Explore the vast range of titles available.

In mammals, imprinted genes are regulated by differentially methylated regions (DMRs) that are inherited from germ cells, leading to monoallelic expression in accordance with parent-of-origin. Yet, it is largely unknown how imprinted DMRs are maintained in human embryos despite global DNA demethylation following fertilization. Here, we explored the mechanisms involved in imprinting regulation by employing human parthenogenetic embryonic stem cells (hpESCs), which lack paternal alleles. We show that although global loss of DNA methylation in hpESCs affects most imprinted DMRs, many paternally-expressed genes (PEGs) remain repressed. To search for factors regulating PEGs, we performed a genome-wide CRISPR/Cas9 screen in haploid hpESCs. This revealed ATF7IP as an essential repressor of a set of PEGs, which we further show is also required for silencing sperm-specific genes. Our study reinforces an important role for histone modifications in regulating imprinted genes and suggests a link between parental imprinting and germ cell identity. Genetic imprinting ensures monoallelic gene expression critical for normal embryonic development. Here the authors take advantage of human haploid parthenogenic embryonic stem cells lacking paternal alleles to identify, by genome-wide screening, factors involved in the regulation of imprinted genes.

The authors surveyed whole-exome and RNA-sequencing data from 252 unique pluripotent stem cell lines, some of which are in the pipeline for clinical use, and found that approximately 5% of cell lines had acquired mutations in the TP53 gene that allow mutant cells to rapidly outcompete non-mutant cells, but do not prevent differentiation. Expansion of human pluripotent stem cells carrying P53 mutations Copy number variants at particular genomic locations have been shown to arise in human pluripotent stem cells (hPSCs) under certain culture conditions, but the extent of acquired mutations in such culture remains to be determined. Kevin Eggan and colleagues surveyed the exomes of 140 human embryonic stem cell (hESC) lines, some of which are in the pipeline for clinical use.They identified mosaic mutations in the TP53 gene in a subset of cells for five unrelated hESC lines and show that the cells carrying the mutations outcompeted the non-mutant cells and could readily differentiate. Similar mutations were also identified by mining published datasets for an additional 14 hESC lines and more than 100 human induced PSC lines. The study highlights the need for in-depth characterization of cells derived from hPSCs before their use in the clinic. Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture 1 , 2 , 3 . The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use 4 . We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line 5 . Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.

Body composition is an important predictor in cancer patients, with skeletal muscle loss and high adiposity associated with poorer prognosis. This study evaluated how body composition affects treatment efficacy in 48 women with metastatic breast cancer receiving trastuzumab deruxtecan. Using computed tomography, skeletal muscle, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were assessed within 60 days before initiating treatment. High SAT and VAT areas were significantly associated with a higher likelihood of dose reductions (Odds Ratio [OR] = 5.34, p = .032 and OR = 5.52, p = 0.032, respectively). Higher SAT areas correlated with a lower objective response rate (OR = 0.22, p = 0.047). Medium SAT and low/medium VAT densities increased the risk of dose reductions. A body mass index over 25 kg/m 2 was linked to higher dose reductions (OR = 4.97, p = 0.016). These findings emphasize the need for personalized treatment strategies based on body composition.

Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and whether cellular differentiation affects chaperone expression. Our bioinformatics analyses show that the myogenic transcription factor HLH-1 (MyoD) can bind to the promoters of chaperone genes expressed or required for the folding of muscle proteins. To test this experimentally, we employed HLH-1 myogenic potential to genetically modulate cellular differentiation of Caenorhabditis elegans embryonic cells by ectopically expressing HLH-1 in all cells of the embryo and monitoring chaperone expression. We found that HLH-1-dependent myogenic conversion specifically induced the expression of putative HLH-1-regulated chaperones in differentiating muscle cells. Moreover, disrupting the putative HLH-1-binding sites on ubiquitously expressed daf-21(Hsp90) and muscle-enriched hsp-12.2(sHsp) promoters abolished their myogenic-dependent expression. Disrupting HLH-1 function in muscle cells reduced the expression of putative HLH-1-regulated chaperones and compromised muscle proteostasis during and after embryogenesis. In turn, we found that modulating the expression of muscle chaperones disrupted the folding and assembly of muscle proteins and thus, myogenesis. Moreover, muscle-specific over-expression of the DNAJB6 homolog DNJ-24, a limb-girdle muscular dystrophy-associated chaperone, disrupted the muscle chaperone network and exposed synthetic motility defects. We propose that cellular differentiation could establish a proteostasis network dedicated to the folding and maintenance of the muscle proteome. Such cell-specific proteostasis networks can explain the selective vulnerability that many diseases of protein misfolding exhibit even when the misfolded protein is ubiquitously expressed.

