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Abstract In advanced non-small cell lung cancer (NSCLC), response to immunotherapy is difficult to predict from pre-treatment information. Given the toxicity of immunotherapy and its financial burden on the healthcare system, we set out to identify patients for whom treatment is effective. To this end, we used mutational signatures from DNA mutations in pre-treatment tissue. Single base substitutions, doublet base substitutions, indels, and copy number alteration signatures were analysed in $$m=101$$ m = 101 patients (the discovery set). We found that tobacco smoking signature (SBS4) and thiopurine chemotherapy exposure-associated signature (SBS87) were linked to durable benefit. Combining both signatures in a machine learning model separated patients with a progression-free survival hazard ratio of 0.40 $$_{-0.17}^{+0.28}$$ - 0.17 + 0.28 on the cross-validated discovery set and 0.24 $$_{-0.14}^{+0.31}$$ - 0.14 + 0.31 on an independent external validation set ( $$m=56$$ m = 56 ). This paper demonstrates that the fingerprints of mutagenesis, codified through mutational signatures, select advanced NSCLC patients who may benefit from immunotherapy, thus potentially reducing unnecessary patient burden.

Abstract Orchestrated modulation of cell adhesion is essential for development and homeostasis in multicellular organisms. It optimizes embedding of the cell in its dynamic environment and facilitates appropriate cell responses and intercellular communication. Chronic disturbance of this delicate equilibrium causes defects in tissue architecture and sometimes cancer. In tumor cell biology, dynamic control of adhesion molecules is important to proceed through the metastatic cascade and to allow cell release from the primary tumor, invasion of the surrounding matrix, intravasation and adhesion to vascular endothelial cells to facilitate extravasation. Intertwined and multiple adhesive interactions rather than individual interactions presumably play critical roles in neoplastic development. Yet, knowledge of the contribution of each individual adhesion molecule is essential to unravel this network of interactions. This review will focus on activated leukocyte cell adhesion molecule (ALCAM/CD166) and its role in human melanoma progression. It is hypothesized that ALCAM may function as a cell surface sensor to register local growth saturation and to regulate cellular signaling and dynamic responses. [ABSTRACT FROM AUTHOR]

Evolution of neoplastic cells has generally been regarded as a cumulative intrinsic process resulting in altered cell characteristics enabling enhanced growth properties, evasion of apoptotic signals, unlimited replicative potential and gain of properties enabling the ability to thrive in ectopic tissues and in some cases, ability to metastasize. Recently however, the role of the neoplastic microenvironment has become appreciated largely due to the realization that tumors are not merely masses of neoplastic cells, but instead, are complex tissues composed of both a non-cellular (matrix proteins) and a cellular 'diploid' component (tumor-associated fibroblasts, capillary-associated cells and inflammatory cells), in addition to the ever-evolving neoplastic cells. With these realizations, it has become evident that early and persistent inflammatory responses observed in or around many solid tumors, play important roles in establishing an environment suitable for neoplastic progression by providing diverse factors that alter tissue homeostasis. Using cutaneous melanoma and squamous cell carcinoma as tumor models, we review the current literature focussing on inflammatory and tumor-associated fibroblast responses as critical mediators of neoplastic progression for these malignancies. [ABSTRACT FROM AUTHOR]

Lactococcus lactis is widely applied by the dairy industry for the fermentation of milk into products such as cheese. Adaptation of L. lactis to the dairy environment often depends on functions encoded by mobile genetic elements (MGEs) such as plasmids. Other L. lactis MGEs that contribute to industrially relevant traits like antimicrobial production and carbohydrate utilization capacities belong to the integrative conjugative elements (ICE). Here we investigate the prevalence of ICEs in L. lactis using an automated search engine that detects colocalized, ICE-associated core-functions (involved in conjugation or mobilization) in lactococcal genomes. This approach enabled the detection of 36 candidate-ICEs in 69 L. lactis genomes. By phylogenetic analysis of conserved protein functions encoded in all lactococcal ICEs, these 36 ICEs could be classified in three main ICE-families that encompass 7 distinguishable ICE-integrases and are characterized by apparent modular-exchangeability and plasticity. Finally, we demonstrate that phylogenetic analysis of the conjugation-associated VirB4 ATPase function differentiates ICE- and plasmid-derived conjugation systems, indicating that conjugal transfer of lactococcal ICEs and plasmids involves genetically distinct machineries. Our genomic analysis and sequence-based classification of lactococcal ICEs creates a comprehensive overview of the conserved functional repertoires encoded by this family of MGEs in L. lactis, which can facilitate the future exploitation of the functional traits they encode by ICE mobilization to appropriate starter culture strains., (© 2024. The Author(s).)

