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Epithelium-derived antimicrobial peptides represent an evolutionarily ancient defense mechanism against pathogens. Regenerating islet-derived protein 3 γ (Reg3γ), the archetypal intestinal antimicrobial peptide, is critical for maintaining host–microbe interactions. Expression of Reg3γ is known to be regulated by the microbiota through two different pathways, although it remains unknown whether specific Reg3γ-inducing bacteria act via one or both of these pathways. In recent work, we identified Ruminococcus gnavus and Limosilactobacillus reuteri as commensal bacteria able to induce Reg3g expression. In this study, we show these bacteria require myeloid differentiation primary response protein 88 and group 3 innate lymphoid cells for induction of Reg3γ in mice. Interestingly, we find that R. gnavus and L. reuteri suppress Reg3γ in the absence of either myeloid differentiation primary response protein 88 or group 3 innate lymphoid cells. In addition, we demonstrate that colonization by these bacteria is not required for induction of Reg3γ, which occurs several days after transient exposure to the organisms. Taken together, our findings highlight the complex mechanisms underlying microbial regulation of Reg3γ.

Using ab initio and non-equilibrium Green's function, the effect of hydrogen and fluorine atom passivation on the electronic and transport properties of borophene nanoribbons are explored.

Introduction: Tonsillectomy is one of the most common surgical procedure in the world performed by Ear, Nose and Throat surgeon. Over the past decade, there has been progress in surgical techniques for tonsillectomy, yet pain and bleeding after tonsillectomy remain important surgical complications. With the increasing need to reduce healthcare costs in developing countries, there is currently a trend towards performing tonsillectomy on a daycare basis and this study aims at evaluating how efficacious it may be in our setting. Methods: A retrospective review of all the daycare tonsillectomy surgeries performed at the Pokhara ENT Center, Pokhara, Nepal from February 2018 to January 2019. Patients aged 15 years and up of either sex who met the paradise criteria were included while patients who met the same but had a contraindication for tonsillectomy surgery were excluded. Demographic information as well as complications within six hours of surgery before discharge and on follow-up on the seventh post-operative day were evaluated, as were any emergency room visits in the first 24 hours and any complications requiring a visit to a healthcare facility. Results: On day of surgery 17% had worst pain and on seventh post-operative day 75% had no pain, only 2% presented with primary hemorrhage and 3% presented with secondary hemorrhage. None of them required revision surgery. Conclusions: Daycare tonsillectomy is being done in only some of the centers owing to the risk of postoperative complications in our country. In our study, the number of complications was lower and not life-threatening. It can be considered a safe and cost-effective method, though patient selection is crucial.

Gastroschisis mortality in sub-Saharan Africa (SSA) remains high at 59-100%. Silo inaccessibility contributes to this disparity. Standard of care (SOC) silos cost $240, while median monthly incomes in SSA are $200. Our multidisciplinary American and Ugandan team designed and bench-tested a low-cost (LC) silo that costs $2 and is constructed from locally available materials. Here we describe in vivo LC silo testing.A piglet gastroschisis model was achieved by eviscerating intestines through a midline incision. Eight piglets were randomized to LC or SOC silos. Bowel was placed into the LC or SOC silo, maintained for 1-h, and reduced. Procedure times for placement, intestinal reduction, and silo removal were recorded. Tissue injury of the abdominal wall and intestine was assessed. Bacterial and fungal growth on silos was also compared.There were no gross injuries to abdominal wall or intestine in either group or difference in minor bleeding. Times for silo application, bowel reduction, and silo removal between groups were not statistically or clinically different, indicating similar ease of use. Microbiologic analysis revealed growth on all samples, but density was below the standard peritoneal inoculum of 10LC silos designed for manufacturing and clinical use in SSA demonstrated similar ease of use, absence of tissue injury, and acceptable microbiology profile, similar to SOC silos. The findings will allow our team to proceed with a pilot study in Uganda.

The interaction between gut microbes and gastrointestinal (GI) tract carcinogenesis has always attracted researchers' attention to identify therapeutic targets or potential prognostic biomarkers. Various studies have suggested that the microbiota do show inflammation and immune dysregulation, which led to carcinogenesis in GI tract. In this review, we have focused on the role of microbes present in the gut, intestine, or faeces in GI tract cancers, including esophageal cancer, gastric cancer, and colorectal cancer. Herein, we have discussed the importance of the microbes and their metabolites, which could serve as diagnostic biomarkers for cancer detection, especially in the early stage, and prognostic markers. To maximize the effect of the treatment strategies, an accurate evaluation of the prognosis is imperative for clinicians. There is a vast difference in the microbiota profiles within a population and across the populations depending upon age, diet, lifestyle, genetic makeup, use of antibiotics, and environmental factors. Therefore, the diagnostic efficiency of the microbial markers needs to be further validated. A deeper understanding of the GI cancer and the host microbiota is needed to acquire pivotal information about disease status.