BackgroundExstrophy-epispadias complex (EEC) is a complex malformation of the lower abdominal wall, bladder, and pelvic floor, which necessitates multiple successive reconstruction procedures. Surgical and infectious complications are frequent. Our aim was to evaluate kidney function in these patients.MethodsThis cross-sectional study included patients with EEC, followed since birth in a pediatric urology clinic, who underwent nephrological evaluation (blood pressure (BP) measurement and blood and urine chemistries) and imaging studies (urinary tract ultrasound and DMSA kidney scan) during 2017–2020.ResultsForty-three patients (29 males), median age 9 years (interquartile range 6–19), were included. Eleven (26%) used clean intermittent catheterization (CIC) for bladder drainage. At least one sign of kidney injury was identified in 32 (74%) patients; elevated BP, decreased kidney function (estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m2), and proteinuria/albuminuria were detected in 29%, 12%, and 36% of patients, respectively. Urinary tract dilatation (UTD) was found in 13 (37%) ultrasound examinations. Parenchymal kidney defects were suspected in 46% and 61% of ultrasound and DMSA scintigraphy, respectively. UTD was significantly associated with DMSA-proven kidney defects (p = 0.043) and with elevated BP, 39% vs. 20% in those without UTD. Decreased eGFR and elevated BP were less frequent among patients on CIC than among patients who voided spontaneously: 10% vs. 14% and 18% vs. 36%, respectively. Recurrent UTIs/bacteriuria and nephro/cystolithiasis were reported by 44% and 29% patients, respectively.ConclusionThe high rate of signs of kidney injury in pediatric patients with EEC dictates early-onset long-term kidney function monitoring by joint pediatric urological and nephrological teams.A higher resolution version of the Graphical abstract is available as Supplementary information

Acute Respiratory Distress Syndrome (ARDS) is a major health concern with urgent unmet need for treatment options. There are three million new ARDS cases annually, and the disease’s mortality rate is high (35–46%). Cluster of differentiation 24 (CD24), a long-known protein with multifaceted functions, is a small, heavily glycosylated, membrane-anchored protein which functions as an immune checkpoint control. CD24 allows for immune discrimination between Damage-Associated Molecular Patterns and Pathogen-Associated Molecular Patterns derived from pathogens. Exosomes are intraluminal vesicles which play an important role in intercellular communication. Exosomes offer the advantage of targeted delivery, which improves safety and efficacy. The safety and efficacy of EXO-CD24 is promising, as was shown in >180 ARDS patients in phase 1b/2a, phase 2b, and compassionate use. CD24 binds Damage-associated molecular patterns (DAMPs) and inhibits the activation of the NF-ĸB pathway, a pivotal mediator of inflammatory responses. In contrast to anti-inflammatory therapies that are cytokine-specific or steroids that shut down the entire immune system, EXO-CD24 acts upstream, reverting the immune system back to normal activity. Herein, the safety and efficacy of mEXO-CD24 is shown in murine models of several pulmonary diseases (sepsis, allergic asthma, Chronic Obstructive Pulmonary Disease(COPD), fibrosis). EXO CD24 can suppress the hyperinflammatory response in the lungs in several pulmonary diseases with a significant unmet need for treatment options.

Purpose To compare the immediate and late complications associated with emergent cesarean sections (CS) performed during the first and second stages of active labor. Methods We conducted a retrospective analysis of electronic medical records from a single academic center, including data from 577 patients who underwent emergent cesarean sections at 4 cm or more of cervical dilatation. Patients were divided into two groups: those who had CS during the first stage of labor (4–9 cm dilatation) and those who had CS at complete dilatation (10 cm). Maternal and neonatal outcomes were compared, including rates of complications such as uterine atony, post-partum hemorrhage, infection, and neonatal intensive care unit (NICU) admission. Results Of the 577 patients, 352 underwent CS during active labor and 255 at complete dilatation. The complete dilatation group exhibited significantly higher rates of uterine atony (19.6% vs. 11.6%, p  = 0.009) and uterine incision extension (34.2% vs. 16.5%, p  = 0.0001). In addition, they had longer hospital stays (4.8 vs. 4.25 days, p  = 0.003) and higher outpatient clinic visit rates (21.3% vs. 9.9%, p  = 0.0001). Infection-related complications on readmission were more common in the complete dilatation group (20% vs. 9.7%, p  = 0.001). Neonatal outcomes, including APGAR scores and NICU admissions, did not differ significantly between the groups. Conclusion Emergent cesarean sections performed at complete cervical dilatation are associated with increased intra-operative and post-operative complications compared to those performed during active labor. These findings highlight the importance of considering the stage of labor when planning cesarean delivery to minimize risks and optimize outcomes for both mother and neonate.