Loss of sharp foveal vision, as is inherent to Macular Degeneration (MD), severely impacts reading. One strategy for preserving patients' reading ability involves a one-by-one serial visual presentation (SVP) of words, whereby words are viewed extrafoveally. However, the method is limited as patients often retain the natural tendency to foveate words, thus bringing those words in the scotomal region. Additionally, SVP offers no compensation for the fact that orthographic input is degraded outside the fovea. Addressing these issues, here we tested a novel interface wherein texts are presented word-by-word, but with multiple repetitions (Multi-Res) of each word being displayed simultaneously around the fovea. We hypothesized that the Multi-Res setup would lead readers to make fewer detrimental eye movements, and to recognize words faster as a consequence of multiplied orthographic input. We used eye-tracking to simulate a gaze-contingent foveal scotoma in normally-sighted participants, who read words either in classic SVP or in Multi-Res mode. In line with our hypotheses, reading was drastically better in the Multi-Res condition, with faster recognition, fewer saccades and increased oculomotor stability. We surmise that the Multi-Res method has good potential for improving reading in central vision loss, over and above classic SVP techniques., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127 lo Foxp3 + Tregs by flow cytometry and used ELISA to quantify antibodies against ADAMTSL5, a recently discovered autoantigen in psoriatic disease. In comparison with their circulating counterparts, Tregs from inflamed joints express increased levels of ICOS, CTLA-4 and TIGIT. Furthermore, synovial fluid-derived Tregs have a distinct phenotype, characterized by IL-17A production and upregulation of CD161 and RORγt. We identified a subset of Tregs with intermediate Foxp3 expression as the major cytokine producer. Furthermore, ICOS + Tregs associate with PsA disease activity as measured by PASDAS. Lastly, we observed that presence of the Foxp3 int Tregs associates with an increased abundance of anti-ADAMTSL5 autoantibodies. Tregs derived from the inflammatory environment of inflamed PsA joints exhibit a distinct phenotype, which associates with loss of peripheral immune tolerance in psoriatic disease., (© 2022. The Author(s).)

Dietary fibre (DF) is implicated in gastrointestinal health of weaned piglets, either through its physiochemical properties, through modulation of gut microbiota and (or) improved gut integrity. We aimed to study the effect of DF enriched supplemental diets fed to suckling piglets ('creep feed') on health and performance after weaning when challenged with an enterotoxigenic E. coli (ETEC). Seventy-two piglets originating from 28 litters had been fed four creep diets, that is a low-fibre control (CON); a diet containing 2% long-chain arabinoxylans from wheat (lc-AXOS) or 5% purified cellulose (CELL) or a diet containing the high fermentable and the low-fermentable fibre source (i.e. 2% lc-AXOS and 5% CELL). Upon weaning, piglets were individually housed and all fed the same diet. On days 7, 8 and 9, animals received an oral dose of ETEC (5 ml containing 10 7 to 10 8  CFU/ml). Besides growth performance, faecal and skin scores were recorded daily. Gut permeability was assessed by urinary excretion of Co-EDTA prior and post-ETEC challenge. Repeated measures in time were statistically evaluated with generalized linear mixed models. We used a binominal distribution for evaluating the faecal and skin scores. Feed intake and body weight gain did not differ between treatments (p > .05). Piglets on CELL decreased gain:feed ratio in week 2 + 3 week compared to CON (p = .035). Prior to ETEC challenge, gut permeability tended to increase for lc-AXOS (p = .092). Moreover, lc-AXOS as main effect increased intestinal permeability before ETEC challenge (p = .013), whereas the low-fermentable fibre lead to elevated intestinal permeability after ETEC challenge (p = .014). The incidence of diarrhoea was higher for lc-AXOS + CELL compared with lc-AXOS (p = .036), while skin condition was unaffected. In conclusion, neither the high fermentable nor the low-fermentable fibre source improved post-weaning growth or gastrointestinal health of the piglets., (© 2020 Wiley-VCH GmbH.)

