Secondary Sites Research Articles

Adsorption of organophosphate nerve agent VX on the (101) surface of anatase titanium dioxide

We quantify the adsorption of the organophosphate venomous agent X (VX) on the clean and hydroxylated (101) surfaces of anatase titanium dioxide (TiO2) with density functional theory (DFT) calculations. Our results show that adsorption on the clean anatase (101) surface occurs through the VX phosphoryl oxygen (OP) site and involves the formation of a Ti···OP dative bond. Steric effects inhibit adsorption through the VX nitrogen and sulfur sites by the formation of Ti···N and Ti···S dative bonds. On the hydroxylated (101) surface, adsorption similarly proceeds through the VX phosphoryl oxygen site but entails the formation of surface–adsorbate hydrogen bonds. Additionally, weak non-covalent interactions between the surface hydroxyl groups and the adsorbate’s nitrogen and sulfur atoms stabilize VX/(101) complexes formed by adsorption through these secondary sites. The energies of VX/(101) adsorption through the phosphoryl oxygen site are –19.4 and –11.3 kcal mol−1 on the clean and hydroxylated surfaces, respectively.

Beyond Agriculture: Alternative Geographies of Rural Land Investment and Place Effects across the United Kingdom

Global land ownership patterns have been shifting in recent decades, as institutional and non-traditional investors redirect capital into rural areas. Such investment is a stimulating alternative for innovative profit-driven land uses that move beyond agriculture. This paper explores how ‘new money’ economies have created place effects in three rural case studies across the United Kingdom, through concepts of built, natural, social, and economic capital. The case studies are informed by secondary research, site visits, and interviews, providing snapshots of investment impact. They represent diverse transformations in rural land use via new forms of direct investment, active investment, and processes of financing rather than financialisation, with distinct spatial and temporal characteristics. The case studies include new wine production in Kent, England; transforming the Menie Estate into Trump International Golf Links Scotland (TIGLS); and farm diversification in Northern Ireland. The conclusions tell three investment stories, where place effects reflect the dichotomies, contestation, and symbiosis between investors and local contexts. New land uses create place effects where economic potential often conflicts with natural capital impacts, although they foster knowledge creation and exchange. The underlying values of the investors and their navigation of local politics also have key roles to play in shaping the built, natural, social, and economic place effects.

Hypopharyngeal Carcinoma With Synchronous and Metachronous Multiple Malignancies: Clinical Characteristics and Prognosis Analysis of 673 Real World Cases

Hypopharyngeal carcinoma (HPC) is one of the most devastating malignancies among head and neck cancers. Our aim is to analyze the clinical characteristics and prognosis of synchronous and metachronous second primary malignancies (SPMs) in patients with hypopharyngeal carcinoma.We retrospectively reviewed 673 patients diagnosed in our institution between May 2009 and October 2019. Endoscopic examination was performed in 97.1% (654/673) of patients before treatment. We defined a synchronous SPM as which developed within 6 months of the index HPC diagnosis, while a metachronous SPM as which developed more than 6 months after initial diagnosis of HPC. The Kaplan-Meier method, propensity score-matched (PSM) and Cox model were used to analyze the data.Within the median follow-up of 66.5 months, 71 (10.5%) patients developed gastric/esophageal tumor in situ (Tis) and 143 (21.2%), patients developed SPMs, consisting of 78 with synchronous SPMs and 75 with metachronous SPMs, respectively, with patient overlap. Among the 143 patients, the most common secondary site was esophagus (n = 85), followed by the head and neck squamous cell carcinoma (HNSCC, n = 36), lung (n = 20) and other cancers (n = 19). The 5-year overall survivals (OS) for non-SPMs (n = 459), SPMs (n = 143) and Tis group (n = 71) were 43.8% vs 37.1% vs 42.9%, respectively. Accordingly, the disease-specific survivals (DSS) were 46.3% vs 56.2% vs 47.8%, respectively. We compared synchronous SPMs and no-SPMs groups, the 5-year OS and DSS were 37.1% and 56.2% for synchronous SPMs group (n = 78), compared with 43.8% (P = 0.093) and 46.3% (P = 0.098) for no-SPMs group (n = 459). We use PSM to balance two arms with the ratio of 1:1, resulting in the number of 62 patients in each group. The adjusted 5-year OS and DSS were 23.6% and 32.7% for synchronous SPMs group (n = 62), compared with 49.8% (P < 0.001) and 52.4% (P < 0.001) for no-SPMs group (n = 62). For synchronous and metachronous SPMs, the 5-year OS and DSS were 27.3% and 40.8% for synchronous SPMs group (n = 78) vs 48.8% (P = 0.001) and 70.7% (P = 0.001) for metachronous SPMs group (n = 75). According to the site of the SPMs, the 5-year OS and DSS were 24.5% and 40.4% for esophagus (n = 85), 51.9% and 66.9% for HNSCC (n = 36), 52.0% and 75.1% for lung (n = 20), 60.7% and 83.9% for others (n = 19). The SPMs in esophagus had worse OS than the other three groups (P<0.05). In multivariable analysis, synchronous SPMs, site of the SPMs, alcohol consumption and N stage were independently significant for OS.Approximately 30% of patients with HPC develop multiple malignancies during the course of disease and the most frequently involved site is the upper aero digestive tract. We should be aware of the possible coexistence of SPMs in HPC. Co-existence of gastric/esophageal tumor in situ does not affect outcome. The OS and DSS for synchronous SPMs are significantly worse than that for metachronous SPMs and no-SPMs. The SPMs in esophagus is the most common site and present the worst outcome than others.

