Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Ability of Countermovement Jumps to Detect Bilateral Asymmetry in Hip and Knee Strength in Elite Youth Soccer Players

Clinicians frequently assess asymmetry in strength, flexibility, and performance characteristics as a method of screening for potential musculoskeletal injury. The identification of asymmetry in countermovement jumps may be an ideal method to reveal asymmetry in other lower extremity characteristics such as strength that otherwise may require additional testing, potentially reducing the time and burden on both the athlete and clinicians. The present study aims to examine the ability of asymmetry in both the single-leg and two-leg countermovement jump tests to accurately detect hip abduction, hip adduction, and eccentric hamstring strength asymmetry. Fifty-eight young male elite soccer players from the same professional academy performed a full battery of functional performance tests which included an assessment of hip adductor and abductor strength profiles, eccentric hamstring strength profiles, and neuromuscular performance and asymmetries during countermovement jumps. Bilateral variables attained from both the single-leg and two-leg countermovement jump tests included concentric impulse (Ns), eccentric mean force (N), and concentric mean force (N) computed by the VALD ForceDecks software. Average maximal force (N) was calculated bilaterally for the strength assessments. Asymmetry was calculated for each variable using 100 × |(right leg − left leg)/(right leg)| and grouped into three categories: 0 to <10%, 10% to <20%, and 20% or greater. Analyses were performed for the two higher asymmetry groups. The accuracy to detect strength asymmetry was assessed as the sensitivity, specificity, and predictive values for positive and negative tests. The outcomes from the accuracy assessments suggest that the single-leg countermovement jump concentric impulse variable at the 20% threshold is indicative of a youth male soccer player having hip adduction strength asymmetry while also demonstrating more accuracy and applicability than the two-leg countermovement jump concentric impulse variable

Using Medicare claims in identifying Alzheimer’s disease and related dementias

IntroductionThis study develops a measure of Alzheimer’s disease and related dementias (ADRD) using Medicare claims.MethodsValidation resembles the approach of the American Psychological Association, including (1) content validity, (2) construct validity, and (3) predictive validity.ResultsWe found that four items—a Medicare claim recording ADRD 1 year ago, 2 years ago, 3 years ago, and a total stay of 6 months in a nursing home—exhibit a pattern of association consistent with a single underlying ADRD construct, and presence of any two of these four items predict a direct measure of cognitive function and also future claims for ADRD.DiscussionOur four items are internally consistent with the measurement of a single quantity. The presence of any two items do a better job than a single claim when predicting both a direct measure of cognitive function and future ADRD claims.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167116/1/alz12199_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167116/2/alz12199.pd

Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release

International audienc