A novel model for predicting diabetes remission after bariatric surgery based on the measurement of C-peptide and creatinine in serum: A pilot study.

BACKGROUND AND AIMS: Bariatric surgery is effective for treating type 2 diabetes (T2D) in patients with obesity, although a significant proportion of these patients do not achieve diabetes remission after the surgery even after significant weight loss and metabolic improvement. C-peptide is a valuable marker of beta cell function and insulin secretion, but renal function must be considered when interpreting measurements in patients with T2D. The study aims to investigate the association of serum levels of C-peptide adjusted for creatinine with diabetes remission and glycemic target achievement after bariatric surgery in patients with obesity and T2D. METHODS AND RESULTS: Prospective data from a cohort of 84 patients with obesity and T2D submitted to Roux-en-Y gastric bypass (RYGB) were collected at baseline and at least a 6-month follow up. A multivariate binomial regression model showed that Ln(C-peptide/creatinine) and age were significantly associated with 6-month T2D remission. The area under the curve for the receiver operating characteristic analysis (AUROC) to predict remission was 0.87, and more accurate than the AUROC based on C-peptide levels alone (0.75). The same model was also able to predict achieving an HbA1c target of 7 % (53 mmol/mol) (AUROC 0.96). CONCLUSION: In conclusion, Ln(C-peptide/creatinine) ratio could be a useful tool in predicting T2D remission and target achievement after RYGB surgery, providing a more accurate reflection of beta cell function in bariatric patients.

Exploring Factors Affecting Patient-Provider Interactions and Healthcare Engagement Among a Diverse Sample of Women Who Have Sex with Women in New York City.

Women who have sex with women (WSW) have lower rates of engagement in health care and preventive screenings than women who have sex exclusively with men. Existing literature provides limited insight into how intersecting and overlapping identities, such as race, ethnicity, sexual orientation, gender identity, and identities related to gender expression, may shape individuals' experiences within health care. We conducted qualitative interviews in New York City with 30 people who identified as women, reported sex with people who identify as women, were age 18-65, and were diverse in race, ethnicity, and sexual orientation and gender identity. The semi-structured questionnaire asked participants about positive and negative healthcare experiences to elicit what could encourage or prevent seeking care, with a focus on provider-related factors. Factors that led to positive healthcare experiences included having a provider who was knowledgeable about LGBTQ experience and health and who affirmed their sexuality, gender identity, and other intersecting identities. Factors that contributed to negative healthcare experiences included poor interactions with providers, and providers' perceived heteronormativity and lack of awareness of WSW healthcare needs. WSW of different races, ethnicities, sexual orientations, and gender identities seek validating healthcare experiences that acknowledge and affirm their identities. We present a visual summary of the main thematic factors that contributed to positive and negative WSW healthcare experiences. Increasing access to care requires training providers on how to engage WSW patients, including WSW of diverse race/ethnicity and gender identity and expression.

Haspin kinase modulates nuclear architecture and Polycomb-dependent gene silencing.

Haspin, a highly conserved kinase in eukaryotes, has been shown to be responsible for phosphorylation of histone H3 at threonine 3 (H3T3ph) during mitosis, in mammals and yeast. Here we report that haspin is the kinase that phosphorylates H3T3 in Drosophila melanogaster and it is involved in sister chromatid cohesion during mitosis. Our data reveal that haspin also phosphorylates H3T3 in interphase. H3T3ph localizes in broad silenced domains at heterochromatin and lamin-enriched euchromatic regions. Loss of haspin compromises insulator activity in enhancer-blocking assays and triggers a decrease in nuclear size that is accompanied by changes in nuclear envelope morphology. We show that haspin is a suppressor of position-effect variegation involved in heterochromatin organization. Our results also demonstrate that haspin is necessary for pairing-sensitive silencing and it is required for robust Polycomb-dependent homeotic gene silencing. Haspin associates with the cohesin complex in interphase, mediates Pds5 binding to chromatin and cooperates with Pds5-cohesin to modify Polycomb-dependent homeotic transformations. Therefore, this study uncovers an unanticipated role for haspin kinase in genome organization of interphase cells and demonstrates that haspin is required for homeotic gene regulation.