Seeding metastases: The role and clinical utility of circulating tumour cells.

Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for various solid cancers. Enumeration of CTCs from blood is becoming a common practice in informing prognosis and may guide therapy decisions. It is further recognized that enumeration alone does not capture perspective on the heterogeneity of tumours and varying functional abilities of the CTCs to interact with the secondary microenvironment. Characterizing the isolated CTCs further, in particular assessing their functional abilities, can track molecular changes in the disease progress. As a step towards identifying a suite of functional features of CTCs that could aid in clinical decisions, developing a CTC isolation technique based on extracellular matrix (ECM) interactions may provide a more solid foundation for isolating the cells of interest. Techniques based on size, charge, density, and single biomarkers are not sufficient as they underutilize other characteristics of cancer cells. The ability of cancer cells to interact with ECM proteins presents an opportunity to utilize their full character in capturing, and also allows assessment of the features that reveal how cells might behave at secondary sites during metastasis. This article will review some common techniques and recent advances in CTC capture technologies. It will further explore the heterogeneity of the CTC population, challenges they experience in their metastatic journey, and the advantages of utilizing an ECM-based platform for CTC capture. Lastly, we will discuss how tailored ECM approaches may present an optimal platform to capture an influential heterogeneous population of CTCs.

Discrepancy Regarding the Dethreading of a Dibenzo‐24‐crown‐8 Macrocycle through a Perfluorobutyl End in [2]Pseudorotaxanes

AbstractHere are reported the synthesis and characterization of four new dibenzo‐24‐crown‐8 (DB24C8)‐based ammonium‐containing pseudorotaxanes, for which one of the two encircled axle's extremities consists of a perfluorobutyl moiety. The subsequent dethreading of the DB24C8 over the perfluorobutyl extremity was studied. Although the perfluorobutyl extremity of an ammonium‐containing axle did not allow threading of DB24C8, dethreading of a perfluorobutyl extremity‐containing pseudorotaxane was possible and its rate depended on both the strength of the template‐to‐DB24C8 complex and the nature of the axle. In particular, dethreading process may be assisted by the presence, in the threaded axle, of a poor secondary site of interaction for the DB24C8 and this assistance proved to be higher when this site is close to the DB24C8.

