Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans

Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a "strong" level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval

Expanding the allelic spectrum of ELOVL4‐related autosomal recessive neuro‐ichthyosis

Background Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. Methods We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. Results We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Conclusion Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation

Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling

Sexually dimorphic gene expression emerges with embryonic genome activation and is dynamic throughout development

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainVKR is supported by grants from the Biotechnology and Biological Sciences Research Council, UK (BB/M012494/1), VKR and CG by (BB/G00711/X/1). MLH is supported by a Research Council UK Academic Fellowship. RL is supported by EU-FP7 BLUEPRINT

Women’s responses to changes in U.S. preventive task force’s mammography screening guidelines: results of focus groups with ethnically diverse women

Background: The 2009 U.S. Preventive Services Task Force (USPSTF) changed mammography guidelines to recommend routine biennial screening starting at age 50. This study describes women’s awareness of, attitudes toward, and intention to comply with these new guidelines. Methods: Women ages 40–50 years old were recruited from the Boston area to participate in focus groups (k = 8; n = 77). Groups were segmented by race/ethnicity (Caucasian = 39%; African American = 35%; Latina = 26%), audio-taped, and transcribed. Thematic content analysis was used. Results: Participants were largely unaware of the revised guidelines and suspicious that it was a cost-savings measure by insurers and/or providers. Most did not intend to comply with the change, viewing screening as obligatory. Few felt prepared to participate in shared decision-making or advocate for their preferences with respect to screening. Conclusions: Communication about the rationale for mammography guideline changes has left many women unconvinced about potential disadvantages or limitations of screening. Since further guideline changes are likely to occur with advances in technology and science, it is important to help women become informed consumers of health information and active participants in shared decision-making with providers. Additional research is needed to determine the impact of the USPSTF change on women’s screening behaviors and on breast cancer outcomes

The Liberation of Embryonic Stem Cells

Mouse embryonic stem (ES) cells are defined by their capacity to self-renew and their ability to differentiate into all adult tissues including the germ line. Along with efficient clonal propagation, these properties have made them an unparalleled tool for manipulation of the mouse genome. Traditionally, mouse ES (mES) cells have been isolated and cultured in complex, poorly defined conditions that only permit efficient derivation from the 129 mouse strain; genuine ES cells have not been isolated from another species in these conditions. Recently, use of small molecule inhibitors of glycogen synthase kinase 3 (Gsk3) and the Fgf-MAPK signaling cascade has permitted efficient derivation of ES cells from all tested mouse strains. Subsequently, the first verified ES cells were established from a non-mouse species, Rattus norvegicus. Here, we summarize the advances in our understanding of the signaling pathways regulating mES cell self-renewal that led to the first derivation of rat ES cells and highlight the new opportunities presented for transgenic modeling on diverse genetic backgrounds. We also comment on the implications of this work for our understanding of pluripotent stem cells across mammalian species

ANALISIS REPRESENTASI TRADISI KEMATIAN PADA NOVEL PUYA KE PUYA KARYA FAISAL ODDANG

Death tradition is a ceremonial process that is done from generation to generation as the delivery of died people before actually going to another world (immortality).One of death traditions in Indonesia that is still done and well-known to foreign countries is Rambu Solo’ in Toraja. Rambu Solo’ is done as the process of perfecting died people. Death tradition is depicted in Puya Ke Puya novel by Faisal Oddang. Based on that thing, the problem formulation in this research, are (1) how is the representation of death ceremony stages in Puya Ke Puya novel by Faisal Oddang, (2) how are the meanings of death ceremony stages in Puya Ke Puya novel by Faisal Oddang. The method used in this research is descriptive method of analysis using literary anthropology approach. The source of data in this study is Puya Ke Puya novel by Faisal Oddang by concerning data quotations, sentences, as well as units of stories in the novel. Data found in this researh is processed through several stages, such as (1) collecting data, (2) classifying data, (3) data assessment, (4) drawing conclusion. The result of the analysis and discussion shows that in Puya Ke Puya novel by Faisal Oddang, it is found two processes of ceremonial stages and the meaning of process stages as representation of death tradition in Rambu Solo '. Death ceremony stages are (1) before death ceremony process and (2) during death ceremony process. Before the ceremony, there are several things that are need to be done and prepared by the family including holding big family meeting to determine when the Rambu Solo’ ceremony will be held, determining the level of death ceremony, preparing or buying buffaloes and pigs, preparing the necessary equipments. The next stage is the process of death ceremony. In this stage which includes Mappassulu ', Mangriu' Batu, Mapopengkaloa, Ma'pasonglo, Tau-tau, Lantang, Mappasilaga Tedong, Mantunu Tedong and ipalao. The meaning of Rambu Solo’ ceremony stage is a process of completion of died people so that they can get to puya. If it is not celebrated, thw aoul of died people will be stuck between heaven and earth in uncertain fate or become ghosts. It is also believed that it brings misfortune for families of died people. This is the belief of Toraja people