PurposePregnancy at advanced maternal age (AMA) has become more common. There has been concern regarding the adverse effect deferring pregnancy might have on pregnancy outcomes. We aimed to prospectively study the effect of AMA on placental pathology.MethodsA prospective case–control study was performed in a single university center. Placental histopathology, maternal demographics, labor characteristics, and neonatal outcomes of pregnancies with AMA were collected and compared to matched controls. We defined AMA as maternal age > 35 years at delivery. In attempt to isolate the effect of maternal age, we excluded cases complicated by preterm birth, hypertensive disorders, diabetes mellitus, small for gestational age, and congenital/genetic anomalies.ResultsThe study group included 110 AMA patients that were matched with controls. The groups did not differ in maternal demographics, but the AMA group had a higher rate of assisted reproductive technologies (ART) as compared to the control group (p < 0.001). Placentas in the AMA group were characterized by a higher rate of maternal vascular lesions (MVM) (39.1% vs. 24.5%, p = 0.003), but not fetal vascular malperfusion lesions (p = 0.576). In multivariable analysis maternal age was associated with placental MVM lesions independent of all other maternal demographics (aOR 1.18 95% CI 1.06–3.17). Neonatal outcomes did not significantly differ between the groups.ConclusionsAfter excluding all background morbidities—AMA was associated with a higher rate of placental MVM lesions vs. controls. These findings suggest an independent effect of AMA on placental function. Large prospective trials are needed to study the clinical importance of these findings.

Integrating multiple biosensors improves the sensitivity and precision of physiological measurements in healthcare monitoring. By combining sensors that target different physiological parameters, a more comprehensive assessment of a subject's health can be achieved. We evaluate the performance of two biosensors for extracting cardiac parameters: a textile-based strain sensor for measuring respiratory rate and an optical sensor for measuring heart rate, , and respiratory rate. The objective is to determine optimal placement conditions for each sensor and assess their feasibility for integration into a single wearable system. Two experimental setups were tested. In the first, the strain sensor was placed on the subject's shirt, while the optical sensor was positioned on the external wrist. In the second, both sensors were placed on the chest, under the shirt. The accuracy and performance of each sensor were analyzed in both configurations. The optical sensor demonstrated improved accuracy when placed on the chest compared to the wrist, whereas the strain sensor provided similar results for both configurations. We demonstrate that sensor placement significantly affects measurement quality, emphasizing the importance of optimizing placement when integrating multiple biosensors. Future work will focus on developing a unified wearable system that leverages the strengths of both sensors for comprehensive physiological monitoring.

Nosema ceranae is a highly prevalent intracellular parasite of honey bees’ midgut worldwide. This Microsporidium was monitored during a long-term study to evaluate the infection at apiary and intra-colony levels in six apiaries in four Mediterranean countries (France, Israel, Portugal, and Spain). Parameters on colony strength, honey production, beekeeping management, and climate were also recorded. Except for São Miguel (Azores, Portugal), all apiaries were positive for N. ceranae, with the lowest prevalence in mainland France and the highest intra-colony infection in Israel. A negative correlation between intra-colony infection and colony strength was observed in Spain and mainland Portugal. In these two apiaries, the queen replacement also influenced the infection levels. The highest colony losses occurred in mainland France and Spain, although they did not correlate with the Nosema infection levels, as parasitism was low in France and high in Spain. These results suggest that both the effects and the level of N. ceranae infection depends on location and beekeeping conditions. Further studies on host-parasite coevolution, and perhaps the interactions with other pathogens and the role of honey bee genetics, could assist in understanding the difference between nosemosis disease and infection, to develop appropriate strategies for its control.