The chromosome 3q29 microdeletion syndrome is characterized by a clinical phenotype that includes behavioral features consistent with autism and attention deficit hyperactivity disorder, mild to ...moderate developmental delay, language-based learning disabilities, and/or dysmorphic features. In addition, recent data suggest that adults with chromosome 3q29 microdeletions have a significantly increased risk for psychosis and neuropsychiatric phenotypes.
We report a 3-year-old male with global developmental delay, anemia, and mild dysmorphic facial features. Clinical chromosomal microarray (CMA) testing of the proband detected a heterozygous 1.21 Mb deletion at chromosome 3q29, consistent with a diagnosis of the 3q29 microdeletion syndrome. Interestingly, subsequent parental testing determined that the pathogenic deletion was inherited from his otherwise healthy mother who had a history of learning disabilities. The chromosome 3q29 microdeletion was not detected in the healthy older sibling of the proband by CMA testing, nor was it prenatally detected in a subsequent maternal pregnancy.
Our report highlights the 3q29 microdeletion syndrome as an illustrative example of the importance of a molecular diagnosis for families that harbor pathogenic copy number aberrations with variable expressivity, in particular those that also impart an increased risk for adult onset neuropsychiatric phenotypes.
Abstract
Despite periodic drops in popularity, Arctic sled dogs continue to play a vital role in northern societies, providing both freight transit and recreational race activities. In this study, we ...selected the Mackenzie River Husky, a freight dog of complex history, and the Chinook, an American Kennel Club recognized freight dog breed whose heritage reportedly overlaps that of the MKRH, for detailed population analysis. We tested each to determine their component breeds and used admixture analysis to ascertain their population structure. We utilized haplotype analysis to identify genomic regions shared between each population and their founding breeds. Our data show that the Alaskan Malamutes and modern Greenland sled dog contributed to both populations, but there are also unexpected contributions from the German Shepherd dog and Collie. We used haplotype analysis to identify genomic regions nearing fixation in population type and identify provocative genes in each region. Finally, in response to recent reports regarding the importance of dietary lipid genes in Arctic dogs, we analyzed 8 such genes in a targeted analysis observing signatures of selection in both populations at the MLXIPL gene loci. These data highlight the genetic routes that breeds of similar function have taken toward their occupation as successful sled dogs.
Abstract
MicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated ...protein 1(KEAP1) expression by targeting its 3′-untranslated region (3′UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, β-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting β-catenin reduced miR-421 levels in A549 cells. In addition, β-catenin upregulation enhanced miR-421 expression, indicating that β-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.
Practitioners in health departments, university extension programs, and nonprofit organizations working in public health face varied challenges to publishing in the peer-reviewed literature. These ...practitioners may lack time, support, skills, and efficacy needed for manuscript submission, which keeps them from sharing their wisdom and experience-based evidence. This exclusion can contribute to literature gaps, a failure of evidence-based practice to inform future research, reduced ability to educate partners, and delays in advancing public health practice. Our article describes the writing workshops offered to Division of Nutrition, Physical Activity, and Obesity (DNPAO), Centers for Disease Control and Prevention (CDC) funded programs in 2021. This project consisted of three 60-minute introductory writing webinars open to all recipients, followed by a Writing for Publications workshop, an 8- to 9-week virtual learning/writing intensive for selected writing team applicants. The Society for Public Health Education staff, consultants, and CDC/DNPAO staff developed, refined, and presented the curriculum. The workshop for public health practitioner writing teams was offered to two cohorts and included extensive coaching and focused on potential submission to a Health Promotion Practice supplement, “Reducing Chronic Disease through Physical Activity and Nutrition: Public Health Practice in the Field” (see Supplemental Material), which was supported by CDC/DNPAO. We describe the webinars, the workshop design, modifications, evaluation methods and results.
Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood, and ...accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory and malignant diseases
. Here we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that respond to the microbiota and express the transcription factor RORγt. We profiled all RORγt
immune cells at single-cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of T regulatory (T
) cells and lymphoid tissue inducer-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s are distinct from extrathymic AIRE-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt
T
cells and prevent their expansion as inflammatory T helper 17 cells. This occurs through ILC3-mediated antigen presentation, αV integrin and competition for interleukin-2. Finally, single-cell analyses suggest that interactions between ILC3s and RORγt
T
cells are impaired in inflammatory bowel disease. Our results define a paradigm whereby ILC3s select for antigen-specific RORγt
T
cells, and against T helper 17 cells, to establish immune tolerance to the microbiota and intestinal health.
Several studies have measured health outcomes in the United States, but none have provided a comprehensive assessment of patterns of health by state.
To use the results of the Global Burden of ...Disease Study (GBD) to report trends in the burden of diseases, injuries, and risk factors at the state level from 1990 to 2016.
A systematic analysis of published studies and available data sources estimates the burden of disease by age, sex, geography, and year.
Prevalence, incidence, mortality, life expectancy, healthy life expectancy (HALE), years of life lost (YLLs) due to premature mortality, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 333 causes and 84 risk factors with 95% uncertainty intervals (UIs) were computed.
