Little is known about how human Y-Chromosome gene expression directly contributes to differences between XX (female) and XY (male) individuals in nonreproductive tissues. Here, we analyzed ...quantitative profiles of Y-Chromosome gene expression across 36 human tissues from hundreds of individuals. Although it is often said that Y-Chromosome genes are lowly expressed outside the testis, we report many instances of elevated Y-Chromosome gene expression in a nonreproductive tissue. A notable example is
, which encodes eukaryotic translation initiation factor 1A Y-linked, together with its X-linked homolog
Evolutionary loss of a Y-linked microRNA target site enabled up-regulation of
, but not of
, in the heart. Consequently, this essential translation initiation factor is nearly twice as abundant in male as in female heart tissue at the protein level. Divergence between the X and Y Chromosomes in regulatory sequence can therefore lead to tissue-specific Y-Chromosome-driven sex biases in expression of critical, dosage-sensitive regulatory genes.
The meiosis-specific chromosomal events of homolog pairing, synapsis, and recombination occur over an extended meiotic prophase I that is many times longer than prophase of mitosis. Here we show ...that, in mice, maintenance of an extended meiotic prophase I requires the gene Meioc, a germ-cell specific factor conserved in most metazoans. In mice, Meioc is expressed in male and female germ cells upon initiation of and throughout meiotic prophase I. Mouse germ cells lacking Meioc initiate meiosis: they undergo pre-meiotic DNA replication, they express proteins involved in synapsis and recombination, and a subset of cells progress as far as the zygotene stage of prophase I. However, cells in early meiotic prophase-as early as the preleptotene stage-proceed to condense their chromosomes and assemble a spindle, as if having progressed to metaphase. Meioc-deficient spermatocytes that have initiated synapsis mis-express CYCLIN A2, which is normally expressed in mitotic spermatogonia, suggesting a failure to properly transition to a meiotic cell cycle program. MEIOC interacts with YTHDC2, and the two proteins pull-down an overlapping set of mitosis-associated transcripts. We conclude that when the meiotic chromosomal program is initiated, Meioc is simultaneously induced so as to extend meiotic prophase. Specifically, MEIOC, together with YTHDC2, promotes a meiotic (as opposed to mitotic) cell cycle program via post-transcriptional control of their target transcripts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sex differences abound in human health and disease, as they do in other mammals used as models. The extent to which sex differences are conserved at the molecular level across species and tissues is ...unknown. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased expression-findings that, combined with genomic analyses of human height, explain ~12% of the difference in height between females and males. We surmise that conserved sex biases in expression of genes otherwise operating equivalently in females and males contribute to sex differences in traits. However, most sex-biased expression arose during the mammalian radiation, which suggests that careful attention to interspecies divergence is needed when modeling human sex differences.
The “inactive” X chromosome (Xi) has been assumed to have little impact, in trans, on the “active” X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to ...three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes.
Display omitted
•Analyzed gene expression in sex chromosome aneuploidy samples using linear models•Xi and Xa transcriptomes are modular•38% of X chromosome genes are affected by Xi copy number—in cis and in trans•10 X chromosome genes likely contribute to male-female differences in somatic tissues
Through RNA sequencing of individuals with sex chromosome aneuploidy, San Roman et al. identify modular “active” (Xa) and “inactive” (Xi) X chromosome transcriptomes. Looking beyond classical X inactivation, which acts in cis, they find that Xi modulates Xa transcript levels in trans. They identify 10 X chromosome genes most likely to contribute to male-female differences in common disease.
Somatic cells of human males and females have 45 chromosomes in common, including the “active” X chromosome. In males the 46th chromosome is a Y; in females it is an “inactive” X (Xi). Through linear ...modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors—ZFX and ZFY—encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.
Display omitted
•Linear modeling of autosomal gene expression in sex chromosome aneuploidy samples•Xi and Y affect expression of 21% of all genes expressed in the cell types tested•Xi and Y have broadly similar effects on gene expression across the genome•A pair of transcription factors on X and Y mediate much of this shared response
Using human cells with variation in sex chromosome copy number, San Roman et al. find widespread transcriptomic impacts of the inactive X (Xi) and Y chromosome on autosomes. While Xi elicited larger gene-by-gene effects, Y’s effects were largely concordant. They demonstrate that ZFX and ZFY, a pair of conserved transcription factors encoded by the X and Y chromosomes, mediate much of this shared genome-wide transcriptional program.