The central region of India is incredibly rich in tribal heritage. It is the most frequent Indian state in terms of tribal population. Understanding the genetic history of the tribal population of India may add detailed information about various demographic processes, including social upliftment. However, to understand these microevolutionary processes, high-resolution genetic analysis is warranted. Therefore, we have used cutting-edge Next-generation sequencing (NGS) techniques and sequenced the mitogenomes of 25 random samples from two major (Gond and Kanwar) tribal populations for complete mitogenome analysis. We aimed to understand the initial peopling of Chhattisgarh from a maternal perspective. The complete genome sequencing enabled us to identify several novel sub-haplogroups. Our results suggested an early expansion and proliferation of maternal ancestry rooted in the time of initial settlement of the subcontinent, which has reached near saturation during 25-30Kya. At the background of founding lineages M and N, we identified maternal haplogroups M2, R5 and U2 as three basal founding haplogroups of this region. Overall, we suggest a high effective (Ne) maternal population in Central India during 25Kya, sustained during the Last Glacial Maximus(LGM).

Perspective on This Article from Metformin Prevents Liver Tumorigenesis by Inhibiting Pathways Driving Hepatic Lipogenesis

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Plant secondary metabolites are high in bioactive chemicals and are employed in the pharmaceutical industry for the manufacture of nutrient-rich food. These bioactive chemicals are administered in both traditional and contemporary ways to cure various ailments and enhance people's health. Present study was undertaken the phytochemical composition and biological potential (antimicrobial, antioxidant, antigenotoxic and antimutagenic) of various extracts obtained by Soxhlet extraction technique from leaves of C. roseus were investigated. Different extracts were accessed for their yield percentage, total polyphenol content (TPC), total flavonoid content (TFC), antioxidant potential (DPPH - 1,1-diphenyl-2-picrylhydrazyl), antimicrobial activity, antigenotoxic and antimutagenic potential. Further, acetone extract was also subjected to gas chromatography - mass spectrometry (GC–MS) analysis in order to assess the composition of various phytoconstituents. The identified major compounds included 9, 12-octadecasienoic acid (19.5%) and n-hexadecanoic acid (16.5%). Acetone extract showed the best activity towards biological potential (antimicrobial, antioxidant, antigenotoxic and antimutagenic). According to the pharmacological properties of these bioactive components, the plant can be utilized as a crude drug or to build a novel medication and these bioactive chemicals are suggested based on known pharmacological literature.

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene co-expression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the African American Genetics of Metabolism and Expression and Metabolic Syndrome in Men. We used weighted gene co-expression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous “consensus genes” whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight co-expressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b) or no previously known role in obesity (e.g., St14, Msa4a6). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.

The recent development of solvent- and polymer-based brain clearing techniques has greatly advanced our ability to visualize the mammalian nervous system in 3D. However, it remains challenging to image the mammalian body en bloc as existing methods can be prohibitively expensive or difficult in practice. Here, we developed HYBRiD (HYdrogel-Based Reinforcement of DISCO), by strategically recombining components of organic- and polymer-based clearing pipelines and achieved superb simplicity, transparency, protein retention, and compatibility with direct fluorescent imaging as well as immunostaining in cleared mammalian bodies. Using parvalbumin- and somatostatin-Cre models, we demonstrated the utility of HYBRiD for whole-body imaging of genetically encoded fluorescent reporters without antibody enhancement of signals in newborn and juvenile mice. Using K18-hACE2 transgenic mice, HYBRiD enabled perfusion-free clearing and visualization of SARS-CoV-2 infection in a whole mouse chest, revealing macroscopic and microscopic features of viral pathology in the same sample. HYBRiD offers a simple, affordable, and universal solution to visualize large heterogeneous body parts or entire animals for basic and translational research.

