activating and repressing chromatin features. We also describe a series of spontaneous forewing homeotic phenotypes obtained in Heliconius butterflies, and discuss their possible mutational basis. By leveraging the extensive wing specialization found in butterflies, our initial exploration of Ubx regulation demonstrates the existence of silencing and insulating sequences that prevent its spurious expression in forewings.

Comparison of adult hesitancy towards COVID-19 vaccines and vaccines in general in the USA.

BACKGROUND: Adults who are hesitant toward routinely recommended vaccines for adults may also be hesitant toward COVID-19 vaccines. However, the distribution and differences in hesitancy between routinely recommended vaccines and COVID-19 vaccines, and the association of hesitancy regarding routinely recommended vaccines and hesitancy with COVID-19 vaccination status and intent, is unknown. METHODS: Using the Research and Development Survey (RANDS) during COVID-19, Round 3, a probability-sampled, nationally representative, web and phone survey fielded from May 17 - June 30, 2021 (n = 5,434), we examined the distribution and difference in prevalence of hesitancy towards COVID-19 and vaccines in general, beliefs associated with vaccine hesitancy, and factors impacting plans to be vaccinated against COVID-19. RESULTS: Reported hesitancy towards COVID-19 vaccines (42.2%) was 6-percentage points higher than hesitancy towards vaccines in general (35.7%). Populations who were most hesitant toward COVID-19 vaccines were younger adults, non-Hispanic Black adults, adults with lower education or income, and adults who were associated with a religion. Beliefs in the social benefit and the importance of vaccination, and the belief that COVID-19 vaccines lower risk for infection, were strongly associated with COVID-19 vaccination and intent to be vaccinated. CONCLUSIONS: Vaccine hesitancy for both COVID-19 vaccines and vaccines in general is common. Health providers and public health officials should utilize strategies to address vaccine hesitancy, including providing strong clear recommendations for needed vaccines, addressing safety and effectiveness concerns, and utilizing trusted messengers such as religious and community leaders to improve vaccine confidence.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.