Crohn's Disease, Host-Microbiota Interactions, and Immunonutrition: Dietary Strategies Targeting Gut Microbiome as Novel Therapeutic Approaches.

Crohn's disease (CD) is a complex, disabling, idiopathic, progressive, and destructive disorder with an unknown etiology. The pathogenesis of CD is multifactorial and involves the interplay between host genetics, and environmental factors, resulting in an aberrant immune response leading to intestinal inflammation. Due to the high morbidity and long-term management of CD, the development of non-pharmacological approaches to mitigate the severity of CD has recently attracted great attention. The gut microbiota has been recognized as an important player in the development of CD, and general alterations in the gut microbiome have been established in these patients. Thus, the gut microbiome has emerged as a pre-eminent target for potential new treatments in CD. Epidemiological and interventional studies have demonstrated that diet could impact the gut microbiome in terms of composition and functionality. However, how specific dietary strategies could modulate the gut microbiota composition and how this would impact host-microbe interactions in CD are still unclear. In this review, we discuss the most recent knowledge on host-microbe interactions and their involvement in CD pathogenesis and severity, and we highlight the most up-to-date information on gut microbiota modulation through nutritional strategies, focusing on the role of the microbiota in gut inflammation and immunity.

Genetic detection of Sonic hedgehog (Shh) expression and cellular response in the progression of acute through chronic demyelination and remyelination.

Multiple sclerosis is a demyelinating disease in which neurological deficits result from damage to myelin, axons, and neuron cell bodies. Prolonged or repeated episodes of demyelination impair remyelination. We hypothesized that augmenting Sonic hedgehog (Shh) signaling in chronically demyelinated lesions could enhance oligodendrogenesis and remyelination. Shh regulates oligodendrocyte development during postnatal myelination, and maintains adult neural stem cells. We used genetic approaches to detect Shh expression and Shh responding cells in vivo. ShhCreERT2 or Gli1CreERT2 mice were crossed to reporter mice for genetic fate-labeling of cells actively transcribing Shh or Gli1, an effective readout of canonical Shh signaling. Tamoxifen induction enabled temporal control of recombination at distinct stages of acute and chronic cuprizone demyelination of the corpus callosum. Gli1 fate-labeled cells were rarely found in the corpus callosum with tamoxifen given during acute demyelination stages to examine activated microglia, reactive astrocytes, or remyelinating cells. Gli1 fate-labeled cells, mainly reactive astrocytes, were observed in the corpus callosum with tamoxifen given after chronic demyelination. However, Shh expressing cells were not detected in the corpus callosum during acute or chronic demyelination. Finally, SAG, an agonist of both canonical and type II non-canonical Hedgehog signaling pathways, was microinjected into the corpus callosum after chronic demyelination. Significantly, SAG delivery increased proliferation and enhanced remyelination. SAG did not increase Gli1 fate-labeled cells in the corpus callosum, which may indicate signaling through the non-canonical Hedgehog pathway. These studies demonstrate that Hedgehog pathway interventions may have therapeutic potential to modulate astrogliosis and to promote remyelination after chronic demyelination.

Metabolomic Analysis of Gastric Cancer Progression within the Correa's Cascade Using Ultraperformance Liquid Chromatography-Mass Spectrometry.