Metastasectomy versus radiation of secondary sites in stage IV breast cancer: Analysis from a national cancer registry

PurposeLocoregional therapy at primary or secondary sites in breast cancer may be associated with improved survival as compared to systemic therapy alone. We explored the sociodemographic and clinicopathologic factors associated with the use of radiation versus surgical resection of metastatic sites (metastasectomy) in patients with de novo stage IV breast cancer, followed by the associated overall survival. MethodsWe sampled the National Cancer Database for patients with de novo stage IV breast cancer, (2010–2017) and described cohort's characteristics using univariate analyses. We identified 5 subgroups based on malignant site involvement: 1. Bone only, 2. Brain only, 3. Liver only, 4. Lung only, and 5. Metastasis involving >1 site. Kaplan-Meier modeling with log-rank testing and multivariate Cox Regression analysis were used to explore differences in overall survival between those that received radiation at secondary sites and those that underwent metastasectomy. ResultsN = 22,749patients were included in this analysis. Radiation (81.2%) was used more commonly than metastasectomy (28.8%). Metastasectomy was associated with better median overall survival across all 5 cohorts (p < .001), with the survival benefit being the most pronounced with lung only (OS: 56.9 months; HR 0.8, 95% CI 0.7–0.9, p = .032), or liver only (OS: 41.6 months; HR: 0.9; 95% CI: 0.7–1.1, p < .001) metastasis. ConclusionMetastasectomy in patients with de novo stage IV breast cancer may be associated with improved overall survival as compared to radiation of secondary lesions, particularly in those with only liver or lung involvement. Prospective randomized controlled trials investigating surgical resection of metastatic sites in patients with breast cancer are warranted.

Cardiovascular risk profile in Portugal: evidence from a large population-based cohort

Abstract Background The rising prevalence of CVD in Portugal translates into more than 35 thousand annual deaths (1,2), with stroke and ischemic heart disease as the leading causes of death (3). Reducing the incidence of ASCVD is a public health priority, for which LDL-C lowering is paramount to halt atherosclerotic plaque progression (4,5). Real-world data is lacking regarding patient characterization, lipid-lowering therapy, and LDL-C levels by CV risk profile. Purpose To assess the proportion of patients with low, intermediate, high, and very high CV risk in a population with a complete spectrum of care, and describe their clinical characteristics, cardiovascular medications, and degree of LDL-C control. Methods This non-interventional, cross-sectional study included adult patients between 40 and 80 years old followed for primary or secondary CV risk prevention at a major healthcare institution that provides both primary and hospital care. Patient data spanned the period from 1/1/2008 to 31/12/2019. The index date for patient identification and characterization was 31/12/2019. CVD risk assessment was computed according to the 2019 ESC/EAS Guidelines for the management of dyslipidemias (6). Every criterion for risk assessment (excluding imaging and family history) was reconstructed using the most granular available records of clinical observations, measurements, episodes, lab orders, diagnosis and medications recorded at all primary and secondary care sites of the institution. We described patient demographic and clinical characteristics for each CV risk level, lipid-lowering treatment (LLT), and LDL-C levels. Results We identified 111.394 patients eligible for analysis. Sufficient records for CV risk assessment were available for 82.271 patients. According to 2019 ESC/EAS Guidelines CV risk categories, 25.7%, 21.4%, 12.2% and 40.7% of patients had low, intermediate, high and very high CV risk. High/very high CV risk patients had a mean (SD) age of 65.6 (10.1) years. Type 2 diabetes was present in 13.1% of high CV risk and 40% of very high CV risk groups. Although approximately 70% of patients with high/very high CV risk were treated with a LLT, only 5.1% of high CV risk and 3.6% of very high CV risk had LDL-C levels within the recommended targets. There was a very low use of high intensity statins or combination therapies in high/very high CV risk categories (table 1). Patients with atherosclerotic CV disease accounted for 34.6% of those at very high CV risk and only 4.8% attained desired goals (table 2). Conclusions There is a pressing need for better control of LDL-C levels at every stage of CV risk, with a particular focus on high and very high CV risk patients. Effective strategies for LCL-C control are thus needed. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was funded by Novartis Farma, Produtos Farmacêuticos S.A.

