Primary mucosal melanomas of the head and neck are characterised by overexpression of the DNA mutating enzyme APOBEC3B.

AIMS: Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B-related mutations are identified through C-to-T/-G base substitutions in 5'-TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs. METHODS AND RESULTS: A3B protein levels were assessed in oral (n = 13) and sinonasal (n = 13) melanomas, and oral melanocytic nevi (n = 13) by immunohistochemistry using a custom rabbit α-A3B mAb (5210-87-13). Heterogeneous, selective-to-diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H-score range = 9-72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H-score range = 1-110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (P < 0.0001 and P = 0.0022, respectively), which were A3B-negative (H-score range = 1-8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours (P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole-genome sequencing (WGS) data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2). CONCLUSION: The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.

Metastatic Tumors to the Oral Soft Tissues and Jawbones: A Retrospective Analysis of 40 Cases and Review of the Literature.

BACKGROUND: Metastasis to the oral soft tissues and jawbones is rare and frequently associated with wide spread disease and dismal prognosis. Herein, we report the clinicopathologic characteristics of 40 intraoral metastatic neoplasms and perform a comprehensive review of the pertinent literature. METHODS: Criteria for inclusion included: (a) archived cases from the UMN Oral Pathology laboratory with available tissue blocks and/or H&E-stained preparations diagnosed between 2003 and 2021, (b) proper documentation of the clinico-radiographic characteristics of oral metastasis along with confirmed history of primary malignancy, or (c) microscopic findings consistent with metastatic disease with or without discovery of the primary site. RESULTS: Intraoral metastases comprised 0.03% of all accessioned cases; 22 (55%) occurred in men and 18 (45%) in women (median age = 66.5; range = 18-94 years). Eighteen cases (45%) involved the gingiva, 16 (40%) the gingiva and jawbones, 5 (12.5%) were exclusively intraosseous, and 1 affected (2.5%) the tongue. The lung was the two most frequent primary site in both men (n = 6, 27.3%) and women (n = 5, 27.7%), followed by the colon (n = 4, 18.2%) and kidney (n = 3, 13.7%) in men, and colon (n = 4, 22.2%) and breast (n = 3, 16.6%) in women. Analysis of 1,084 metastatic cases from the literature (male-to-female ratio = 1.2; mean = 52.3; range = 0.6-90 years) indicated strong preference for the jawbones (69.5%) and significant site-specific predilection of certain primary malignancies. CONCLUSIONS: Oral and gnathic metastases are rare but demonstrate a clear predilection for the gingiva and mandible. Clinicians should remain cognizant of such lesions since they frequently mimic inflammatory, reactive or benign neoplastic processes and, in certain cases, are the first indication of occult disease.

IFN-α blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health.

Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN-inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-ß levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.

Evaluation of the association of length of stay in hospital and outcomes.

BACKGROUND: There exist wide variations in healthcare quality within the National Health Service (NHS). A shorter hospital length of stay (LOS) has been implicated as premature discharge, that may in turn lead to adverse consequences. We tested the hypothesis that a short LOS might be associated with increased risk of readmissions within 28 days of hospital discharge and also post-discharge mortality. METHODS: We conducted a single-centred study of 32 270 (46.1% men) consecutive alive-discharge episodes (mean age = 64.0 years, standard deviation = 20.5, range = 18-107 years), collected between 01/04/2017 and 31/03/2019. Associations of LOS tertiles (middle tertile as a reference) with readmissions and mortality were assessed using observed/expected ratios, and logistic and Cox regressions to estimate odds (OR) and hazard ratios (HR) (adjusted for age, sex, patients' severity of underlying health status and index admissions), with 95% confidence intervals (CIs). RESULTS: The observed numbers of readmissions within 28 days of hospital discharge or post-discharge mortality were lower than expected (observed: expected ratio < 1) in patients in the bottom tertile (<1.2 days) and middle tertile (1.2-4.3 days) of LOS, whilst higher than expected (observed: expected ratio > 1) in patients in the top tertile (>4.3 days), amongst all ages. Patients in the top tertile of LOS had increased risks for one readmission: OR = 2.32 (95% CI = 1.86-2.88) or ≥2 readmissions: OR = 6.17 (95% CI = 5.11-7.45), death within 30 days: OR = 2.87 (95% CI = 2.34-3.51), and within six months of discharge: OR = 2.52 (95% CI = 2.23-2.85), and death over a two-year period: HR = 2.25 (95% CI = 2.05-2.47). The LOS explained 7.4% and 15.9% of the total variance (r2) in one readmission and ≥2 readmissions, and 9.1% and 10.0% of the total variance in mortality with 30 days and within six months of hospital discharge, respectively. Within the bottom, middle and top tertiles of the initial LOS, the median duration from hospital discharge to death progressively shortened from 136, 126 to 80 days, whilst LOS during readmission lengthened from 0.4, 0.9 to 2.8 days, respectively. CONCLUSION: Short LOS in hospital was associated with favourable post-discharge outcomes such as early readmission and mortality, and with a delay in time interval from discharge to death and shorter LOS in hospital during readmission. These findings indicate that timely discharge from our hospital meets the aims of the NHS-generated national improvement programme, Getting It Right First Time.