Gastric cancer (GC) is among the most common cancers worldwide. Gastric carcinogenesis is a multistep and multifactorial process beginning with chronic gastritis induced by Helicobacter pylori (H. pylori) infection. This process is often described via a sequence of events known as Correas's cascade, a stepwise progression from nonactive gastritis, chronic active gastritis, precursor lesions of gastric cancer (atrophy, intestinal metaplasia, and dysplasia), and finally adenocarcinoma. Our aim was to identify a plasma metabolic pattern characteristic of GC through disease progression within the Correa's cascade. This study involved the analysis of plasma samples collected from 143 patients classified in four groups: patients with nonactive gastritis and no H. pylori infection, H. pylori infected patients with chronic active gastritis, infected or noninfected patients with precursor lesions of gastric cancer, and GC. Independent partial least-squares-discriminant binary models of UPLC-ESI(+)-TOFMS metabolic profiles, implemented in a decision-directed acyclic graph, allowed the identification of tryptophan and kynurenine as discriminant metabolites that could be attributed to indoleamine-2,3-dioxygenase upregulation in cancer patients leading to tryptophan depletion and kynurenine metabolites generation. Furthermore, phenylacetylglutamine was also classified as a discriminant metabolite. Our data suggest the use of tryptophan, kynurenine, and phenylacetylglutamine as potential GC biomarkers.

Autophagy modulates the effects of bis-anthracycline WP631 on p53-deficient prostate cancer cells.

Treatment of p53-deficient PC-3 human prostate carcinoma cells with nanomolar concentrations of bis-anthracycline WP631 induced changes in gene expression, which resulted in G2/M cell cycle arrest, autophagy and cell death. The presence of 2-deoxy-D-glucose (2-DG), which induces metabolic stress and autophagy, enhanced the antiproliferative effects of WP631. Changes induced by WP631, 2-DG, or co-treatments with both compounds, in the expression of a variety of genes involved in autophagy and apoptosis were quantified by real-time PCR. They were consistent with a raise in autophagy followed by cell death. Some cells dying from G2/M phase showed features of necrosis like early changes in membrane permeability, while others were dying by apoptosis that occurred in presence of little caspase-3 activity. Our results indicate that WP631 is not only an antiproliferative agent acting on gene transcription, but it can also induce autophagy regardless of the presence of other pro-autophagy stimuli. The development of autophagy seemed to improve the cytotoxicity of WP631 in PC-3 cells. Our results indicate that autophagy would enhance the activity of DNA-binding drugs like WP631 that are potent inhibitors of gene transcription.

Factors related with symptom duration until diagnosis and treatment of symptomatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) survival depends mostly on stage at the time of diagnosis. However, symptom duration at diagnosis or treatment have also been considered as predictors of stage and survival. This study was designed to: 1) establish the distinct time-symptom duration intervals; 2) identify factors associated with symptom duration until diagnosis and treatment. METHODS: This is a cross-sectional study of all incident cases of symptomatic CRC during 2006-2009 (795 incident cases) in 5 Spanish regions. Data were obtained from patients' interviews and reviews of primary care and hospital clinical records. MEASUREMENTS: CRC symptoms, symptom perception, trust in the general practitioner (GP), primary care and hospital examinations/visits before diagnosis, type of referral and tumor characteristics at diagnosis. Symptom Diagnosis Interval (SDI) was calculated as time from first CRC symptoms to date of diagnosis. Symptom Treatment Interval (STI) was defined as time from first CRC symptoms until start of treatment. Nonparametric tests were used to compare SDI and STI according to different variables. RESULTS: Symptom to diagnosis interval for CRC was 128 days and symptom treatment interval was 155. No statistically significant differences were observed between colon and rectum cancers. Women experienced longer intervals than men. Symptom presentation such as vomiting or abdominal pain and the presence of obstruction led to shorter diagnostic or treatment intervals. Time elapsed was also shorter in those patients that perceived their first symptom/s as serious, disclosed it to their acquaintances, contacted emergencies services or had trust in their GPs. Primary care and hospital doctor examinations and investigations appeared to be related to time elapsed to diagnosis or treatment. CONCLUSIONS: Results show that gender, symptom perception and help-seeking behaviour are the main patient factors related to interval duration. Health service performance also has a very important role in symptom to diagnosis and treatment interval. If time to diagnosis is to be reduced, interventions and guidelines must be developed to ensure appropriate examination and diagnosis during both primary and hospital care.

