Abstract We analyze four epochs of Hubble Space Telescope imaging over 18 yr for the Draco dwarf spheroidal galaxy. We measure precise proper motions for hundreds of stars and combine these with ...existing line-of-sight (LOS) velocities. This provides the first radially resolved 3D velocity dispersion profiles for any dwarf galaxy. These constrain the intrinsic velocity anisotropy and resolve the mass–anisotropy degeneracy. We solve the Jeans equations in oblate axisymmetric geometry to infer the mass profile. We find the velocity dispersion to be radially anisotropic along the symmetry axis and tangentially anisotropic in the equatorial plane, with a globally averaged value β B ¯ = − 0.20 − 0.53 + 0.28 , (where 1 – β B ≡ 〈 v tan 2 〉 / 〈 v rad 2 〉 in 3D). The logarithmic dark matter (DM) density slope over the observed radial range, Γ dark , is − 0.83 − 0.37 + 0.32 , consistent with the inner cusp predicted in ΛCDM cosmology. As expected given Draco’s low mass and ancient star formation history, it does not appear to have been dissolved by baryonic processes. We rule out cores larger than 487, 717, and 942 pc at 1 σ , 2 σ , and 3 σ confidence, respectively, thus imposing important constraints on the self-interacting DM cross section. Spherical models yield biased estimates for both the velocity anisotropy and the inferred slope. The circular velocity at our outermost data point (900 pc) is 24.19 − 2.97 + 6.31 km s − 1 . We infer a dynamical distance of 75.37 − 4.00 + 4.73 kpc and show that Draco has a modest LOS rotation, with v / σ = 0.22 ± 0.09 . Our results provide a new stringent test of the so-called “cusp–core” problem that can be readily extended to other dwarfs.
Zika virus (ZIKV) has recently emerged as a pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives. Therefore, the development ...of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins. Here we demonstrate that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope glycoproteins of a strain from the ZIKV outbreak in 2013 elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 μg of nucleoside-modified ZIKV mRNA-LNP protected mice against ZIKV challenges at 2 weeks or 5 months after vaccination, and a single dose of 50 μg was sufficient to protect non-human primates against a challenge at 5 weeks after vaccination. These data demonstrate that nucleoside-modified mRNA-LNP elicits rapid and durable protective immunity and therefore represents a new and promising vaccine candidate for the global fight against ZIKV.
Aberrant expansion of KRT5
basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The ...mechanisms determining activity of KRT5
cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5
cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5
cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5
cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5
cell behaviour and function contributing to remodelling events in the fibrotic niche.
Blocking the PI3K/AKT/mTOR pathway decreases resistance to hormonal therapy in endometrial carcinoma (EC).
In this study, the aim was to assess the efficacy and tolerability of ...everolimus(E)/letrozole (L) or medroxyprogesterone acetate(M)/tamoxifen(T) in the treatment of metastatic EC.
This single stage, open-label two arm randomized phase II trial accrued women with advanced/persistent/recurrent EC. Treatment with E (10 mg daily) and L (2.5 mg daily) or T (20 mg twice daily) and M (200 mg daily alternating weeks) was randomly assigned, and stratified by prior adjuvant therapy. Treatments were administered orally. Primary endpoint was response rate.
Between February 2015 and April 2016, everolimus/letrozole (n = 37) or MT (n = 37) was assigned to 74 patients. Median follow-up was 37 months. Eight (22%; 95% CI 11% to 37%) patients responded on EL (one CR) and nine (25%; 95% CI 14% to 41%) patients responded on MT (three CRs). Median PFS for EL and MT arms was 6 months and 4 months, respectively. On EL, chemo-nave patients demonstrated a 28 month median PFS; prior chemotherapy patients had a 4-month median PFS. On MT, patients without prior therapy had a 5-month median PFS; those with prior chemotherapy demonstrated a 3-month PFS. Common grade 3 adverse events were anemia (9 24% patients EL vs 2 6% MT) and mucositis (2 5% vs 0 0%). Grade 3/4 thromboembolic events were observed with MT but not with EL (0 0% vs 4 11%).
EL and MT demonstrated clinically meaningful efficacy in recurrent EC patients. The higher PFS observed in chemo-naïve patients is worthy of confirmation in future studies.
•Novel treatment for recurrent EC patients remains a significant unmet need•Both the everolimus/letrozole and hormonal therapy arms in this study appear to be clinically active regimens•Combination of everolimus/letrozole had a 22% response rate. Chemo-naïve patients had 28-month progression-free survival.•Everolimus/letrozole and its response frequency in chemo-naïve population are worthy of additional investigation.
Abstract
Forest characteristics, structure, and dynamics within the North American boreal region are heavily influenced by wildfire intensity, severity, and frequency. Increasing temperatures are ...likely to result in drier conditions and longer fire seasons, potentially leading to more intense and frequent fires. However, an increase in deciduous forest cover is also predicted across the region, potentially decreasing flammability. In this study, we use an individual tree-based forest model to test bottom-up (i.e. fuels) vs top-down (i.e. climate) controls on fire activity and project future forest and wildfire dynamics. The University of Virginia Forest Model Enhanced is an individual tree-based forest model that has been successfully updated and validated within the North American boreal zone. We updated the model to better characterize fire ignition and behavior in relation to litter and fire weather conditions, allowing for further interactions between vegetation, soils, fire, and climate. Model output following updates showed good agreement with combustion observations at individual sites within boreal Alaska and western Canada. We then applied the updated model at sites within interior Alaska and the Northwest Territories to simulate wildfire and forest response to climate change under moderate (RCP 4.5) and extreme (RCP 8.5) scenarios. Results suggest that changing climate will act to decrease biomass and increase deciduous fraction in many regions of boreal North America. These changes are accompanied by decreases in fire probability and average fire intensity, despite fuel drying, indicating a negative feedback of fuel loading on wildfire. These simulations demonstrate the importance of dynamic fuels and dynamic vegetation in predicting future forest and wildfire conditions. The vegetation and wildfire changes predicted here have implications for large-scale changes in vegetation composition, biomass, and wildfire severity across boreal North America, potentially resulting in further feedbacks to regional and even global climate and carbon cycling.