In vitro electrochemical assays for vascular cells and organs

AbstractVascular form vascular organs and the walls of blood vessels play a crucial role in transporting nutritive compounds and drugs. Vascular cells also release factors required to maintain the homeostasis of the organs. Since cancer cells travel from tumors to secondary sites during metastasis through the vasculature, it is important to investigate the interactions of vascular and cancer cells. In vitro vascular models, including endothelial cell monolayers, tubular structures in three‐dimensional culture scaffolds, and microfluidic cultures, have been developed to facilitate research on drug discovery and in‐depth disease mechanisms. In addition to the common optical methods proposed for the evaluation of these models, electrochemical assays have been applied for evaluating cell activities and drug effects owing to their numerous advantages such as low invasion, real‐time detection, or high sensitivity and selectivity. The present review focuses on electrochemical assays related to vascular model structure and function. First, we summarize strategies for the electrochemical detection of nitric oxide and reactive oxygen species; assessment of endothelial cell barrier integrity using transepithelial electrical resistance measurements; endothelial permeability measurement using electrochemical tracers; evaluation of respiration activity, topography, and mRNA expression via electrochemical collection. We further discuss the methods for electrochemical cell analysis in detail, along with the variety of electrochemical systems available for these purposes, including microfluidic devices and electrochemical scanning probe microscopes. Finally, we conclude our review and propose perspectives for research that are likely to become relevant in the field.

Mechanical Pain Sensitivity in Postamputation Pain.

Postamputation, clinical markers of pain-related peripheral and central nervous system hypersensitivity remain understudied. This study aimed to identify whether adults with postamputation pain demonstrate greater pain sensitivity in primary (ie, amputated region) and secondary (ie, nonamputated region) sites, as compared with pain-free peers and controls with intact limbs. Ninety-four participants postunilateral, transtibial amputation (59 with pain, 35 pain-free) and 39 controls underwent pain-pressure threshold (PPT) testing at 10 sites. Pain-pressure thresholds were normalized to sex-specific control data using Z score conversions. Normalized primary-site and secondary-site PPTs were compared between groups using multivariate analysis of variance (P<0.050). Compared with pain-free peers, adults with postamputation pain demonstrated reduced normalized PPTs across primary and secondary sites (mean difference=0.61-0.74, P=0.001 to 0.007). Compared with controls, adults with postamputation pain demonstrated reduced normalized PPTs (mean difference=0.52, P=0.026) only at primary sites. Adults with postamputation pain demonstrate greater amputated region pain sensitivity as compared with pain-free peers or controls with intact limbs, indicating peripheral sensitization persists even after limb healing. Secondary-site pain sensitivity was similar between controls and adults with postamputation pain, suggesting central nervous system hypersensitivity may not be ubiquitous with postamputation pain. Studies are needed to investigate mechanisms underlying pain sensitivity differences between adults with and without postamputation pain.

Notch-1 signaling promotes reattachment of suspended cancer cells by cdc42-dependent microtentacles formation.

Circulating tumor cells (CTCs) are associated with a higher risk of metastasis in tumor patients. The adhesion and arrest of CTCs at a secondary site is an essential prerequisite for the occurrence of tumor metastasis. CTC reattachment has shown to be dependent on microtentacle (McTN) formation in vivo. However, the specific molecular mechanism of McTN formation in suspended cancer cells remains largely unclear. Here, we demonstrated that the activation of Notch‐1 signaling triggers McTN formation to facilitate cell reattachment in suspended cell culture conditions. Moreover, molecular mechanistic studies revealed that McTN formation is governed by the balance between microtubule‐driven outgrowth and actomyosin‐driven cell contractility. The activation of Notch‐1 downregulates the acetylation level of microtubules via the Cdc42/HDAC6 pathway, which contributes to microtubule polymerization. Simultaneously, Notch‐1 signaling‐induced Cdc42 activation also reduced phosphorylation of myosin regulatory light chain, leading to cell contractility attenuation. Altogether, these results defined a novel mechanism by which Notch‐1 signaling disturbs the balance between the expansion of microtubules and contraction of the cortical actin, which promotes McTN formation and cell reattachment. Our findings provide a new perspective on the effective therapeutic target to prevent CTC reattachment.