Enhancement of Th1 immune responses to recombinant influenza nucleoprotein by Ribi adjuvant.

A broad coverage influenza vaccine against multiple viral strains based on the viral nucleoprotein (NP) is a goal pursued by many laboratories. If the goal is to formulate the vaccine with recombinant NP it is essential to count on adjuvants capable of inducing cellular immunity. This work have studied the effect of the monophosphoryl lipid A and trehalose dimycolate, known as the Ribi Adjuvant System (RAS), in the immune response induced in mice immunized with recombinant NP. The NP was formulated with RAS and used to immunize BALB/c mice. Immunizations with NP-RAS increased the humoral and cellular immune responses compared to unadjuvanted NP. The predominant antibody isotype was IgG2a, suggesting the development of a Th1 response. Analysis of the cytokines from mice immunized with NP-RAS showed a significant increase in the production of IFN-g and a decreased production of IL-10 and IL-4 compared to controls without RAS. These results are similar to those usually obtained using Freund's adjuvant, known to induce Th1 and CTL responses when co-administered with purified proteins, and suggest that a similar approach may be possible to enhance the performance of a T-cell vaccine containing NP.

Anti-inflammatory potential of digested Brassica sprout extracts in human macrophage-like HL-60 cells.

Cruciferous vegetables have been reported to be a great source of anti-inflammatory compounds. Specifically, sprouts from the Brassicaceae family stand out for their high content of glucosinolates (and their bioactive derivatives, isothiocyanates), phenolic acids, and anthocyanins. Despite the evident anti-inflammatory activity of certain Brassica phytochemicals such as sulforaphane or phenolic acids, the effect of digested Brassica vegetables on inflammation remains understudied. In this work, we aimed to evaluate the anti-inflammatory potential of the bioaccessible forms of cruciferous bioactives (from red cabbage sprouts (RCS) and red radish sprouts (RRS)) obtained upon in vitro gastrointestinal digestion in the HL-60 macrophage-like differentiated human cell line. The study was performed under basal conditions or stimulated with a low dose of LPS for 24 hours as a validated in vitro model of chronic inflammation. The cell viability was determined by MTT assay. The gene expression and production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1ß were determined by RT-qPCR and ELISA respectively. Our results revealed no cytotoxicity with any of the treatments in LPS-stimulated macrophage-like HL60 cells. Regarding cytokine production, digestates significantly decreased the production of the three pro-inflammatory cytokines at concentrations of 50 and 100 µg mL-1 except for IL-1ß treated with RCS digestates. Furthermore, the RT-qPCR analysis showed a decrease in the relative expression of pro-inflammatory cytokines in LPS-stimulated cells treated with RRS digestates at 100 µg mL-1 but not with red cabbage digestates. In conclusion, RRS bioaccessible compounds in the extracts could be used as dietary coadjuvants given their potential anti-inflammatory effect on this in vitro model of chronic inflammation.

Inherited Epigenetic Hallmarks of Childhood Obesity Derived from Prenatal Exposure to Obesogens.

Childhood obesity has reached epidemic levels in developed countries and is becoming a major cause for concern in the developing world. The causes of childhood obesity are complex and multifactorial, involving the interaction between individual genetics and environmental and developmental factors. Among the environmental factors, there is a growing interest in understanding the possible relationship between the so-called environmental obesogens and the development of obesity in children. Exposure to these obesogens such as phthalates, bisphenol A, or parabens, has been identified as a promoter of obesity through different mechanisms such as the alteration of adipocyte development from mesenchymal progenitors, the interference with hormone receptors, and induced inflammation. However, less attention has been paid to the inheritance of epigenetic modifications due to maternal exposure to these compounds during pregnancy. Thus, the aim of this review is to summarize the current knowledge of epigenetic modifications due to maternal exposure to those obesogens during pregnancy as well as their potential implication on long-term obesity development in the offspring and transgenerational inheritance of epiphenotypes.

