Small molecule CCR4 antagonists in cutaneous T-cell lymphoma.

Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor 4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. While small molecule CCR4 antagonists have been studied in other diseases involving CCR4+ Th2 cells and regulatory T-cells, but their effects in CTCL have not been previously explored. This study assessed the effects of two small molecule CCR4 antagonists, C021 (Class I) and AZD2098 (Class II), in MF derived cell line (MJ) and SS derived cell line (HuT 78) in vitro and in vivo. As results, both C021 and AZD2098 inhibited chemotactic responses to CCL17 and CCL22 in MJ and HuT 78 cells. However, only C021 downregulated CCR4 expression, inhibited cell proliferation, induced cell apoptosis and cell cycle arrest, and decreased colony formation in MJ and HuT 78 cells in vitro. Furthermore, only C021 inhibited tumor growth in CTCL xenograft mice in vivo. These findings suggest that Class I CCR4 antagonists such as C021 exerts more potent anti-tumor effects on CTCL cells in vitro and in vivo compared to Class II CCR4 antagonists like AZD2098, highlighting its potential for clinical application.

Why do physicians practice osteopathic manipulative treatment (OMT)? A survey study.

CONTEXT: Few osteopathic physicians (Doctors of Osteopathic Medicine [DOs]) utilize osteopathic manipulative treatment (OMT) in their clinical practice, although all DOs are trained to do so. The reasons why many do not utilize OMT are not entirely clear. Anecdotally, these authors have observed that if a physician utilizes OMT, it is because they witnessed the efficacy for themselves in real-life clinical diagnoses found on patients or volunteers. This study seeks to explore this phenomenon. OBJECTIVES: This study seeks to explore the relationship between witnessing the efficacy of OMT and the future use of OMT in clinical practice. METHODS: Surveys were sent to DOs who work with Des Moines University's College of Osteopathic Medicine (COM) clinical students as well as osteopathic medical students enrolled at the Des Moines University's COM. Survey data were analyzed by separating physicians into cohorts based on their use of OMT and students into cohorts based on their interest in utilizing OMT in future practice. RESULTS: DOs who practice OMT reported at least one, and often multiple, instances of witnessing the efficacy of OMT on real-life patients or volunteers while in their first 2 years of medical school. Those who do not utilize OMT reported few opportunities to witness the efficacy of OMT on a real-life patient. For physicians, 96.1 % of those who utilize OMT in their practice had the opportunity to see it work positively during the first 2 years of medical school, whereas only 7.4 % who do not utilize OMT had the opportunity. These findings are mirrored in the experience of current osteopathic medical students who are interested and uninterested in utilizing OMT in their future practice. CONCLUSIONS: These findings emphasize the importance of exposing our medical students to some type of 'real-life' experience early in their careers; the data show that these experiences can be very beneficial in expanding the interest in utilizing osteopathic manipulative medicine (OMM) in future practice. COMs can consider the implementation of programs that provide this experience to students, including extracurricular activities dedicated to the use of OMT.

Plant-Derived Terpenoids: A Plethora of Bioactive Compounds with Several Health Functions and Industrial Applications-A Comprehensive Overview.

Terpenoids are a large class of natural secondary plant metabolites which are highly diverse in structure, formed from isoprene units (C-5), associated with a wide range of biological properties, including antioxidant, antimicrobial, anti-inflammatory, antiallergic, anticancer, antimetastatic, antiangiogenesis, and apoptosis induction, and are considered for potential application in the food, cosmetics, pharmaceutical, and medical industries. In plants, terpenoids exert a variety of basic functions in growth and development. This review gives an overview, highlighting the current knowledge of terpenoids and recent advances in our understanding of the organization, regulation, and diversification of core and specialized terpenoid metabolic pathways and addressing the most important functions of volatile and non-volatile specialized terpenoid metabolites in plants. A comprehensive description of different aspects of plant-derived terpenoids as a sustainable source of bioactive compounds, their biosynthetic pathway, the several biological properties attributed to these secondary metabolites associated with health-promoting effects, and their potential industrial applications in several fields will be provided, and emerging and green extraction methods will also be discussed. In addition, future research perspectives within this framework will be highlighted. Literature selection was carried out using the National Library of Medicine, PubMed, and international reference data for the period from 2010 to 2024 using the keyword "terpenoids". A total of 177,633 published papers were found, of which 196 original and review papers were included in this review according to the criteria of their scientific reliability, their completeness, and their relevance to the theme considered.