In Silico Analysis of Fungal and Chloride-Dependent α-Amylases within the Family GH13 with Identification of Possible Secondary Surface-Binding Sites.

This study brings a detailed bioinformatics analysis of fungal and chloride-dependent α-amylases from the family GH13. Overall, 268 α-amylase sequences were retrieved from subfamilies GH13_1 (39 sequences), GH13_5 (35 sequences), GH13_15 (28 sequences), GH13_24 (23 sequences), GH13_32 (140 sequences) and GH13_42 (3 sequences). Eight conserved sequence regions (CSRs) characteristic for the family GH13 were identified in all sequences and respective sequence logos were analysed in an effort to identify unique sequence features of each subfamily. The main emphasis was given on the subfamily GH13_32 since it contains both fungal α-amylases and their bacterial chloride-activated counterparts. In addition to in silico analysis focused on eventual ability to bind the chloride anion, the property typical mainly for animal α-amylases from subfamilies GH13_15 and GH13_24, attention has been paid also to the potential presence of the so-called secondary surface-binding sites (SBSs) identified in complexed crystal structures of some particular α-amylases from the studied subfamilies. As template enzymes with already experimentally determined SBSs, the α-amylases from Aspergillus niger (GH13_1), Bacillus halmapalus, Bacillus paralicheniformis and Halothermothrix orenii (all from GH13_5) and Homo sapiens (saliva; GH13_24) were used. Evolutionary relationships between GH13 fungal and chloride-dependent α-amylases were demonstrated by two evolutionary trees—one based on the alignment of the segment of sequences spanning almost the entire catalytic TIM-barrel domain and the other one based on the alignment of eight extracted CSRs. Although both trees demonstrated similar results in terms of a closer evolutionary relatedness of subfamilies GH13_1 with GH13_42 including in a wider sense also the subfamily GH13_5 as well as for subfamilies GH13_32, GH13_15 and GH13_24, some subtle differences in clustering of particular α-amylases may nevertheless be observed.

Diagnosis of patients with heart failure with preserved ejection fraction in primary care: cohort study

AimsHeart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure (HF), but low awareness and diagnostic challenges hinder identification in primary care. Our aims were to evaluate the recruitment and diagnostic strategy in the Optimise HFpEF cohort and compare with recent recommendations for diagnosing HFpEF.Methods and resultsPatients were recruited from 30 primary care practices in two regions in England using an electronic screening algorithm and two secondary care sites. Baseline assessment collected clinical and patient‐reported data and diagnosis by history, assessment, and trans‐thoracic echocardiogram (TTE). A retrospective evaluation compared study diagnosis with H2FPEF score and HFA‐PEFF diagnostic algorithm. A total of 152 patients (86% primary care, mean age 78.5, 40% female) were enrolled; 93 (61%) had HFpEF confirmed. Most participants had clinical features of HFpEF, but those with confirmed HFpEF were more likely female, obese, functionally impaired, and symptomatic. Some echocardiographic findings were diagnostic for HFpEF, but no difference in natriuretic peptide levels were observed. The H2FPEF and HFA‐PEFF scores were not significantly different by group, although confirmed HFpEF cases were more likely to have scores indicating high probability of HFpEF.ConclusionsPatients with HFpEF in primary care are difficult to identify, and greater awareness of the condition, with clear diagnostic pathways and specialist support, are needed. Use of diagnostic algorithms and scores can provide systematic approaches to diagnosis but may be challenging to apply in older multi‐morbid patients. Where diagnostic uncertainty remains, pragmatic decisions are needed regarding the value of additional testing versus management of presumptive HFpEF.

Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche.

