Sleep and the gut microbiota in preschool aged children

Sleep plays a significant role in the mental and physical development of children. Emerging evidence in animals and human adults indicates a relationship between sleep and the gut microbiota; however, it is unclear whether the sleep of preschoolers during a key developmental period, associates with features of their gut microbiota. The objective of this study was to assess the relationship between sleep and gut microbiota in preschool aged children (4.37 ±0.48 years, n=143). Sleep measures included total nighttime sleep (TST), sleep efficiency (SE), and wake-time after sleep onset (WASO) assessed using actigraphy. Beta-diversity differences between children with low and high TST (p =0.048) suggest gut microbiota community differences. Particularly, relative abundance of Bifidobacterium was higher in the high TST group and Bacteroides, was higher in children who had higher SE and low WASO (LDA score >2). In contrast, some Lachnospiraceae members including Blautia and Coprococcus 1 were associated with shorter nighttime sleep duration and less efficiency, respectively. We also found a group of faecal metabolites, including specific neuroactive compounds and immunomodulating metabolites were associated with greater sleep efficiency and less time awake at night. Notably, tryptophan and its metabolizing products were higher in children who had higher SE or lower WASO (LDA score >2); concentration of propionate was higher in children with lower WASO (p =0.036). Overall, our results reveal a novel association between sleep and gut microbiota in preschool aged children. Longer nighttime sleep and greater sleep efficiency were associated with specific commensal bacteria that may regulate sleep through modulating neurotransmitter metabolism and the immune system.

Goldberg Shprintzen Syndrome: The Novel Association with Congenital Unilateral Anorchia (Monorchism)

Background: Goldberg Shprintzen syndrome is a very rare autosomal recessive mental-growth retardation syndrome associated with characteristic facial dysmorphism, Hirschsprung disease, and a variety of neurological abnormalities, and abnormalities on brain imaging studies. However, the association of the syndrome with congenital unilateral absence of the testis (monorchism) has not been reported before. We have previously reported the thirty fourth and thirty fifth cases of the syndrome which occurred in Iraqi brothers, and described a novel therapeutic approach which was used to treat the younger brother. The aim of this paper is to report the novel association of Goldberg Shprintzen syndrome with congenital right monorchism. Patients and methods: T.A.S, the younger of two brothers with Goldberg Shprintzen syndrome was first seen at the age of four years and 10 months at the pediatric neuro-psychiatric clinic on the 29th of August, 2019. He had spastic right hemiparesis and was unable to walk alone, and was not saying any word and had characteristic facial features including hypertelorism, narrow palpebral fissures, open mouth, and laterally lifted ear. He also had neonatal intestinal obstruction which was attributed to Hirschsprung disease, and was treated surgically with resection and colostomy. The boy was treated successfully with novel therapeutic approach and experienced improvement in cognitive abilities, speech, and motor function, and after treatment was able to walk alone. Results: During July, 2021, the family reminded us that the child had single testis in the scrotum, and during early infancy an MRI study failed to find any second testis anywhere. An ultrasound was performed and showed normal left testis. However, the right testis could not found in the right hemi-scrotal sac nor with the right inguinal canal or within the abdomen. Thus, the ultrasound confirmed the earlier MRI findings which suggested congenital absence of the right testis (monorchism). Conclusion: This paper reported the novel association of Goldberg Shprintzen syndrome with monorchism, and this case represented the third case of congenital syndromic monorchism in the world.

TYMS 3′-UTR Polymorphism: A Novel Association with FOLFIRINOX-Induced Neurotoxicity in Pancreatic Cancer Patients

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that has the worst 5-year survival rate of all of the common malignant tumors. Surgery, chemotherapy, and/or chemoradiation remain the main tactics for PDAC treatment. The efficacy of chemotherapy is often compromised because of the substantial risk of severe toxicities. In our study, we focused on identification of polymorphisms in the genes involved in drug metabolism, DNA repair and replication that are associated with inter-individual differences in drug-induced toxicities. Using the microarray, we genotyped 12 polymorphisms in the DPYD, XPC, GSTP1, MTHFR, ERCC1, UGT1A1, and TYMS genes in 78 PDAC patients treated with FOLFIRINOX. It was found that the TYMS rs11280056 polymorphism (6 bp-deletion in TYMS 3′-UTR) predicted grade 1–2 neurotoxicity (p = 0.0072 and p = 0.0019, according to co-dominant (CDM) and recessive model (RM), respectively). It is the first report on the association between TYMS rs11280056 and peripheral neuropathy. We also found that PDAC patients carrying the GSTP1 rs1695 GG genotype had a decreased risk for grade 3–4 hematological toxicity as compared to those with the AA or AG genotypes (p = 0.032 and p = 0.014, CDM and RM, respectively). Due to relatively high p-values, we consider that the impact of GSTP1 rs1695 requires further investigation in a larger sample size.