The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.

Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb.

HPV-induced cervical cancer is one of the prevalent gynecological cancers world-wide. In the present study, we determined the efficacy of Minnelide, a prodrug which is converted to its active form (Triptolide) in vivo against cervical cancer cells. Our studies show that Triptolide inhibited HPV-16 and HPV-18 positive cells at nanomolar concentrations. Tumor cells treated with Triptolide failed to grow in 3-D cultures in a concentration-dependent manner. Triptolide markedly reduced E6 and E7 transcript levels. Further studies revealed that exposure to Triptolide increased the levels of p53 and pRb. As a consequence, Caspase-3/7 activation and apoptosis was induced in cervical cancer cells by Triptolide. Subsequently, we evaluated the efficacy of Minnelide in xenotransplantation models of cervical cancer. Minnelide at very low doses effectively inhibited the growth of established cervical cancers in all the three animal models tested. Furthermore, Minnelide treatment was more effective when combined with platinum-based chemotherapy. These studies show that Minnelide can be used to inhibit the growth of cervical cancer.

Automating the assessment of biofouling in images using expert agreement as a gold standard.

Biofouling is the accumulation of organisms on surfaces immersed in water. It is of particular concern to the international shipping industry because it increases fuel costs and presents a biosecurity risk by providing a pathway for non-indigenous marine species to establish in new areas. There is growing interest within jurisdictions to strengthen biofouling risk-management regulations, but it is expensive to conduct in-water inspections and assess the collected data to determine the biofouling state of vessel hulls. Machine learning is well suited to tackle the latter challenge, and here we apply deep learning to automate the classification of images from in-water inspections to identify the presence and severity of fouling. We combined several datasets to obtain over 10,000 images collected from in-water surveys which were annotated by a group biofouling experts. We compared the annotations from three experts on a 120-sample subset of these images, and found that they showed 89% agreement (95% CI: 87-92%). Subsequent labelling of the whole dataset by one of these experts achieved similar levels of agreement with this group of experts, which we defined as performing at most 5% worse (p [Formula: see text] 0.009-0.054). Using these expert labels, we were able to train a deep learning model that also agreed similarly with the group of experts (p [Formula: see text] 0.001-0.014), demonstrating that automated analysis of biofouling in images is feasible and effective using this method.

Examining the factor structure, reliability, and validity of the main outcome measure used in mentalization-based therapy skills training.