Intracellular infection with the parasite Leishmania major features a state of concomitant immunity in which CD4+ T helper 1 (Th1) cell-mediated immunity against reinfection coincides with a chronic but sub-clinical primary infection. In this setting, the rapidity of the Th1 response at a secondary site of challenge in the skin represents the best correlate of parasite elimination and has been associated with a reversal in Leishmania-mediated modulation of monocytic host cells. Remarkably, the degree to which Th1 cells are absolutely reliant upon the time at which they interact with infected monocytes to mediate their protective effect has not been defined. In the present work, we report that CXCR3-dependent recruitment of Ly6C+ Th1 effector (Th1EFF) cells is indispensable for concomitant immunity and acute (<4 days post-infection) Th1EFF cell-phagocyte interactions are critical to prevent the establishment of a permissive pathogen niche, as evidenced by altered recruitment, gene expression and functional capacity of innate and adaptive immune cells at the site of secondary challenge. Surprisingly, provision of Th1EFF cells after establishment of the pathogen niche, even when Th1 cells were provided in large quantities, abrogated protection, Th1EFF cell accumulation and IFN-γ production, and iNOS production by inflammatory monocytes. These findings indicate that protective Th1 immunity is critically dependent on activation of permissive phagocytic host cells by preactivated Th1EFF cells at the time of infection.

Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression.

Simple SummaryBreast cancer comprises a wide variety of cancer cells that present distinct phenotypes and develop various nutrient dependencies to grow and survive in stressful microenvironments. Breast cancer treatment remains challenging due to resistance to anticancer drugs, recurrence, and dissemination of cancer cells to secondary sites. Here, we review the diverse dependencies of breast cancer cells on various metabolites and metabolic pathways that support breast tumour progression. Moreover, we explore potential strategies to use metabolic dependencies as a therapeutic target for breast cancer patients.Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.

Stationed or Relocating: The Seesawing EMT/MET Determinants from Embryonic Development to Cancer Metastasis.

Epithelial and mesenchymal transition mechanisms continue to occur during the cell cycle and throughout human development from the embryo stage to death. In embryo development, epithelial-mesenchymal transition (EMT) can be divided into three essential steps. First, endoderm, mesoderm, and neural crest cells form, then the cells are subdivided, and finally, cardiac valve formation occurs. After the embryonic period, the human body will be subjected to ongoing mechanical stress or injury. The formation of a wound requires EMT to recruit fibroblasts to generate granulation tissues, repair the wound and re-create an intact skin barrier. However, once cells transform into a malignant tumor, the tumor cells acquire the characteristic of immortality. Local cell growth with no growth inhibition creates a solid tumor. If the tumor cannot obtain enough nutrition in situ, the tumor cells will undergo EMT and invade the basal membrane of nearby blood vessels. The tumor cells are transported through the bloodstream to secondary sites and then begin to form colonies and undergo reverse EMT, the so-called “mesenchymal-epithelial transition (MET).” This dynamic change involves cell morphology, environmental conditions, and external stimuli. Therefore, in this manuscript, the similarities and differences between EMT and MET will be dissected from embryonic development to the stage of cancer metastasis.

Genome-wide identification, evolution, and transcript profiling of Aldehyde dehydrogenase superfamily in potato during development stages and stress conditions

The Aldehyde dehydrogenase (ALDH) superfamily comprises a group of enzymes involved in the scavenging of toxic aldehyde molecules by converting them into their corresponding non-toxic carboxylic acids. A genome-wide study in potato identified a total of 22 ALDH genes grouped into ten families that are presented unevenly throughout all the 12 chromosomes. Based on the evolutionary analysis of ALDH proteins from different plant species, ALDH2 and ALDH3 were found to be the most abundant families in the plant, while ALDH18 was found to be the most distantly related one. Gene expression analysis revealed that the expression of StALDH genes is highly tissue-specific and divergent in various abiotic, biotic, and hormonal treatments. Structural modelling and functional analysis of selected StALDH members revealed conservancy in their secondary structures and cofactor binding sites. Taken together, our findings provide comprehensive information on the ALDH gene family in potato that will help in developing a framework for further functional studies.