Macroscopic and Microscopic Thermodynamics: From Fundamentals to Present Applications, 2nd Edition.

This Special Issue, "Macroscopic and Microscopic Thermodynamics: From Fundamentals to Present Applications [...].

Deletion of the Ebf1, a mouse deafness gene, causes a dramatic increase in hair cells and support cells of the organ of Corti.

Following up on our previous observation that early B cell factor (EBF) sites are enriched in open chromatin of the developing sensory epithelium of the mouse cochlea, we investigated the effect of deletion of Ebf1 on inner ear development. We used a Cre driver to delete Ebf1 at the otocyst stage before development of the cochlea. We examined the cochlea at postnatal day (P) 1 and found that the sensory epithelium had doubled in size but the length of the cochlear duct was unaffected. We also found that deletion of Ebf1 led to ectopic sensory patches in the Kölliker's organ. Innervation of the developing organ of Corti was disrupted with no obvious spiral bundles. The ectopic patches were also innervated. All the extra hair cells (HCs) within the sensory epithelium and Kölliker's organ contained mechanoelectrical transduction channels, as indicated by rapid uptake of FM1-43. The excessive numbers of HCs were still present in the adult Ebf1 conditional knockout (cKO) animal. The animals had significantly elevated auditory brainstem response thresholds, suggesting that this gene is essential for hearing development.

Transcriptomic Analysis Reveals Early Alterations Associated with Intrinsic Resistance to Targeted Therapy in Lung Adenocarcinoma Cell Lines.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer.

Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children.

Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.

Secondary Bioactive Metabolites from Foods of Plant Origin as Theravention Agents against Neurodegenerative Disorders.

Neurodegenerative disorders (NDDs) such as Alzheimer's (AD) and Parkinson's (PD) are on the rise, robbing people of their memories and independence. While risk factors such as age and genetics play an important role, exciting studies suggest that a diet rich in foods from plant origin may offer a line of defense. These kinds of foods, namely fruits and vegetables, are packed with a plethora of powerful bioactive secondary metabolites (SBMs), including terpenoids, polyphenols, glucosinolates, phytosterols and capsaicinoids, which exhibit a wide range of biological activities including antioxidant, antidiabetic, antihypertensive, anti-Alzheimer's, antiproliferative, and antimicrobial properties, associated with preventive effects in the development of chronic diseases mediated by oxidative stress such as type 2 diabetes mellitus, respiratory diseases, cancer, cardiovascular diseases, and NDDs. This review explores the potential of SBMs as theravention agents (metabolites with therapeutic and preventive action) against NDDs. By understanding the science behind plant-based prevention, we may be able to develop new strategies to promote brain health and prevent the rise in NDDs. The proposed review stands out by emphasizing the integration of multiple SBMs in plant-based foods and their potential in preventing NDDs. Previous research has often focused on individual compounds or specific foods, but this review aims to present a comprehensive fingerprint of how a diet rich in various SBMs can synergistically contribute to brain health. The risk factors related to NDD development and the diagnostic process, in addition to some examples of food-related products and medicinal plants that significantly reduce the inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), are highlighted.

