Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader–Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation.Research in contextPoorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

Inhibition of bladder activity by tibial nerve stimulation was investigated in α-chloralose-anesthetized cats with an intact spinal cord. Short-duration (3-5 min) tibial nerve stimulation at both low (5 Hz) and high (30 Hz) frequencies applied repeatedly during rhythmic isovolumetric bladder contractions was effective in inhibiting reflex bladder activity. Both frequencies of stimulation were also effective in inducing inhibition that persisted after the termination of the stimulation. The poststimulation inhibitory effect induced by the short-duration stimulation significantly increased bladder capacity to 181.6 ± 24.36% of the control capacity measured before applying the stimulation. Thirty-minute continuous stimulation induced prolonged poststimulation inhibition of bladder activity, which lasted for more than 2 h and significantly increased bladder capacity to 161.1 ± 2.9% of the control capacity. During the poststimulation periods, 5-Hz stimulation applied during the cystometrogram elicited a further increase (~30% on average) in bladder capacity, but 30-Hz stimulation was ineffective. These results in cats support the clinical observation that tibial nerve neuromodulation induces a long-lasting poststimulation inhibitory effect that is useful in treating overactive bladder symptoms.

This study indicates that a neural prosthetic device based on pudendal nerve stimulation might be developed to restore micturition function for people with SCI.

Naloxone (an opioid receptor antagonist) was used to examine the role of opioid mechanisms in bladder reflexes and in somatic afferent inhibition of these reflexes by tibial nerve stimulation (TNS). Experiments were conducted in α-chloralose-anesthetized cats when the bladder was infused with saline or 0.25% acetic acid (AA). The bladder volume was measured at the first large-amplitude (>30 cmH(2)O) contraction during a cystometrogram and termed "estimated bladder capacity" (EBC). AA irritated the bladder, induced bladder overactivity, and significantly (P < 0.0001) reduced EBC to 14.3 ± 1.9% of the saline control. TNS (5 Hz, 0.2 ms) at 4 and 8 times the threshold (T) intensity for inducing an observable toe movement suppressed AA-induced bladder overactivity and significantly increased EBC to 41.5 ± 9.9% (4T, P < 0.05) and 46.1 ± 7.9% (8T, P < 0.01) of the saline control. Naloxone (1 mg/kg iv) completely eliminated TNS inhibition of bladder overactivity. Naloxone (0.001-1 mg/kg iv) did not change EBC during AA irritation. However, during saline infusion naloxone (1 mg/kg iv) significantly (P < 0.01) reduced EBC to 66.5 ± 8.1% of the control EBC. During saline infusion, TNS induced an acute increase in EBC and an increase that persisted following the stimulation. Naloxone (1 mg/kg) did not alter either type of inhibition. However, naloxone administered during the poststimulation inhibition decreased EBC. These results indicate that opioid receptors have different roles in modulation of nociceptive and nonnociceptive bladder reflexes and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders.

Bone marrow mesenchymal stem cells (BMSCs), which were first discovered in bone marrow, are capable of differentiating into osteoblasts, chondrocytes, fat cells, and even myoblasts, and are considered multipotent cells. As a result of their potential for multipotential differentiation, self-renewal, immune regulation, and other effects, BMSCs have become an important source of seed cells for gene therapy, tissue engineering, cell replacement therapy, and regenerative medicine. MicroRNA (miRNA) is a highly conserved type of endogenous non-protein-encoding RNA of about 19–25 nucleotides in length, whose transcription process is independent of other genes. Generally, miRNA plays roles in regulating cell proliferation, differentiation, apoptosis, and development by binding to the 3′ untranslated region of target mRNAs, whereby they can degrade or induce translational silencing. Although miRNAs play a regulatory role in various metabolic processes, they are not translated into proteins. Several studies have shown that miRNAs play an important role in the osteogenic differentiation of BMSCs. Herein, we describe in-depth studies of roles for miRNAs during the osteogenic differentiation of BMSCs, as they provide new theoretical and experimental rationales for bone tissue engineering and clinical treatment.