Cutaneous Metastasis of Signet Ring Cell Carcinoma: An Unusual Case Report

Introduction: Signet ring cell carcinoma is a rare form of highly malignant adenocarcinoma, with the prevalence rate of &lt; 1%. The most common site of the primary tumor is the stomach, and the secondary sites are the breast, gall bladder, urinary bladder, and pancreas. Moreover, the common metastasis sites of signet ring cell carcinomas are the lung and the liver. Skin metastasis is extremely rare, with the prevalence rate of 0.3%. Signet ring cell carcinomas are usually diagnosed during the late stages of the disease; hence, the tumors spread more aggressively than non-signet ring cell types, thereby making treatment challenging. Case presentation: We report a 30-year-old male with cutaneous metastasis of signet ring cell carcinoma in the form of multiple, asymptomatic, skin-colored, nodular lesions on his neck and chest. Conclusions: Signet ring cell carcinoma is a rare type of adenocarcinoma, the primary site of which is the stomach. Moreover, the usual metastasis sites of the tumor are the lung and the liver. The timely diagnosis of such a malignant and aggressive tumor is possible by detecting the unusual presentations of cutaneous metastasis, which would result in offering timely interventions and saving patient’s lives.

Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells

Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.

Insights into 6S RNA in lactic acid bacteria (LAB)

Background6S RNA is a regulator of cellular transcription that tunes the metabolism of cells. This small non-coding RNA is found in nearly all bacteria and among the most abundant transcripts. Lactic acid bacteria (LAB) constitute a group of microorganisms with strong biotechnological relevance, often exploited as starter cultures for industrial products through fermentation. Some strains are used as probiotics while others represent potential pathogens. Occasional reports of 6S RNA within this group already indicate striking metabolic implications. A conceivable idea is that LAB with 6S RNA defects may metabolize nutrients faster, as inferred from studies of Echerichia coli. This may accelerate fermentation processes with the potential to reduce production costs. Similarly, elevated levels of secondary metabolites might be produced. Evidence for this possibility comes from preliminary findings regarding the production of surfactin in Bacillus subtilis, which has functions similar to those of bacteriocins. The prerequisite for its potential biotechnological utility is a general characterization of 6S RNA in LAB.ResultsWe provide a genomic annotation of 6S RNA throughout the Lactobacillales order. It laid the foundation for a bioinformatic characterization of common 6S RNA features. This covers secondary structures, synteny, phylogeny, and product RNA start sites. The canonical 6S RNA structure is formed by a central bulge flanked by helical arms and a template site for product RNA synthesis. 6S RNA exhibits strong syntenic conservation. It is usually flanked by the replication-associated recombination protein A and the universal stress protein A. A catabolite responsive element was identified in over a third of all 6S RNA genes. It is known to modulate gene expression based on the available carbon sources. The presence of antisense transcripts could not be verified as a general trait of LAB 6S RNAs.ConclusionsDespite a large number of species and the heterogeneity of LAB, the stress regulator 6S RNA is well-conserved both from a structural as well as a syntenic perspective. This is the first approach to describe 6S RNAs and short 6S RNA-derived transcripts beyond a single species, spanning a large taxonomic group covering multiple families. It yields universal insights into this regulator and complements the findings derived from other bacterial model organisms.

Stable NiPt–Mo2C active site pairs enable boosted water splitting and direct methanol fuel cell

Sluggish kinetics of methanol oxidation reaction (MOR) and alkaline hydrogen evolution reaction (HER) even on precious Pt catalyst impede the large-scale commercialization of direct methanol fuel cell (DMFC) and water electrolysis technologies. Since both of MOR and alkaline HER are related to water dissociation reaction (WDR), it is reasonable to invite secondary active sites toward WDR to pair with Pt for boosted MOR and alkaline HER activity on Pt. Mo2C and Ni species are therefore employed to engineer NiPt–Mo2C active site pairs, which can be encapsulated in carbon cages, via an in-situ self-confinement strategy. Mass activity of Pt in NiPt–Mo2C@C toward HER is boosted to 11.3 A mgpt−1, 33 times higher than that of Pt/C. Similarly, MOR catalytic activity of Pt in NiPt–Mo2C@C is also improved by 10.5 times and the DMFC maximum power density is hence improved by 9-fold. By considering the great stability, NiPt–Mo2C@C exhibits great practical application potential in DMFCs and water electrolysers.