Between 1990 and 2016, overall death rates in the United States declined from 745.2 (95% UI, 740.6 to 749.8) per 100 000 persons to 578.0 (95% UI, 569.4 to 587.1) per 100 000 persons. The probability of death among adults aged 20 to 55 years declined in 31 states and Washington, DC from 1990 to 2016. In 2016, Hawaii had the highest life expectancy at birth (81.3 years) and Mississippi had the lowest (74.7 years), a 6.6-year difference. Minnesota had the highest HALE at birth (70.3 years), and West Virginia had the lowest (63.8 years), a 6.5-year difference. The leading causes of DALYs in the United States for 1990 and 2016 were ischemic heart disease and lung cancer, while the third leading cause in 1990 was low back pain, and the third leading cause in 2016 was chronic obstructive pulmonary disease. Opioid use disorders moved from the 11th leading cause of DALYs in 1990 to the 7th leading cause in 2016, representing a 74.5% (95% UI, 42.8% to 93.9%) change. In 2016, each of the following 6 risks individually accounted for more than 5% of risk-attributable DALYs: tobacco consumption, high body mass index (BMI), poor diet, alcohol and drug use, high fasting plasma glucose, and high blood pressure. Across all US states, the top risk factors in terms of attributable DALYs were due to 1 of the 3 following causes: tobacco consumption (32 states), high BMI (10 states), or alcohol and drug use (8 states).
There are wide differences in the burden of disease at the state level. Specific diseases and risk factors, such as drug use disorders, high BMI, poor diet, high fasting plasma glucose level, and alcohol use disorders are increasing and warrant increased attention. These data can be used to inform national health priorities for research, clinical care, and policy.
Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y ...crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome of
(bull) and find it to be dominated by massive, lineage-specific amplification of testis-expressed gene families, making it the most gene-dense Y Chromosome sequenced to date. As in mice, an X-linked homolog of a bull Y-amplified gene has become testis-specific and amplified. This evolutionary convergence implies that lineage-specific X-Y coevolution through gene amplification, and the selfish forces underlying this phenomenon, were dominatingly powerful among diverse mammalian lineages. Together with Y gene decay, X-Y arms races molded mammalian sex chromosomes and influenced the course of mammalian evolution.
The use of modular components in total hip arthroplasty introduced an additional interface with the potential for fretting and corrosion to occur. Fretting and corrosion at this interface have been ...reported as a potential cause of early failure of the implant system. Using finite element (FE) analyses the mechanics at the taper junction can be studied. However, most FE studies are based on a single load condition and do not take geometry changes over time into account. Therefore, in this study an FE routine was developed, in which adaptations to the implant geometry are made to account for material removal during the fretting process. Material removal was simulated based on Archard's Law, incorporating contact pressure, micromotions and a wear factor which used input from in vitro fretting tests. A wear factor of 2.7*10
mm
/Nmm was used to match the FE predicted volumetric wear to the measured experimental volumetric wear of 0.79mm
after 10 million cycles. The maximum experimental wear depth found was 30.5 ± 17µm, while the FE predicted a maximum wear depth of 27µm. The adaptive meshing method has delivered results that are more similar to the experimental test data in comparison to the results from modelling a single cycle without adaptive meshing.
Abstract
OBJECTIVES
Rapid diameter growth is a criterion for ascending thoracic aortic aneurysm repair; however, there are sparse data on aneurysm elongation rate. The purpose of this study was to ...assess aortic elongation rates in nonsyndromic, nonsurgical aneurysms to understand length dynamics and correlate with aortic diameter over time.
METHODS
Patients with <5.5-cm aneurysms and computed tomography angiography imaging at baseline and 3–5 years follow-up underwent patient-specific three-dimensional aneurysm reconstruction using MeVisLab. Aortic length was measured along the vessel centreline between the annulus and aortic arch. Maximum aneurysm diameter was determined from imaging in a plane normal to the vessel centreline. Average rates of aneurysm growth were evaluated using the longest available follow-up.
RESULTS
Over the follow-up period, the mean aortic length for 67 identified patients increased from 118.2 (95% confidence interval: 115.4–121.1) mm to 120.2 (117.3–123.0) mm (P = 0.02) and 15 patients (22%) experienced a change in length of ≥5% from baseline. The mean annual growth rate for length 0.38 (95% confidence interval: 0.11–0.65) mm/year was correlated with annual growth rate for diameter 0.1 (0.03–0.2) mm/year (rho = 0.30, P = 0.01). Additionally, annual percentage change in length 0.3 (0.1–0.5)%/year was similar to percentage change in diameter 0.2 (0.007–0.4)%/year, P = 0.95.
CONCLUSIONS
Aortic length increases in parallel with aortic diameter at a similar percentage rate. Further work is needed to identify whether elongation rate is associated with dissection risk. Such studies may provide insight into why patients with aortic diameters smaller than surgical guidelines continue to experience dissection events.
Acute type A aortic dissection (ATAD) is a rare but highly fatal phenomenon, with an incidence of 2.0 per 100 000 persons but a total hospital mortality rate as high as 53% 1, 2.
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