The functions of the lower urinary tract are controlled by complex pathways in the brain that act like switching circuits to voluntarily or reflexly shift the activity of various pelvic organs (bladder, urethra, urethral sphincter, and pelvic floor muscles) from urine storage to micturition. In this study, functional magnetic resonance imaging (fMRI) was used to visualize the brain switching circuits controlling reflex micturition in anesthetized rats. The fMRI images confirmed the hypothesis based on previous neuroanatomical and neurophysiological studies that the brain stem switch for reflex micturition control involves both the periaqueductal gray (PAG) and the pontine micturition center (PMC). During storage, the PAG was activated by afferent input from the urinary bladder while the PMC was inactive. When bladder volume increased to the micturition threshold, the switch from storage to micturition was associated with PMC activation and enhanced PAG activity. A complex brain network that may regulate the brain stem micturition switch and control storage and voiding was also identified. Storage was accompanied by activation of the motor cortex, somatosensory cortex, cingulate cortex, retrosplenial cortex, thalamus, putamen, insula, and septal nucleus. On the other hand, micturition was associated with: 1) increased activity of the motor cortex, thalamus, and putamen; 2) a shift in the locus of activity in the cingulate and insula; and 3) the emergence of activity in the hypothalamus, substantia nigra, globus pallidus, hippocampus, and inferior colliculus. Understanding brain control of reflex micturition is important for elucidating the mechanisms underlying neurogenic bladder dysfunctions including frequency, urgency, and incontinence.

From 16 samples of traditional fermented koumiss collected in Inner Mongolia Autonomous Region of China, forty-eight lactobacilli strains were isolated and phenotypically characterized by their abilities to ferment different carbohydrates and by additional biochemical tests. The dominant lactobacilli species were identified as L. casei (17 strains), L. helveticus (10 strains) and L. plantarum (8 strains), with a lower frequency of isolation for L. coryniformis subsp. coryniformis (5 strains), L. paracasei (3 strains), L. kefiranofaciens (2 strains), L. curvatus (1 strain), L. fermentum (1 strain) and W. kandleri (1 strain). The pH values of all these samples were ranging from 3.37 to 3.94. In isolates, L. casei Zhang, L. helveticus ZL12-1, and L. plantarum BX6-6 were selected as potentially probiotic strains through the preliminary tests including resistance to low acid, abilities to grow in MRS with bile salts, antimicrobial activities and the viabilities during prolonged cold storage in fermented milk. Moreover 16S rDNA was conducted to confirm the identification.

Mutants in the Big Blue transgenic mouse system show spontaneous clustered multiple mutations with unexpectedly high frequency, consistent with chronocoordinate events. We tested the prediction that the multiple mutations seen within the lacI mutation target sometimes occur in the context of chronocoordinate multiple mutations spanning multiple kilobases (mutation showers). Additional sequencing of mutants was performed in regions immediately flanking the lacI region (total of 10.7 kb). Nineteen additional mutations were found outside the lacI region (''ectomutations'') from 10 mutants containing two or more lacI mutations, whereas only one ectomutation was found in 130 mutants with a single mutation (P < 0.0001). The mutation showers had an average of approximately one mutation per 3 kb. Four mutants showed closely spaced double mutations in the new sequence, and analysis of the spacing between these mutations revealed significant clustering (P ‫؍‬ 0.0098). To determine the extent of the mutation showers, regions (8.5 kb total) remote from the lacI region (Ϸ16 -17 kb away) were sequenced. Only two additional ectomutations were found in these remote regions, consistent with mutation showers that generally do not extend more than Ϸ30 kb. We conclude that mutation showers exist and that they constitute at least 0.2% and possibly 1% or more of mutational events observed in this system. The existence of mutation showers has implications for oncogenesis and evolution, raising the possibilities of ''cancer in an instant'' and ''introns as sponges to reduce the deleterious impact of mutation showers.'' Big Blue mouse ͉ lacI transgene ͉ multiple mutations ͉ mutation clusters ͉ transient hypermutability