Real-World Acute Toxicity and 90-Day Mortality in Patients With Stage I NSCLC Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) has firmly established its role in stage I NSCLC. Clinical trial results may not fully apply to real-world scenarios. This study aimed to uncover the real-world incidence of acute toxicity and 90-day mortality in patients with SBRT-treated stage I NSCLC and develop prediction models for these outcomes. METHODS: Prospective data from the Dutch Lung Cancer Audit for Radiotherapy (DLCA-R) were collected nationally. Patients with stage I NSCLC (cT1-2aN0M0) treated with SBRT in 2017 to 2021 were included. Acute toxicity was assessed, defined as grade greater than or equal to 2 radiation pneumonitis or grade greater than or equal to 3 non-hematologic toxicity less than or equal to 90 days after SBRT. Prediction models for acute toxicity and 90-day mortality were developed and internally validated. RESULTS: Among 7279 patients, the mean age was 72.5 years, with 21.6% being above 80 years. Most were male (50.7%), had WHO scores 0 to 1 (73.3%), and had cT1a-b tumors (64.6%), predominantly in the upper lobes (65.2%). Acute toxicity was observed in 280 (3.8%) of patients and 90-day mortality in 122 (1.7%). Predictors for acute toxicity included WHO greater than or equal to 2, lower forced expiratory volume in 1 second and diffusion capacity for carbon monoxide, no pathology confirmation, middle or lower lobe tumor location, cT1c-cT2a stage, and higher mean lung dose (c-statistic 0.68). Male sex, WHO greater than or equal to 2, and acute toxicity predicted higher 90-day mortality (c-statistic 0.73). CONCLUSIONS: This nationwide study revealed a low rate of acute toxicity and an acceptable 90-day mortality rate in patients with SBRT-treated stage I NSCLC. Notably, advanced age did not increase acute toxicity or mortality risk. Our predictive models, with satisfactory performance, offer valuable tools for identifying high-risk patients.

Genetic analyses and dispersal patterns unveil the Amazonian origin of guava domestication.

Guava (Psidium guajava L.) is a semi-domesticated fruit tree of moderate importance in the Neotropics, utilized for millennia due to its nutritional and medicinal benefits, but its origin of domestication remains unknown. In this study, we examine genetic diversity and population structure in 215 plants from 11 countries in Mesoamerica, the Andes, and Amazonia using 25 nuclear microsatellite loci to propose an origin of domestication. Genetic analyses reveal one gene pool in Mesoamerica (Mexico) and four in South America (Brazilian Amazonia, Peruvian Amazonia and Andes, and Colombia), indicating greater differentiation among localities, possibly due to isolation between guava populations, particularly in the Amazonian and Andean regions. Moreover, Mesoamerican populations show high genetic diversity, with moderate genetic structure due to gene flow from northern South American populations. Dispersal scenarios suggest that Brazilian Amazonia is the probable origin of guava domestication, spreading from there to the Peruvian Andes, northern South America, Central America, and Mexico. These findings present the first evidence of guava domestication in the Americas, contributing to a deeper understanding of its evolutionary history.

Inhibition of DXR in the MEP pathway with lipophilic N-alkoxyaryl FR900098 analogs.

In Mycobacterium tuberculosis (Mtb) and Plasmodium falciparum (Pf), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. This pathway and its products are vital to bacterial/parasitic metabolism and survival, and represent an attractive set of drug targets due to their essentiality in these pathogens but absence in humans. The second step in the MEP pathway is the conversion of 1-deoxy-d-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR). Natural products fosmidomycin and FR900098 inhibit DXR, but are too polar to reach the desired target inside some cells, such as Mtb. Synthesized FR900098 analogs with lipophilic substitution in the position α to the phosphorous atom showed promise, resulting in increased activity against Mtb and Pf. Here, an α substitution, consisting of a 3,4-dichlorophenyl substituent, in combination with various O-linked alkylaryl substituents on the hydroxamate moiety is utilized in the synthesis of a novel series of FR900098 analogs. The purpose of the O-linked alkylaryl substituents is to further enhance DXR inhibition by extending the structure into the adjacent NADPH binding pocket, blocking the binding of both DXP and NADPH. Of the initial O-linked alkylaryl substituted analogs, compound 6e showed most potent activity against Pf parasites at 3.60 µM. Additional compounds varying the phenyl ring of 6e were synthesized. The most potent phosphonic acids, 6l and 6n, display nM activity against PfDXR and low µM activity against Pf parasites. Prodrugs of these compounds were less effective against Pf parasites but showed modest activity against Mtb cells. Data from this series of compounds suggests that this combination of substituents can be advantageous in designing a new generation of antimicrobials.