Racial differences in genomic features and new trans-ancestry prognosis subtypes in bladder cancer

The incidence and survival of bladder cancer vary greatly among different populations but the influence of the associated molecular features and evolutionary processes on its clinical treatment and prognostication remains unknown. Here, we analyze the genomic architectures of over 500 bladder cancer patients from Asian/Black/White populations. We identify novel association between AHNAK mutations and APOBEC-a mutational signature whose activities vary substantially across populations. All significantly mutated genes but only half of arm-level somatic copy number alterations (SCNAs) are enriched with clonal events, indicating large-scale SCNAs as rich sources fostering bladder cancer clonal diversities. The prevalence of TP53 and ATM clonal mutations as well as the associated burden of SCNAs is significantly higher in Whites/Blacks than in Asians. We identify a trans-ancestry prognostic subtype of bladder cancer characterized by: enrichment of non-muscle-invasive patients and muscle-invasive patients with good prognosis, increased CREBBP/FGFR3/HRAS/NFE2L2 mutations, decreased intra-tumor heterogeneity and genome instability and activated tumor microenvironment.

Entangled architecture of rough endoplasmic reticulum (RER) and vacuoles enables topological damping in cytoplasm of an ultra-fast giant cell

Cellular systems are known to exhibit some of the fastest movements in the biological world - but little is known as to how single cells can dissipate this energy rapidly and adapt to such large accelerations without sub-cellular damage. To study intracellular adaptations under extreme forces - we investigate Spirostomum ambiguum - a giant cell (1-4mm in length) well known to exhibit ultrafast contractions (50% of body length) within 5 msec with a peak acceleration of 15g. Utilizing transmitted electron microscopy (TEM) and confocal imaging, we discover a novel association of rough endoplasmic reticulum (RER) and vacuoles throughout the cell - forming a contiguous fenestrated cubic membrane architecture that topologically entangles these two organelles. A nearly uniform inter-organelle spacing of 60nm is observed between RER and vacuoles, closely packing the entire cell. Using an overdamped molecular dynamics simulation, we demonstrate how this unique entangled metamaterial responds to external loads by rapidly dissipating energy and helps preserve spatial relationships between organelles. Because this dynamics arises primarily from entanglement of two networks incurring jamming transition at a subcritical volume fraction - we term this phenomena "topological damping". Our findings suggest a new mechanical role of RER-vacuolar meshwork as a metamaterial capable of dissipating energy in an ultra-fast contraction event.

Detection of Novel Variations Related to Litter Size in BMP15 Gene of Luzhong Mutton Sheep (Ovis aries)

Litter size is an important economic trait in the mutton sheep industry. BMP15 is one of the key candidate genes for litter size in sheep. In this study, the entire ORF region of BMP15 was sequenced in 154 Luzhong mutton ewes, and the novel variations were determined. The association between polymorphism in BMP15 and litter size was analyzed using a general linear model. Six out of a total of thirteen variations were identified to be novel. Association analysis indicated that four (SNPs ENSOART00000010201.1:c.352+342C>A, c.352+1232T>C, c.352+1165A>G and c.353-2036T>A) were significantly associated with litter size. The joint analysis among three major genes (BMP15, BMPR1B and GDF9) exhibited significant interaction effects in three combinations (FecB and c.352+1232T>C of BMP15; FecB and c.352+1165A>G of BMP15; c.352+342C>A of BMP15 and ENSOART00000014382.1:c.994G>A of GDF9). For the SNPs c.352+1232T>C and c.352+342C>A, the global distribution of allele frequencies showed that the highest variation frequency occurs in Western Europe. In conclusion, the results demonstrated that BMP15 is a major gene for litter size in Luzhong mutton sheep and candidate SNPs associated with litter size were identified.