Objective: To identify novel serum proteins involved in the pathogenesis of PsA as compared with healthy controls, psoriasis (Pso) and AS, and to explore which proteins best correlated to major clinical features of the disease., Methods: A high-throughput serum biomarker platform (Olink) was used to assess the level of 951 unique proteins in serum of patients with PsA (n = 20), Pso (n = 18) and AS (n = 19), as well as healthy controls (HC, n = 20). Pso and PsA were matched for Psoriasis Area and Severity Index (PASI) and other clinical parameters., Results: We found 68 differentially expressed proteins (DEPs) in PsA as compared with HC. Of those DEPs, 48 proteins (71%) were also dysregulated in Pso and/or AS. Strikingly, there were no DEPs when comparing PsA with Pso directly. On the contrary, hierarchical cluster analysis and multidimensional scaling revealed that HC clustered distinctly from all patients, and that PsA and Pso grouped together. The number of swollen joints had the strongest positive correlation to ICAM-1 (r = 0.81, P < 0.001) and CCL18 (0.76, P < 0.001). PASI score was best correlated to PI3 (r = 0.54, P < 0.001) and IL-17 receptor A (r = -0.51, P < 0.01). There were more proteins correlated to PASI score when analysing Pso and PsA patients separately, as compared with analysing Pso and PsA patients pooled together., Conclusion: PsA and Pso patients share a serum proteomic signature, which supports the concept of a single psoriatic spectrum of disease. Future studies should target skin and synovial tissues to uncover differences in local factors driving arthritis development in Pso., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Methane emissions due to accidents in the oil and natural gas sector are very challenging to monitor, and hence are seldom considered in emission inventories and reporting. One of the main reasons is the lack of measurements during such events. Here we report the detection of large methane emissions from a gas well blowout in Ohio during February to March 2018 in the total column methane measurements from the spaceborne Tropospheric Monitoring Instrument (TROPOMI). From these data, we derive a methane emission rate of 120 ± 32 metric tons per hour. This hourly emission rate is twice that of the widely reported Aliso Canyon event in California in 2015. Assuming the detected emission represents the average rate for the 20-d blowout period, we find the total methane emission from the well blowout is comparable to one-quarter of the entire state of Ohio's reported annual oil and natural gas methane emission, or, alternatively, a substantial fraction of the annual anthropogenic methane emissions from several European countries. Our work demonstrates the strength and effectiveness of routine satellite measurements in detecting and quantifying greenhouse gas emission from unpredictable events. In this specific case, the magnitude of a relatively unknown yet extremely large accidental leakage was revealed using measurements of TROPOMI in its routine global survey, providing quantitative assessment of associated methane emissions.

White striping (WS) is a major problem affecting the broiler industry. Fillets affected by this myopathy present pathologies that compromise the quality of the meat, and most importantly, make the fillets more prone to rejection by the consumer. The exact etiology is still unknown, which is why a metabolomics analysis was performed on breast samples of broilers. The overall objective was to identify biological pathways involved in the pathogenesis of WS. The analysis was performed on a total of 51 muscle samples and distinction was made between normal (n = 19), moderately affected (n = 24) and severely affected (n = 8) breast fillets. Samples were analyzed using gas chromatographic mass spectral analysis and liquid chromatography quadrupole time-of-flight mass spectrometry. Data were subsequently standardized, normalized and analyzed using various multivariate statistical procedures. Metabolomics allowed for the identification of several pathways that were altered in white striped breast fillets. The tricarboxylic acid cycle exhibited opposing directionalities. This is described in literature as the backflux and enables the TCA cycle to produce high-energy phosphates through matrix-level phosphorylation and, therefore, produce energy under conditions of hypoxia. Mitochondrial fatty acid oxidation was limited due to disturbances in especially cis-5-14:1 carnitine (log2 FC of 2, P < 0.01). Because of this, accumulation of harmful fatty acids took place, especially long-chain ones, which damages cell structures. Conversion of arginine to citrulline increased presumably to produce nitric oxide, which enhances blood flow under conditions of hypoxia. Nitric oxide however also increases oxidative damage. Increases in taurine (log2 FC of 1.2, P < 0.05) suggests stabilization of the sarcolemma under hypoxic conditions. Lastly, organic osmolytes (sorbitol, taurine, and alanine) increased (P < 0.05) in severely affected birds; likely this disrupts cell volume maintenance. Based on the results of this study, hypoxia was the most likely cause/initiator of WS in broilers. We speculate that birds suffering from WS have a vascular support system in muscle that is borderline adequate to support growth, but triggers like activity results in local hypoxia that damages tissue.