To describe the referral patterns of children with primary childhood glaucoma (PCG) or secondary childhood glaucoma (SCG) and their presenting symptoms in Northern Tanzania.
A retrospective ...observational study of children <17y with PCG or SCG who were referred to Kilimanjaro Christian Medical Centre (KCMC) Eye Department between 2000 and 2013 was conducted. Presenting symptoms, age at presentation, place of origin, distance to hospital, type of glaucoma, visual acuity, optic disc appearance (vertical cup-to-disc ratio) and type of referral were described.
Seventy patients with PCG and 27 patients with SCG were included in the study. Median age at first presentation was 1y in the PCG group (range 0-16y) and 9y in the SCG group (range 1-15y). In both groups around 87% of the children presented already with low vision (logMAR>0.48, better eye). Most of the children (60%) and their caretakers presented on their own initiative, while 24% were sent by different general health cadres and 16% by eye care professionals. Buphthalmos was the main symptom mentioned as a trigger for presentation.
The study shows that most of the children presented late resulting in advanced stages of glaucoma at the time of initiation of treatment. The majority attended the referral eye department on their own initiative with buphthalmos being the most commonly described symptom. Awareness creation among caretakers of children, general health and eye care providers, ideally embedded in general child health promotion activities, is needed to increase and accelerate referrals.
Measles (rubeola) is a highly contagious childhood vaccine-preventable disease caused by the measles virus.1 2 Complications occur in 10% to 40% of affected patients, and treatment is mainly ...symptomatic.1 3 4 5 6 In developed countries, routine immunisation with measles-containing vaccine is recommended with the first dose at age 12 to 15 months and the second dose at age 4 to 6 years.7 8 In regions with high rates of measles transmission, the World Health Organization (WHO) recommends that the first dose of measles-containing vaccine be given at age 9 months and the second dose at age 15 to 18 months.9 Studies have shown that one dose of measles vaccine given at or after 1 year of age is 93% to 95% effective in protecting against measles whereas two doses given at appropriate intervals is close to 100% effective.8 Measles vaccination given to susceptible contacts within 72 hours of exposure is effective in preventing illness or modifying the severity of the illness.9 10 Recently, outbreaks of measles have been reported globally, especially in Asia.1 11 12 An outbreak in early 2019 at the Hong Kong International Airport also created a public health concern, with wide national media coverage.13 Between March and mid-May 2019, 73 individuals were identified to have been infected with measles, including 29 airport workers.14 In general, patients with measles after vaccine failure were less ill than unvaccinated patients. ...these patients required the same amount of effort from public health workers in tracing contacts.15 Of the 50 individuals infected with measles, six had two doses of measles vaccination. The Centers for Disease Control and Prevention recommends that medical staff who have no antibodies to measles should not be allowed to work for 5 to 14 days after exposure to measles, even after receiving post-exposure prophylaxis with measles vaccine.18 Issue 2: Infection control Several infectious diseases have been a cause for concern at Hong Kong International Airport, including SARS (severe acute respiratory syndrome),21 MERS (Middle East respiratory syndrome),22 Avian Influenza, and seasonal influenza.23 Ordinary surgical masks are not designed for airborne infection and it is uncertain if aircrew and other staff wearing such masks plays any role in the prevention of spread of measles and other airborne diseases.24 For infectious diseases including measles, although infection control is an important gesture, universal immunisation is the definitive management strategy.1 3 6 8 9 The rise of anti-vaccination material on social media has been connected to the dramatic increase in cases of measles and various vaccine-preventable communicable diseases.25 Healthcare workers should join efforts to promote immunisation as an effective healthcare policy in infection control.26 Summary Epidemics of infectious diseases raise many dilemmas, such as the effectiveness of vaccination programmes, which groups are most at risk, and how to prioritise further treatment or vaccination.
Human induced pluripotent stem cells (hiPSCs) are useful in disease modeling and drug discovery, and they promise to provide a new generation of cell-based therapeutics. To date there has been no ...systematic evaluation of the most widely used techniques for generating integration-free hiPSCs. Here we compare Sendai-viral (SeV), episomal (Epi) and mRNA transfection mRNA methods using a number of criteria. All methods generated high-quality hiPSCs, but significant differences existed in aneuploidy rates, reprogramming efficiency, reliability and workload. We discuss the advantages and shortcomings of each approach, and present and review the results of a survey of a large number of human reprogramming laboratories on their independent experiences and preferences. Our analysis provides a valuable resource to inform the use of specific reprogramming methods for different laboratories and different applications, including clinical translation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