Sex-Specific Relationships of Physical Activity and Sedentary Behaviour with Oxidative Stress and Inflammatory Markers in Young Adults.

This study aims to analyse sex-specific associations of physical activity and sedentary behaviour with oxidative stress and inflammatory markers in a young-adult population. Sixty participants (21 women, 22.63 ± 4.62 years old) wore a hip accelerometer for 7 consecutive days to estimate their physical activity and sedentarism. Oxidative stress (catalase, superoxide dismutase, glutathione peroxidase, glutathione, malondialdehyde, and advanced oxidation protein products) and inflammatory (tumour necrosis factor-alpha and interleukin-6) markers were measured. Student t-tests and single linear regressions were applied. The women presented higher catalase activity and glutathione concentrations, and lower levels of advanced protein-oxidation products, tumour necrosis factor-alpha, and interleukin-6 than the men (p < 0.05). In the men, longer sedentary time was associated with lower catalase activity (ß = −0.315, p = 0.04), and longer sedentary breaks and higher physical-activity expenditures were associated with malondialdehyde (ß = −0.308, p = 0.04). Vigorous physical activity was related to inflammatory markers in the women (tumour necrosis factor-alpha, ß = 0.437, p = 0.02) and men (interleukin−6, ß = 0.528, p < 0.01). In conclusion, the women presented a better redox and inflammatory status than the men; however, oxidative-stress markers were associated with physical activity and sedentary behaviours only in the men. In light of this, women could have better protection against the deleterious effect of sedentarism but a worse adaptation to daily physical activity.

Plasma short-chain fatty acid changes after bariatric surgery in patients with severe obesity.

BACKGROUND: Obesity has reached epidemic dimensions in recent decades. Bariatric surgery (BS) is one of the most effective interventions for weight loss and metabolic improvement in patients with obesity. Short-chain fatty acids (SCFA) are gut microbiota-derived metabolites with a key role in body weight control and insulin sensitivity. Although BS is known to induce significant changes in the gut microbiota composition, its impact on the circulating levels of certain metabolites produced by the gut microbiota such as SCFA remains poorly understood. OBJECTIVE: To determine the impact of BS on the circulating SCFA levels in patients with severe obesity. SETTING: University hospital. METHODS: An observational, prospective study was performed on 51 patients undergoing Roux-en-Y gastric bypass. Plasma samples were collected at baseline (1 day before surgery) and at 6 and 12 months after BS. Plasma SCFA levels were determined by liquid chromatography-mass spectrometry. RESULTS: The results revealed significant changes in the circulating levels of SCFA after BS. A marked increase in propionate, butyrate, isobutyrate, and isovalerate levels and a decrease in acetate, valerate, hexanoate, and heptanoate levels were observed 12 months after BS. Furthermore, the changes in the levels of propionate, butyrate, and isobutyrate negatively correlated with changes in body mass index, while those of isobutyrate correlated negatively with changes in the homeostatic model assessment for insulin resistance index. CONCLUSION: These results suggest that propionate, butyrate, and isobutyrate levels could be related to weight loss and improved insulin sensitivity in patients with severe obesity after BS.

Akkermansia muciniphila reduces susceptibility to Listeria monocytogenes infection in mice fed a high-fat diet.

A high-fat (HF) diet reduces resistance to the foodborne pathogen Listeria monocytogenes. We demonstrate that short-term gavage with A. muciniphila increases resistance to oral and systemic L. monocytogenes infection in mice fed a HF diet. A. muciniphila reduced inflammation in the gut and liver of mice fed a high-fat diet prior to infection and reduced inflammatory cell infiltration in the ileum to levels similar to mice fed a low-fat (LF) diet. Akkermansia administration had minimal impacts upon the microbiota and microbial metabolites and did not affect individual taxa or impact the Bacteroidetes to Firmicutes ratio. In summary, A. muciniphila increased resistance to L. monocytogenes infection in mice fed a HF diet by moderating immune/physiological effects through specific interaction between A. muciniphila and the host gut.