BACKGROUND AND AIMS: Multiple national guidelines stress the importance for clinicians to possess good therapeutic skills for working with patients with significant relational difficulties (who may receive a diagnosis of personality disorder). Training clinicians in mentalization-based treatment skills (MBT-S) is one approach to address this. The main outcome measure used in MBT-S studies is the Knowledge and Application of MBT Questionnaire (KAMQ). However, an absence of research into the properties and validity of the KAMQ has limited the methodological quality of MBT-S evaluations so far. The aim of this study was therefore to investigate the factor structure, internal consistency, reliability, and validity of the KAMQ. METHODS: Using an existing multiprofessional sample of 217 clinicians from 2014 to 2016, we undertook exploratory factor analysis to determine the factor structure and internal consistency of the KAMQ. Convergent validity of the measure with the Attitudes to Personality Disorder Questionnaire (APDQ) was assessed in a subset of this dataset where both questionnaires had been administered (n = 92). Additionally, by recruiting a new sample of 70 clinicians, we assessed the measure's test-retest reliability. RESULTS: Factor analysis found three factors underlying 17 of the 20 KAMQ items, relating to therapeutic skills in mentalizing, beliefs about applying MBT in practice, and specific MBT knowledge. The KAMQ was revised following the factor analysis to form the KAMQ-2 with 17 items. Internal consistency (α = .85, 95% confidence interval [CI] = 0.80-0.89) and test-retest reliability (ICC = 0.84, 95% CI = 0.73-0.91) were good. In correlation analyses, the KAMQ-2 showed convergent validity with the main factor from the APDQ (n = 48; r s = 0.39, P < .01). CONCLUSION: The KAMQ-2 provides a short, reliable self-report instrument which probes clinicians' knowledge about mentalizing skills, and beliefs about using these. There was preliminary evidence for validity. The properties of the KAMQ-2 mean that more robust evaluation and development of MBT-S is now possible.

Endogenous APOBEC3B overexpression characterizes HPV-positive and HPV-negative oral epithelial dysplasias and head and neck cancers.

The DNA cytosine deaminase APOBEC3B (A3B) is a newly recognized endogenous source of mutations in a range of human tumors, including head/neck cancer. A3B inflicts C-to-T and C-to-G base substitutions in 5'-TCA/T trinucleotide motifs, contributes to accelerated rates of tumor development, and affects clinical outcomes in a variety of cancer types. High-risk human papillomavirus (HPV) infection causes A3B overexpression, and HPV-positive cervical and head/neck cancers are among tumor types with the highest degree of APOBEC signature mutations. A3B overexpression in HPV-positive tumor types is caused by the viral E6/E7 oncoproteins and may be an early off-to-on switch in tumorigenesis. In comparison, less is known about the molecular mechanisms responsible for A3B overexpression in HPV-negative head/neck cancers. Here, we utilize an immunohistochemical approach to determine whether A3B is turned from off-to-on or if it undergoes a more gradual transition to overexpression in HPV-negative head/neck cancers. As positive controls, almost all HPV-positive oral epithelial dysplasias and oropharyngeal cancers showed high levels of nuclear A3B staining regardless of diagnosis. As negative controls, A3B levels were low in phenotypically normal epithelium adjacent to cancer and oral epithelial hyperplasias. Interestingly, HPV-negative and low-grade oral epithelial dysplasias showed intermediate A3B levels, while high-grade oral dysplasias showed high A3B levels similar to oral squamous cell carcinomas. A3B levels were highest in grade 2 and grade 3 oral squamous cell carcinomas. In addition, a strong positive association was found between nuclear A3B and Ki67 scores suggesting a linkage to the cell cycle. Overall, these results support a model in which gradual activation of A3B expression occurs during HPV-negative tumor development and suggest that A3B overexpression may provide a marker for advanced grade oral dysplasia and cancer.

Primary prevention of cardiovascular disease: Updated review of contemporary guidance and literature.

Cardiovascular disease remains a substantial concern in terms of global mortality and morbidity, while prevalence of cardiovascular disease is increasing as treatment modalities improve survival. With an ageing population and increasing costs of chronic medical care, primary prevention of cardiovascular disease is an important target for healthcare providers. Since the previous iteration of this paper, new international guidelines have been produced regarding hypertension and lipid lowering therapies, whilst there is a growing body of evidence and new therapies emerging in other areas of lifestyle and pharmacotherapeutic intervention. This review outlines emerging evidence in the field and compares and contrasts contemporary recommendations from European and American guidelines.

Balint-style reflective practice groups in a year 4 undergraduate general practice attachment: experience of the first two years.