Morphological comparison of the larynx and trachea of Chelonia mydas (Linnaeus, 1758), Caiman yacare (Daudin, 1802) and Caiman latirostris (Daudin, 1802).

The larynx is in the lower respiratory tract and has the function of protecting the airways, controlling, and modulating breathing, assisting the circulatory system, and vocalizing. This study aims to describe the anatomy and histology of the skeleton of the larynx and trachea of the species Chelonia mydas, Caiman yacare and Caiman latirostris. The study was conducted at the Federal University of Espírito Santo (UFES), using nine specimens of Ch. mydas, 20 of Ca. yacare and four of Ca. latirostris. Samples of the larynx and trachea were collected, fixed, and sent for dissection of the structures and subsequent macroscopic analysis. For histology, samples were processed by the routine paraffin embedding method and stained with hematoxylin-eosin and Verhoeff. For the three species, two arytenoid cartilages, a cricoid cartilage, a hyoid apparatus composed of a base and two horns were found. In Ch. mydas, two structures called thyroid wings were observed, not found in crocodilians. The trachea of crocodilians presented incomplete tracheal rings and musculature, while the trachea of Ch. mydas presented complete tracheal rings. Histologically, the entire cartilaginous skeleton of the larynx of the three species, as well as the tracheal rings, are constituted by hyaline cartilage.

Sequential Separation of Essential Oil Components during Hydrodistillation of Fresh Foliage from Azorean Cryptomeria japonica (Cupressaceae): Effects on Antibacterial, Antifungal, and Free Radical Scavenging Activities.

Cryptomeria japonica wood industry generates large amounts of foliage biomass residues. Due to the increasing applications and markets for essential oils (EOs), fresh Azorean C. japonica foliage (Az-CJF) residues are used for local EO production. Hydrodistillation (HD), a common process for obtaining EOs, also provides the possibility to fractionate them. Thus, this study evaluated the in vitro antimicrobial and antioxidant activities of six Az-CJF EO fractions (Frs. 1-6), collected at sequential HD timeframes (HDTs: 0-2, 2-10, 10-30, 30-60, 60-120, and 120-240 min), in comparison to the crude EO, obtained from a non-fractionated HD (0-240 min HDT). Antimicrobial activities were assessed via disc diffusion method against seven bacteria (foodborne and/or human pathogens) and two Penicillium spp. (phytopathogenic fungi), and antioxidant activity was estimated using DPPH and ABTS assays. Concerning the antibacterial activity, all the EO samples were effective only toward Gram-positive bacteria. Fractions 1-3 (<30 min HDT) were the most active, with growth inhibition zones (GIZ) of 7.0-23.3 mm (1.4-2.2 times higher than those of the crude EO), being Bacillus spp. (B. licheniformis and B. subtilis) the most sensitive, followed by Staphylococcus aureus and Micrococcus luteus. Regarding the antifungal activity, Frs. 1-3 also displayed the best activities, but only against P. italicum (GIZ around 9.0 mm), while the crude EO showed no antifungal activity. Overall, the best antimicrobial properties of Frs. 1-3 could be attributed, at least in part, to their highest content in α-pinene and bornyl acetate. On the other hand, Frs. 4-6 (>30 min HDT) exhibited the strongest antioxidant activities (EC50 values: 1.5-2.3 and 1.0-1.7 mg mL-1 for DPPH and ABTS, respectively), being at least 1.3-fold higher than those of the crude EO. The presence of nezukol, elemol, and eudesmol isomers could strongly contribute to the best free radical scavenging properties of Frs. 4-6. In conclusion, HD was found to be an efficient process for obtaining new Az-CJF EO fractions with variable and enhanced bioactivities due to their differential composition, as assessed using GC-MS. Hence, these findings could contribute to increasing the commercial potential of the C. japonica EO industry, namely, the Fr2 and Fr6, which presented the most significant activities and can have potential applications in the food, medical, and agriculture sectors.