Health factors associated with cognitive frailty in older adults living in the community.

Introduction: This study aims to investigate the health factors associated with cognitive frailty in frail and pre-frail older adults living in the community. Methods: A total of 233 older adults meeting Fried's criteria for pre-frailty or frailty were included. Cognitive status was evaluated using the Short Portable Mental Status Questionnaire. Health factors encompassed nutritional status (evaluated using the Mini Nutritional Assessment tool, body mass index, and waist, arm, and leg circumferences), physical function (assessed with the Short Physical Performance Battery), quality of life (measured with the total index of the EuroQoL 5-Dimension 5-Level questionnaire - EQoL-Index -, and the Visual-Analogue Scale - QoL-VAS - for today's health state), as well as sleep, physical activity, and inactivity estimated through wrist-worn accelerometers. Multivariable logistic regression analyses were conducted to identify potential predictors of cognitive frailty, considering age as a confounding factor. Results: Cognitive frail participants exhibited advanced age, heightened self-reported exhaustion, diminished overall physical performance, reduced leg perimeter, decreased engagement in moderate-to-vigorous physical activity, and higher levels of inactivity (all p<0.05). However, after adjusting for age, only QoL-VAS emerged as a cognitive frailty risk factor (Odds ratio: 1.024), while the EQoL-Index, calf perimeter, and levels of moderate-to-vigorous physical activity were identified as protective factors (Odds ratios: 0.025, 0.929, and 0.973, respectively). Discussion: This study highlights the complex relationship between non-modifiable factors such as age, and modifiable factors including quality of life, nutritional status, and physical activity in the development of cognitive frailty among older adults with a frailty phenotype living in the community.

Associations Between Physical Activity and Inactivity Levels on Physical Function and Sleep Parameters of Older Adults With Frailty Phenotype.

This study investigated the relationship between physical activity, inactivity, physical function, and sleep in older adults with a frailty phenotype. A total of 184 pre-frail/frail older adults were included. Physical activity, inactive behavior, and sleep parameters were assessed using a wrist-worn accelerometer. Participants were categorized into four groups based on their levels of inactivity and physical activity. The results showed that individuals with lower levels of inactivity had better lower body mean velocity and sleep regularity than those with higher levels of inactivity. Physically active older adults exhibited faster gait speed and performed better in lower body strength tests than physically inactive participants. Further analysis revealed that specific combinations of inactivity and physical activity were associated with varying levels of physical function. The findings highlight the importance of physical activity and the negative impact of inactivity on physical function and sleep in older adults with a frailty phenotype.

Overexpression of SET is a recurrent event associated with poor outcome and contributes to protein phosphatase 2A inhibition in acute myeloid leukemia.

BACKGROUND: Protein phosphatase 2A is a novel potential therapeutic target in several types of chronic and acute leukemia, and its inhibition is a common event in acute myeloid leukemia. Upregulation of SET is essential to inhibit protein phosphatase 2A in chronic myeloid leukemia, but its importance in acute myeloid leukemia has not yet been explored. DESIGN AND METHODS: We quantified SET expression by real time reverse transcriptase polymerase chain reaction in 214 acute myeloid leukemia patients at diagnosis. Western blot was performed in acute myeloid leukemia cell lines and in 16 patients' samples. We studied the effect of SET using cell viability assays. Bioinformatics analysis of the SET promoter, chromatin immunoprecipitation, and luciferase assays were performed to evaluate the transcriptional regulation of SET. RESULTS: SET overexpression was found in 60/214 patients, for a prevalence of 28%. Patients with SET overexpression had worse overall survival (P<0.01) and event-free survival (P<0.01). Deregulation of SET was confirmed by western blot in both cell lines and patients' samples. Functional analysis showed that SET promotes proliferation, and restores cell viability after protein phosphatase 2A overexpression. We identified EVI1 overexpression as a mechanism involved in SET deregulation in acute myeloid leukemia cells. CONCLUSIONS: These findings suggest that SET overexpression is a key mechanism in the inhibition of PP2A in acute myeloid leukemia, and that EVI1 overexpression contributes to the deregulation of SET. Furthermore, SET overexpression is associated with a poor outcome in acute myeloid leukemia, and it can be used to identify a subgroup of patients who could benefit from future treatments based on PP2A activators.