BACKGROUND AND AIMS: Many undergraduate medical curricula include reflective practice sessions based on traditional Balint-groups. Those sessions can help students to acknowledge that experiencing 'negative' feelings in relation to patients is normal and may contain important information about the clinical encounter. They may also help to protect students from some of the emotional challenges of studying medicine. The Edinburgh University scheme provides all students in their first clinical year with two dedicated reflective practice sessions. Here we report on experience of the first two years. METHODS: Students' attitudes to the sessions were ascertained using a questionnaire, and views of the group leaders were assessed using a questionnaire and through informal verbal and email discussions. Practical difficulties were recorded as they arose. RESULTS: Students generally rated the sessions positively with regard to exploring relationships and self-reflection, and they found the sessions interesting and helpful. The sessions did not seem to affect career choice. The free-text comments suggested four positive themes and four areas for future modification. CONCLUSION: We have succeeded in providing all undergraduate students with an opportunity to take part in a reflective practice. We have highlighted aspects which have been successful and suggested future improvements.

Primary Intraosseous Xanthomas of the Jaws: A Series of Six Cases Including an Example with Formation of Apoptosis-Related Hyaline Globules, So-Called "Thanatosomes".

Primary intraosseous xanthomas of the jaws (PIXJ) are rare and predominantly affect the posterior mandible (86%) of normolipemic patients, with a mean age of 30 years and no gender predilection. Clinically, PIXJ exhibit indolent biologic behavior; curettage is considered treatment of choice. Only 36 PIXJ have been reported. Apoptosis-related hyaline globules (HGs), also known as "thanatosomes", have not been previously reported in PIXJ. Cases diagnosed as xanthoma of bone were retrieved. Six cases fulfilling currently accepted criteria were identified and their clinicopathologic and immunohistochemical properties are presented herein. Mean age for PIXJ was 21.8 years (range = 12-33) and F:M ratio = 2:1. All cases presented as well-demarcated, unilocular or multilocular radiolucencies. Microscopically, PIXJ featured sheets of lipid-laden macrophages with eosinophilic or foamy cytoplasm. A secondary fibroblastic population lacking storiform pattern was evident in two cases. Adipocytes (3/6), peripheral neurovascular bundles (1/6), bone fragments (3/6) and dystrophic calcifications (3/6) were observed enclosed by the xanthoma cells. Notably, one case exhibited numerous, spherical, eosinophilic HGs containing apoptotic nuclei. PIXJ were consistently CD68(+) and negative for CD1α and S100. CD45 decorated lymphocytes and the membrane of foamy histiocytes. Xanthoma cells stained for lysozyme and plasma proteins including alpha-1 antitrypsin (AAT), IgG and IgA in one probed case. HGs were lysozyme(+), AAT(+), IgG(+), IgA(+), PAS(+) and diastase-resistant, and fuchsinophilic with Masson's trichrome. PIXJ represent infrequent, solitary, mandibular lesions with a predilection for the second and third decade of life. Thanatosomes associated with cell injury and death can be present in PIXJ.

Intraoral Cutaneous Hamartomas-Clinicopathologic and Immunohistochemical Characteristics of 3 Cases.

Intraoral cutaneous hamartomas (ICHs) are uncommon mucosal lesions characterized microscopically by a combination of cutaneous structures, including various stages of follicular and sebaceous elements. Due to their rarity, the clinicopathologic and immunohistochemical attributes of ICHs have not been thoroughly delineated. Three cases of ICH were identified from our records, and formalin-fixed paraffin-embedded sections were immunohistochemically stained with antibodies against androgen receptor, estrogen receptor, and progesterone receptor, p63, factor XIIIα, and CD34. All 3 ICHs involved the buccal mucosa with an M:F ratio = 2:1 and mean age = 42.3 years (age range: 27-61 years). ICHs presented as thickened, painless, white and yellow plaques or nodules of long duration, measuring 0.6-1.5 cm. No history of skin graft in the area of the lesions was reported. Histopathologically, the lesions showed aggregates of rudimentary folliculosebaceous structures. Although well-defined piloerector muscles were present in all cases of ICH, bona fide hair follicles and isolated hair shafts were identified only in 1 case. The overlying oral epithelium exhibited epidermis-like morphological features, while inflammation was generally absent. Immunohistochemically, strong and diffuse nuclear staining for androgen receptor and factor XIIIα was observed in the sebaceous glands, and estrogen receptor and p63 reactivity were confined exclusively to the peripheral basal cells, while progesterone receptor staining was negative in ICHs. CD34 diffusely decorated the lesional stroma. In conclusion, ICH is a rare lesion composed of cutaneous elements in an abnormal location. A predilection for the buccal mucosa is reported in the current study.