Tumors and Metastasis in KRas+/LA1;Dicer+/2SD mice

Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. Dicer is phosphorylated by the ERK-MAP kinase pathway and because this pathway is activated in human cancers, we asked whether phosphorylated Dicer1 contributed to tumor development. In human endometrioid cancers, we discovered that phosphorylated DICER1 is significantly associated with invasive disease. To test a direct involvement of Dicer1 phosphorylation in tumor development, we studied mice with phosphomimetic alterations at the two conserved serines phosphorylated by ERK and discovered that a phosphomimetic Dicer1 drives tumor development and dissemination in two independent murine cancer models (KRas+/LA1 and p53+/−). Our findings demonstrate that phosphomimetic Dicer1 promotes tumor development and invasion.Significance:This work highlights the relevance of Dicer1 phosphorylation in mammalian tumor development and dissemination.

PDF file - 131KB, Supplemental Figure 1 Withaferin A inhibits cell viability of breast cancer cells.

Supplementary Figure Legends 1-2 from Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor

Supplementary Figure 1 from Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor

PDF file - 141KB, Supplemental Figure 6 ERK and RSK activation is important for WFA-mediated inhibition of clonogenicity of breast cancer cells.

PDF file - 103KB, Supplementary Figure 10 Withaferin A induces recruitment of CHOP, pElk1 and release of HDAC1 from DR5 promoter.

Withaferin A (WFA) is a steroidal lactone with antitumor effects manifested at multiple levels that are mechanistically obscure. Using a phospho-kinase screening array, we discovered that WFA activated phosphorylation of the S6 kinase RSK (ribosomal S6 kinase) in breast cancer cells. Pursuing this observation, we defined activation of extracellular signal–regulated kinase (ERK)–RSK and ETS-like transcription factor 1 (Elk1)–CHOP (C-EBP homologous protein) kinase pathways in upregulating transcription of the death receptor 5 (DR5). Through this route, WFA acted as an effective DR5 activator capable of potentiating the biologic effects of celecoxib, etoposide, and TRAIL. Accordingly, WFA treatment inhibited breast tumor formation in xenograft and mouse mammary tumor virus (MMTV)-neu mouse models in a manner associated with activation of the ERK/RSK axis, DR5 upregulation, and elevated nuclear accumulation of Elk1 and CHOP. Together, our results offer mechanistic insight into how WFA inhibits breast tumor growth. Cancer Res; 74(9); 2617–29. ©2014 AACR.

Supplementary Figure 2 from Bidirectional Crosstalk between Leptin and Insulin-like Growth Factor-I Signaling Promotes Invasion and Migration of Breast Cancer Cells via Transactivation of Epidermal Growth Factor Receptor

PDF file - 99KB, Supplementary Figure 8 CHOP is important for Withaferin A mediated inhibition of breast cancer cell growth.

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PDF file - 115KB, Supplemental Figure 3 WFA increases phosphorylation of ERK and RSK.

PDF file - 147KB, Supplemental Figure 4 WFA activates RSK in an ERK-dependent manner.

PDF file - 126KB, Supplemental Figure 7 Withaferin A induces phosphorylation of Elk1 in ERK-dependent manner.

PDF file - 156KB, Supplementary Figure 9 WFA increases DR5 expression in multiple breast cancer cell lines and CHOP and Elk1 contribute to WFA-induced upregulation of Death receptor 5 in breast cancer cells.

PDF file - 112KB, Supplemental Figure 5 WFA activates RSK in an ERK-dependent manner. ERK and RSK activation is important for WFA-mediated cleavage of apoptotic marker, PARP.

PDF file - 89KB, Supplemental Figure 2 Withaferin A treatment inhibits expression of anti-apoptotic proteins, Survivin and XIAP and increases PARP cleavage.

SummaryFor decades, the expression of immediate early genes (IEGs) such as c-foshas been the most widely used molecular marker representing neuronal activation. However, to date, there is no equivalent surrogate available for the decrease of neuronal activity (i.e., inhibition). Here, we developed an optogenetic-based biochemical screen in which population neural activities can be controlled by light with single action potential precision, followed by unbiased phosphoproteomic profiling. We identified that the phosphorylation of pyruvate dehydrogenase (pPDH) inversely correlated with the intensity of action potential firing in primary neurons. Inin vivomouse models, monoclonal antibody-based pPDH immunostaining detected neuronal inhibition across the brain induced by a wide range of factors including general anesthesia, sensory experiences, and natural behaviors. Thus, as anin vivomarker for neuronal inhibition, pPDH can be used together with IEGs or other cell-type markers to profile and identify bi-directional neural dynamics induced by experiences or behaviors.