A considerable body of research supports the use of behavioral communication treatment as the standard of care for aphasia. In spite of robust progress in clinical aphasiology, many questions ...regarding optimal care remain unanswered. One of the major challenges to progress in the field is the lack of a common framework to adequately describe individual treatments, which, if available, would allow comparisons across studies as well as improved communication among researchers, clinicians, and other stakeholders. Here, we describe how aphasia treatment approaches can be systematically characterized using the Rehabilitation Treatment Specification System (RTSS). At the core of the RTSS is a tripartite structure that focuses on targets (the behavior that is expected to change as a result of treatment), ingredients (what a clinician does to affect change in the target), and mechanism(s) of action (why a given treatment works by linking the ingredients to the target). Three separate articles in the current issue specifically describe how the RTSS can be used to describe different kinds of aphasia treatment approaches: functional approaches, cognitive-linguistic approaches, and biological approaches. It is our hope that the application of the RTSS in clinical aphasiology will improve communication in published studies, grant proposals, and in the clinical care of persons with aphasia.
Obesity is a prevailing problem across the globe. Women who are obese have difficulty initiating and sustaining lactation. However, the impact of genetics and diet on breastfeeding outcomes is ...understudied. Here we explore the effect of diet and genotype on lactation. We utilized the low-density lipoprotein receptor (
KO) transgenic mouse model as an obesity and hypercholesterolemia model. Additionally, we used the tryptophan hydroxylase 1 (
-KO) mouse, recently identified as a potential anti-obesogenic model, to investigate if addition of
-KO could ameliorate negative effects of obesity in
-KO mice. We created a novel transgenic mouse line by combining the
and
double knockout (DKO) mice to study the interaction between the two genotypes. Female mice were fed a low-fat diet (LFD; 10% fat) or high-fat diet (HFD; 60% fat) from 3 wk of age through early lactation
(L3) or peak lactation lactation
(L11). After 4 wk of consuming either LFD or HFD, female mice were bred. On L2 and L10, dams were milked to investigate the effect of diet and genotype on milk composition. Dams were euthanized on L3 or L11. There was no impact of diet or genotype on milk protein or triglycerides (TGs) on L2; however, by L10,
KO and DKO dams had increased TG levels in milk. RNA-sequencing of L11 mammary glands demonstrated
-KO dams fed HFD displayed enrichment of genes involved in immune system pathways. Interestingly, the DKO may alter vesicle budding and biogenesis during lactation. We also quantified macrophages by immunostaining for F4/80+ cells at L3 and L11. Diet played a significant role on L3 (
= 0.013), but genotype played a role at L11 (
< 0.0001) on numbers of F4/80+ cells. Thus the impact of diet and genotype on lactation differs depending on stage of lactation, illustrating complexities of understanding the intersection of these parameters.
We have created a novel mouse model that is focused on understanding the intersection of diet and genotype on mammary gland function during lactation.
Abstract
BACKGROUND:
Severe traumatic brain injury (TBI) in children is associated with substantial long-term morbidity and mortality. Currently, there are no successful ...neuroprotective/neuroreparative treatments for TBI. Numerous preclinical studies suggest that bone marrow-derived mononuclear cells (BMMNCs), their derivative cells (marrow stromal cells), or similar cells (umbilical cord blood cells) offer neuroprotection.
OBJECTIVE:
To determine whether autologous BMMNCs are a safe treatment for severe TBI in children.
METHODS:
Ten children aged 5 to 14 years with a postresuscitation Glasgow Coma Scale of 5 to 8 were treated with 6 × 106 autologous BMMNCs/kg body weight delivered intravenously within 48 hours after TBI. To determine the safety of the procedure, systemic and cerebral hemodynamics were monitored during bone marrow harvest; infusion-related toxicity was determined by pediatric logistic organ dysfunction (PELOD) scores, hepatic enzymes, Murray lung injury scores, and renal function. Conventional magnetic resonance imaging (cMRI) data were obtained at 1 and 6 months postinjury, as were neuropsychological and functional outcome measures.
RESULTS:
All patients survived. There were no episodes of harvest-related depression of systemic or cerebral hemodynamics. There was no detectable infusion-related toxicity as determined by PELOD score, hepatic enzymes, Murray lung injury scores, or renal function. cMRI imaging comparing gray matter, white matter, and CSF volumes showed no reduction from 1 to 6 months postinjury. Dichotomized Glasgow Outcome Score at 6 months showed 70% with good outcomes and 30% with moderate to severe disability.
CONCLUSION:
Bone marrow harvest and intravenous mononuclear cell infusion as treatment for severe TBI in children is logistically feasible and safe.
Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers ...with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19.
Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients >7 days to <1 year old hospitalized with symptomatic acute COVID-19.
We report 232 infants >7 days to <1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients >7 days to <18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and <1% died.
Infants accounted for over a fifth of children <18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were <6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant.
This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on ...regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma.
This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21-24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response.
Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively,
= 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (
= 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (
< 0.008).
This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.
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