Adenosine deaminase-1 delineates human follicular helper T cell function and is altered with HIV.

Follicular helper T cells (Tfh) play critical roles instructing, and initiating T-cell dependent antibody responses. The underlying mechanisms that enhance their function is therefore critical for vaccine development. Here we apply gene array analysis identifying adenosine deaminase (ADA) as a key molecule that delineates a human Tfh helper program in proliferating circulating Tfh (cTfh) cells and Germinal Centers Tfh (GC-Tfh). ADA-1 expression and enzymatic activity are increased in efficient cTfh2-17/GC-Tfh cells. Exogenous ADA-1 enhances less efficient cTfh1 and pro-follicular Tfh PD-1+ CXCR5+ cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impedes cTfh2-17/GC-Tfh function and diminished antibody response. Mechanistically, ADA-1 controls the Tfh program by influencing IL6/IL-2 production, controlling CD26 extracellular expression and could balance signals through adenosine receptors. Interestingly, dysfunctional Tfh from HIV infected-individual fail to regulate the ADA pathway. Thus, ADA-1 regulates human Tfh and represents a potential target for development of vaccine strategy.

Reduced Chronic Lymphocyte Activation following Interferon Alpha Blockade during the Acute Phase of Simian Immunodeficiency Virus Infection in Rhesus Macaques.

Pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection of humans and rhesus macaques (RMs) induces persistently high production of type I interferon (IFN-I), which is thought to contribute to disease progression. To elucidate the specific role of interferon alpha (IFN-α) in SIV pathogenesis, 12 RMs were treated prior to intravenous (i.v.) SIVmac239 infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN-α subtypes and were compared with six mock-infused, SIV-infected controls. Plasma viremia was measured postinfection to assess the effect of IFN-α blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypic staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute-phase viral loads versus controls. Four out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4+ T cell counts that was associated with progression to AIDS. Interestingly, 50% of the animals treated with AGS-009 (6/12) developed AIDS within 1 year of infection compared with 17% (1/6) of untreated controls. Finally, blockade of IFN-α decreased the levels of activated CD4+ and CD8+ T cells, as well as B cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-α-blockaded animals supports the hypothesis that IFN-α signaling contributes to lymphocyte activation during SIV infection and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals.IMPORTANCE Interferon alpha (IFN-α) is a member of a family of molecules (type I interferons) that prevent or limit virus infections in mammals. However, IFN-α production may contribute to the chronic immune activation that is thought to be the primary cause of immune decline and AIDS in HIV-infected patients. The study presented here attempts to understand the contribution of IFN-α to the natural history and progression of SIV infection of rhesus macaques, the primary nonhuman primate model system for testing hypotheses about HIV infection in humans. Here, we show that blockade of IFN-α action promotes lower chronic immune activation but higher early viral loads, with a trend toward faster disease progression. This study has significant implications for new treatments designed to impact the type I interferon system.

Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate.