The aim of this study was to relate the course of parturition to the condition of piglets at birth, based on umbilical cord blood acid-base values, and relate the condition at birth to neonatal survival and performance up to 10 weeks of life. Data were collected from 37 spontaneous unassisted parturitions, and neonatal performance was based on observations of 516 piglets. Stillbirth rate increased from 2% in the first piglets, to 17% in piglets born 13th in the litter or later. This was aggravated in sows with longer than average stage II of parturition. Umbilical cord blood values also reflected the effect of birth order, with pH decreasing and lactate increasing in the course of parturition. Interestingly, sows that had a long expulsion stage of parturition also took longer to give birth to the first four piglets (r = 0.74), suggesting that sows with complicated parturition were already experiencing problems at the start of expulsion of piglets. Piglets with signs of asphyxia, based on umbilical blood lactate higher than 4.46 mmol/L, were slower to start suckling, had a higher risk of neonatal mortality, and had a slower growth rate over the first 10 weeks of life.

Bioprinting is the most convenient microfabrication method to create biomimetic three-dimensional (3D) cardiac tissue constructs, which can be used to regenerate damaged tissue and provide platforms for drug screening. However, existing bioinks, which are usually composed of polymeric biomaterials, are poorly conductive and delay efficient electrical coupling between adjacent cardiac cells. To solve this problem, we developed a gold nanorod (GNR) incorporated gelatin methacryloyl (GelMA)-based bioink for printing 3D functional cardiac tissue constructs. The GNR concentration was adjusted to create a proper microenvironment for the spreading and organization of cardiac cells. At optimized concentration of GNR, the nanocomposite bioink had a low viscosity, similar to pristine inks, which allowed for the easy integration of cells at high densities. As a result, rapid deposition of cell-laden fibers at a high resolution was possible, while reducing shear stress on the encapsulated cells. In the printed GNR constructs, cardiac cells showed improved cell adhesion and organization when compared to the constructs without GNRs. Furthermore, the incorporated GNRs bridged the electrically resistant pore walls of polymers, improved the cell-to-cell coupling, and promoted synchronized contraction of the bioprinted constructs. Given its advantageous properties, this gold nanocomposite bioink may find wide application in cardiac tissue engineering., Competing Interests: The authors declare no conflict of interests in this work.

The incidence of hypertension increases after menopause. Similar to humans, "slow-pressor" doses of angiotensin II (AngII) increase blood pressure in young males, but not in young female mice. However, AngII increases blood pressure in aged female mice, paralleling reproductive hormonal changes. These changes could influence receptor trafficking in central cardiovascular circuits and contribute to hypertension. Increased postsynaptic N-methyl-D-aspartate (NMDA) receptor activity in the hypothalamic paraventricular nucleus (PVN) is crucial for the sympathoexcitation driving AngII hypertension. Estrogen receptors β (ERβs) are present in PVN neurons. We tested the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ-containing PVN neurons. Transgenic mice expressing enhanced green fluorescent protein (EGFP) in ERβ-containing cells were implanted with osmotic minipumps delivering AngII (600 ng/kg/min) or saline for 2 weeks. AngII increased blood pressure in 2-month-old males and 18-month-old females, but not in 2-month-old females. By electron microscopy, NR1-silver-intensified immunogold (SIG) was mainly in ERβ-EGFP dendrites. At baseline, NR1-SIG density was greater in 2-month-old females than in 2-month-old males or 18-month-old females. After AngII infusion, NR1-SIG density was decreased in 2-month-old females, but increased in 2-month-old males and 18-month-old females. These findings suggest that, in young female mice, NR1 density is decreased in ERβ-PVN dendrites thus reducing NMDA receptor activity and preventing hypertension. Conversely, in young males and aged females, NR1 density is upregulated in ERβ-PVN dendrites and ultimately leads to the neurohumoral dysfunction driving hypertension., (© 2014 Wiley Periodicals, Inc.)

Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

The objective of this study was to investigate whether reducing dietary CP concentration decreases fecal VFA, manure ammonia (NH3) emission and odor, and urinary phenolic metabolites. Six barrows were allotted to one of six dietary treatments in a Latin square design. Treatments consisted of four corn-soybean meal based diets containing 15, 12, 9, and 6% CP, a casein-based diet containing 15% CP, and a protein-free diet (0% protein). Crystalline AA were included in the 12, 9, and 6% CP diets. The casein-based and protein-free diets were used to determine basal endogenous contribution of VFA, phenolics, NH3, and manure odor. Pigs were housed individually in metabolism cages to allow total collection of feces and urine. Feces and urine were collected and pooled within pig and period. Feces and urine were analyzed for VFA and phenolic metabolite concentrations, respectively. Feces and urine were then mixed, stored, and fermented at room temperature for 30 d. For NH3 determination, headspace air was sampled from manure slurries at 24, 48, and 72 h after fermentation. Slurry samples were placed into vials, capped, and randomized before odor panel evaluation. Odor offensiveness was classified on severity: 1 = non-offensive; 2 = mildly offensive; 3 = moderately offensive; 4 = strongly offensive; and 5 = extremely offensive. Reducing dietary CP increased (P < 0.05) fecal VFA concentrations but did not affect phenolic concentrations in urine. Manure NH3 emission was reduced (P < 0.05) as dietary CP concentration decreased from 15 to 0%. The 15% diet had the least offensive manure slurry with odor qualitative ranking of 2.58 (i.e., mild-moderately offensive). Compared with the 15% CP diet, manure from the 9 and 6% CP diets was found to be more offensive (P < 0.05), with qualitative rankings of 2.92 and 3.10, respectively. Odor qualitative rank for the 12% CP, protein-free diet, and casein-based diet did not differ from that of the 15% CP diet. These results indicate that reduction in dietary CP concentrations decreases manure NH3 emission, but it does not diminish manure odor offensiveness and fecal VFA concentrations.

A 2 x 3 factorial experiment was conducted with 24 finishing pigs (Yorkshire x [Finnish Landrace x Dutch Landrace]) to determine the effects of dietary buffering capacity (BC) and carbohydrate sources on apparent total tract digestibility (TD), N retention, and manure characteristics. Twelve of these pigs were fitted with steered ileo-cecal value cannulas to measure the apparent ileal digestibility (ID) of N. Experimental variables were two levels of BC (High = 600 mEq/kg and Low = 530 mEq/kg) and three dietary carbohydrates (tapioca [28%], soybean hulls [25%], and sugar beet pulp [25%]). The two levels of BC were achieved by adjusting the amounts of alkalogenic limestone and acidogenic Ca sulfate in the diet. Pigs were fed twice daily at 2.4 x maintenance requirement for metabolizable energy (418 kJ ME/BW(0.75)). Chromic oxide was used as an indigestible marker. Feces and urine were collected over 5 d for nutrient balance and in vitro measurements of pH and ammonia emission over 7 d. No significant interactions between BC and dietary carbohydrates on the ID, TD, N retention, or manure characteristics were observed. Lowering BC with Ca sulfate did not affect digestibility of most nutrients, except for a negative impact on the TD of Ca (P = 0.015) and Mg (P = 0.003). Although all pigs receiving Ca sulfate had more acidic urine (by 0.49 pH units; P = 0.001), ammonia emission from manure was not lowered, irrespective of the carbohydrate source. Carbohydrates affected significantly the ID and TD of most nutrients, whereas N retention remained similar (P > 0.10). Urinary N:fecal N ratios in manure of pigs fed diets with tapioca, soybean hulls, and beet pulp were 2.09, 1.35, and 1.67, respectively. These ratios corresponded with in vitro ammonia emission (169, 125, and 148 mmol/7 d; P = 0.023). In conclusion, these results indicate that the acidification of urine in pigs fed Ca sulfate in the presence of NSP-rich carbohydrates was achieved. However, acidity of manure and ammonia emission were not affected. The addition of NSP from soybean hulls and(or) sugar beet pulp reduced ratios of urinary:fecal N, and thereby ammonia emission.

Fifty growing pigs were used in two experiments to evaluate the effects of cannulation and hyperalimentation on performance and body composition responses. Surgical implantation of a cannula into the greater curvature of the stomach and subsequent management associated with maintenance of the cannula did not result in a reduction (P > .05) of voluntary feed intake. Cannulation did not negatively affect gain (P > .05). Over the entire trial, feed efficiency was not changed by cannulation (P > .05). Cannulation itself did not affect protein or fat deposition (P > .05) in the carcass. Hyperalimentation to approximately 120% of control intake resulted in increased daily gain (P < .05) and similar feed efficiency (P > .05) compared with that of control animals. Hyperalimentation decreased protein deposition (P < .05) and tended to increase fat deposition.