Novel drug design and repurposing: An opportunity to improve translational research in cardiovascular diseases?

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.

Estimating the alcohol-related burden of child maltreatment among Maori in Aotearoa, New Zealand.

INTRODUCTION: To assesses the alcohol-related burden of child maltreatment among Maori in Aotearoa New Zealand. We compared the risk of child maltreatment among Maori (0-17 years) exposed to parents with alcohol-related hospitalisation or mental health/addiction service use. We also conducted a sensitivity analysis to estimate the number of cases of maltreatment that could be attributed to alcohol among Maori. METHODS: A cohort study of 16,617 Maori aged 0-17 and their parents from 2000 to 2017 was conducted using the Statistics New Zealand Integrated Data Infrastructure. A Bayesian piecewise exponential model estimated the risk of time to first child maltreatment event. This analysis used data from child protection, hospital, mortality and police records, and specifically focused on the risk associated with exposure to parents with an alcohol-attributable hospitalisation or mental health/addiction service use event. Potential confounders for both parents and Maori (0-17 years) were included. We calculated a population-attributable fraction to estimate the proportion of maltreatment cases that could be attributed to alcohol in 2017. RESULTS: Results showed a 65% increased risk for young Maori exposed to parents with heavy alcohol use. We estimated 17% of substantiated child maltreatment among Maori could be attributed to parental hazardous alcohol consumption. DISCUSSION AND CONCLUSIONS: Severe or hazardous alcohol consumption among parents is a risk factor for child maltreatment among Maori. Maori alcohol consumption and harm are symptomatic of wider inequities related, among other things, to the ongoing effects of colonisation, as well as gaps in the regulation of alcohol sales.

Optical coherence tomography features in vitreoretinal lymphoma compared with non-infectious uveitis.

BACKGROUND: Vitreoretinal lymphoma (VRL) is a rare intraocular malignancy that poses a diagnostic challenge due to the non-specific clinical presentation that resembles uveitis. The use of spectral domain optical coherence tomography (SD-OCT) has emerged as a valuable imaging tool to characterize VRL. Therefore, we sought to determine the specific OCT features in VRL compared to the uveitides. METHODS: Retrospective chart review of patients who were seen at Mayo Clinic from January 1, 2010 through December 31, 2022. The medical records and SD-OCT images at time of initial presentation were reviewed in patients with biopsy-proven VRL, intermediate uveitis, or biopsy-confirmed sarcoid posterior uveitis. Patients with VRL or similar uveitides including intermediate uveitis or sarcoid posterior uveitis were included. RESULTS: There were 95 eyes of 56 patients in the VRL group and 86 eyes of 45 patients in the uveitis group, of whom 15 (33.3%) were diagnosed with intermediate uveitis and 30 (66.7%) with sarcoid chorioretinitis. The SD-OCT features more commonly seen at initial presentation in VRL patients (vs. uveitis) included preretinal deposits (31.6% vs. 9.3%, p = 0.002), intraretinal infiltrates (34% vs. 3.5%, p < 0.001), inner retinal hyperreflective spots (15.8% vs. 0%, p < 0.001), outer retinal atrophy (22.1% vs. 2.3%, p < 0.001), subretinal focal deposits (21.1% vs. 4.7%, p = 0.001), retinal pigmented epithelium (RPE) changes (49.5% vs. 3.5%, p < 0.001), and sub-RPE deposits (34.7% vs. 0%, p < 0.001). Features more frequently seen in uveitis included epiretinal membrane (ERM) (82.6% vs. 44.2%, p < 0.001), central macular thickening (95.3% vs. 51.6%, p < 0.001), cystoid macular edema (36% vs. 11.7%, p < 0.001), subretinal fluid (16.3% vs 6.4%, p = 0.04), and subfoveal fluid (16.3% vs. 3.2%, p = 0.003). Multivariate regression analysis controlling for age and sex showed absence of ERM (OR 0.14 [0.04,0.41], p < 0.001) and absence of central macular thickening (OR 0.03 [0,0.15], p = 0.02) were associated with VRL as opposed to uveitis. CONCLUSION: OCT features most predictive of VRL (vs. uveitis) included absence of ERM and central macular thickening.