BACKGROUND: Alcohol increases intestinal permeability to proinflammatory microbial products that promote liver disease, even after a period of sobriety. We sought to test the hypothesis that alcohol affects intestinal stem cells using an in vivo model and ex vivo organoids generated from jejunum and colon from mice fed chronic alcohol. METHODS: Mice were fed a control or an alcohol diet. Intestinal permeability, liver steatosis-inflammation, and stool short-chain fatty acids (SCFAs) were measured. Jejunum and colonic organoids and tissue were stained for stem cell, cell lineage, and apical junction markers with assessment of mRNA by PCR and RNA-seq. ChIP-PCR analysis was carried out for Notch1 using an antibody specific for acetylated histone 3. RESULTS: Alcohol-fed mice exhibited colonic (but not small intestinal) hyperpermeability, steatohepatitis, and decreased butyrate/total SCFA ratio in stool. Stem cell, cell lineage, and apical junction marker staining in tissue or organoids from jejunum tissue were not impacted by alcohol. Only chromogranin A (Chga) was increased in jejunum organoids by qPCR. However, colonic tissue and organoid staining exhibited an alcohol-induced significant decrease in cytokeratin 20+  (Krt20+) absorptive lineage enterocytes, a decrease in occludin and E-cadherin apical junction proteins, an increase in Chga, and an increase in the Lgr5 stem cell marker. qPCR revealed an alcohol-induced decrease in colonic organoid and tissue Notch1, Hes1, and Krt20 and increased Chga, supporting an alteration in stem cell fate due to decreased Notch1 expression. Colonic tissue ChIP-PCR revealed alcohol feeding suppressed Notch1 mRNA expression (via deacetylation of histone H3) and decreased Notch1 tissue staining. CONCLUSIONS: Data support a model for alcohol-induced colonic hyperpermeability via epigenetic effects on Notch1, and thus Hes1, suppression through a mechanism involving histone H3 deacetylation at the Notch1 locus. This decreased enterocyte and increased enteroendocrine cell colonic stem cell fate and decreased apical junctional proteins leading to hyperpermeability.

Human Monocyte Subsets Are Transcriptionally and Functionally Altered in Aging in Response to Pattern Recognition Receptor Agonists.

Age-related alterations in immunity have been linked to increased incidence of infections and decreased responses to vaccines in the aging population. Human peripheral blood monocytes are known to promote Ag presentation and antiviral activities; however, the impact of aging on monocyte functions remains an open question. We present an in-depth global analysis examining the impact of aging on classical (CD14+CD16-), intermediate (CD14+CD16+), and nonclassical (CD14dimCD16+) monocytes. Monocytes sorted from nonfrail healthy adults (21-40 y) and old (≥65 y) individuals were analyzed after stimulation with TLR4, TLR7/8, and retinoic acid-inducible gene I agonists. Our data showed that under nonstimulated conditions, monocyte subsets did not reveal significant age-related alternations; however, agonist stimulated-monocytes from adults and old subjects did show differences at the transcriptional and functional levels. These alternations in many immune-related transcripts and biological processes resulted in reduced production of IFN-α, IFN-γ, IL-1ß, CCL20, and CCL8, and higher expression of CX3CR1 in monocytes from old subjects. Our findings represent a comprehensive analysis of the influence of human aging on pattern recognition receptors signaling and monocyte functions, and have implications for strategies to enhance the immune response in the context of infection and immunization.

Primary prevention of cardiovascular disease: A review of contemporary guidance and literature.

Cardiovascular disease is a significant and ever-growing problem in the United Kingdom, accounting for nearly one-third of all deaths and leading to significant morbidity. It is also of particular and pressing interest as developing countries experience a change in lifestyle which introduces novel risk factors for cardiovascular disease, leading to a boom in cardiovascular disease risk throughout the developing world. The burden of cardiovascular disease can be ameliorated by careful risk reduction and, as such, primary prevention is an important priority for all developers of health policy. Strong consensus exists between international guidelines regarding the necessity of smoking cessation, weight optimisation and the importance of exercise, whilst guidelines vary slightly in their approach to hypertension and considerably regarding their approach to optimal lipid profile which remains a contentious issue. Previously fashionable ideas such as the polypill appear devoid of in-vivo efficacy, but there remain areas of future interest such as the benefit of serum urate reduction and utility of reduction of homocysteine levels.

Small phase pattern 2D beam steering and a single LCOS design of 40 1 × 12 stacked wavelength selective switches.

Two-dimensional beam steering by small, square, phase patterns as small as 50 × 50 pixels on a phase-only liquid crystal on silicon (LCOS) device is experimentally verified as suitable for the application of wavelength selective switches (WSSs), in terms of the diffraction efficiency and steering accuracy. This enables a proposed highly functional and versatile stacked switch architecture, where 40 independent 1 × 12 WSSs can be realised on a single 4k LCOS device. They can be configured to support a 1 × N WSSs with N≤144, or an N × N wavelength crossconnect with N≤12.