Factors associated with neuropathic pain in Colombian patients with spinal cord injury of traumatic origin: case-control study.

STUDY DESIGN: Case-control study. OBJECTIVES: To identify factors associated with neuropathic pain (NP) in patients with spinal cord injury of traumatic origin (TSCI). SETTING: University Hospital of Valle, Cali, Colombia. METHODS: Study participants were individuals with diagnosis of TSCI who visited a trauma referral center from January 1st, 2016, to December 31st, 2016. Information was retrospectively extracted from the Hospital's Spinal Cord Injury registry and patients' medical records. Cases were defined as patients with NP and controls were those without NP. The exposure of interest was intentional injuries. Individuals were matched by age and stratified into 11 groups of ±3 years each. RESULTS: We found 164 participants with an average age of 34 ± 13 years, of whom 95.1% were male, and 53.6% had NP. Neurogenic bladder and bowel occurred in 94.3% of NP patients. Cause of injury was not associated with NP. Older injuries were protective for NP (>10 years since injury OR = 0.10, 95% CI = 0.03-0.37, p < 0.0001) and neurogenic bladder and bowel were found as risk factors (OR = 5.89, 95% CI = 1.84-18.88; p = 0.003). CONCLUSIONS: Our study uniquely shows time since injury as a protective factor for NP and neurogenic bladder and bowel as a risk factor, while violence was not found associated. This could help guide the scope of future research about NP secondary to SCI.

Microbial bile salt hydrolase activity influences gene expression profiles and gastrointestinal maturation in infant mice.

The mechanisms by which early microbial colonizers of the neonate influence gut development are poorly understood. Bacterial bile salt hydrolase (BSH) acts as a putative colonization factor that influences bile acid signatures and microbe-host signaling pathways and we considered whether this activity can influence infant gut development. In silico analysis of the human neonatal gut metagenome confirmed that BSH enzyme sequences are present as early as one day postpartum. Gastrointestinal delivery of cloned BSH to immature gnotobiotic mice accelerated shortening of the colon and regularized gene expression profiles, with monocolonised mice more closely resembling conventionally raised animals. In situ expression of BSH decreased markers of cell proliferation (Ki67, Hes2 and Ascl2) and strongly increased expression of ALPI, a marker of cell differentiation and barrier function. These data suggest an evolutionary paradigm whereby microbial BSH activity potentially influences bacterial colonization and in-turn benefits host gastrointestinal maturation.

Combined loss of p21(waf1/cip1) and p27(kip1) enhances tumorigenesis in mice.

The cell cycle inhibitors p21(Waf1/Cip1) and p27(Kip1) are frequently downregulated in many human cancers, and correlate with a worse prognosis. We show here that combined deficiency in p21 and p27 proteins in mice is linked to more aggressive spontaneous tumorigenesis, resulting in a decreased lifespan. The most common tumors developed in p21p27 double-null mice were endocrine, with a higher incidence of pituitary adenomas, pheochromocytomas and thyroid adenomas. The combined absence of p21 and p27 proteins delays the incidence of radiation-induced thymic lymphomas with a higher apoptotic rate, measured by active caspase-3 and cleaved PARP-1 immunoexpresion. These results provide experimental evidence for a cooperation of both cyclin-dependent kinase inhibitors in tumorigenesis in mice.