Nobody's land? The oldest evidence of early Upper Paleolithic settlements in inland Iberia.

The Iberian Peninsula is a key region for unraveling human settlement histories of Eurasia during the period spanning the decline of Neandertals and the emergence of anatomically modern humans (AMH). There is no evidence of human occupation in central Iberia after the disappearance of Neandertals ~42,000 years ago until approximately 26,000 years ago, rendering the region "nobody's land" during the Aurignacian period. The Abrigo de la Malia provides irrefutable evidence of human settlements dating back to 36,200 to 31,760 calibrated years before the present (cal B.P.) This site also records additional levels of occupation around 32,420 to 26,260 cal B.P., suggesting repeated settlement of this territory. Our multiproxy examination identifies a change in climate trending toward colder and more arid conditions. However, this climatic deterioration does not appear to have affected AMH subsistence strategies or their capacity to inhabit this region. These findings reveal the ability of AMH groups to colonize regions hitherto considered uninhabitable, reopening the debate on early Upper Paleolithic population dynamics of southwestern Europe.

Polymicrobial Septic Peritonitis Caused by Enterococcus faecium and Enterococcus casseliflavus following Uterine Rupture in a Goat.

A one-year-old female miniature goat was presented to an emergency service after calving a dead goatling. Physical and ultrasonographic examination revealed the presence of a viable fetus; therefore, the goat was submitted to an emergency cesarean section. In the postoperative period, the animal had septic peritonitis caused by Enterococcus faecium and Enterococcus casseliflavus. Both bacterial strains showed contrasting antimicrobial resistance profiles. Laparohysterectomy and abdominal cavity lavage were performed, but, once the animal had adhesions and necrotic lesions in abdominal organs, euthanasia was executed. A post-mortem examination revealed fibrino-necrotic septic peritonitis secondary to uterine rupture. To the authors' knowledge, this is the first detailed report of polymicrobial septic peritonitis in a miniature goat and the first report of septic peritonitis caused by E. faecium and E. casseliflavus.

Exploring the Associated Genetic Causes of Diabetic Retinopathy as a Model of Inflammation in Retinal Diseases.

To investigate potential biomarkers and biological processes associated with diabetic retinopathy (DR) using transcriptomic and proteomic data. The OmicsPred PheWAS application was interrogated to identify genes and proteins associated with DR and diabetes mellitus (DM) at a false discovery rate (FDR)-adjusted p-value of <0.05 and also <0.005. Gene Ontology PANTHER analysis and STRING database analysis were conducted to explore the biological processes and protein interactions related to the identified biomarkers. The interrogation identified 49 genes and 22 proteins associated with DR and/or DM; these were divided into those uniquely associated with diabetic retinopathy, uniquely associated with diabetes mellitus, and the ones seen in both conditions. The Gene Ontology PANTHER and STRING database analyses highlighted associations of several genes and proteins associated with diabetic retinopathy with adaptive immune response, valyl-TRNA aminoacylation, complement activation, and immune system processes. Our analyses highlight potential transcriptomic and proteomic biomarkers for DR and emphasize the association of known aspects of immune response, the complement system, advanced glycosylation end-product formation, and specific receptor and mitochondrial function with DR pathophysiology. These findings may suggest pathways for future research into novel diagnostic and therapeutic strategies for DR.