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Abstract While epidemiological evidence has long linked obesity with an increased risk of breast cancer, the intricate interactions between adipocytes and cancer cells within the tumor microenvironment remain largely uncharted territory. The use of organotypic three-dimensional (3D) cell cultures that more accurately mimic the spatial architecture of tumors represents an innovative approach to this complex issue. In the present study, we investigated the effects of adipocytes on the proteome of Hs578t breast cancer cells cultured in a 3D microenvironment. Using different treatments, we rigorously optimized the experimental conditions to induce the optimal differentiation of 3T3-L1 fibroblasts into mature adipocytes. Then, we grow the Hs578t cells in a simulated microenvironment using an on-top model for organotypic 3D cultures. Our data showed that cancer cells formed 3D stellate-like architectures when grown over an extracellular matrix proteins-enriched scaffold for 48 h. Proteomic profiling using LC-MS/MS mass spectrometry of Hs578t cells grown in 3D conditions with or without the adipocyte-enriched culture discovered 916 unique proteins. Of these, 605 showed no significant changes in abundance, whereas 87 proteins were significantly upregulated and 224 downregulated after interaction with fat cells (p 2.0). Bioinformatic analysis of upregulated proteins indicated that the most enriched GO terms and molecular functions were related to lipids transport, cell differentiation, hypoxia response, and cell junctions. In addition, several modulated proteins have been previously associated with breast cancer progression. Interestingly, lipid transport proteins, including PITPNM2, ATP2C1, ABCA12, HDLBP, and APOB, showed perturbations in their expression, which were also associated with low overall survival in breast cancer patients. Functional studies showed that the knockdown of apolipoprotein B (APOB) expression in Hs578t cells reduced the size of 3D cellular structures. Moreover, APOB-knocked cells cocultured with adipocytes for 48 h exhibited a significant decrease of intracellular lipids, whereas an increase in the adipocytes was found. Our results indicate that the 3D microenvironment and the adipocytes crosstalk reprogram the proteome of breast cancer cells. These data help us understand the environmental effects in gene expression and contribute to discovering novel tumor proteins with potential intervention in breast cancer therapy.

Abstract Background Vasculogenic mimicry (VM) is an alternative intratumoral microcirculation system that depends on the capacity of tumor cells to reorganize and grow in three-dimensional (3D) channel architectures like the capillaries formed by endothelial cells. Both VM and angiogenesis may coordinately function to feed cancer cells, allowing tumor growth. Long noncoding RNAs (lncRNAs) regulate critical cellular functions in cancer cells, including cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. The lncRNA, known as actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1), has been described as an oncogene in diverse types of cancers. However, its role in VM and metastasis in triple-negative breast cancer (TNBC) is unknown. Methods Reverse transcription and quantitative polymerase chain reaction (RT‒qPCR) experiments were performed to evaluate the expression of 10 selected lncRNAs from literature in metastatic and nonmetastatic biopsies from TNBC patients. The expression of AFAP1-AS1 was analyzed in Genotype-Tissue Expression Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. The AFAP1-AS1 expression was knocked in TNBC Hs578T cells by transfection of specific siRNAs. Channel-like formation assays were performed using 3D cultures over Matrigel in hypoxia-treated Hs578T cancer cells with diminished expression of AFAP1-AS1. The angiogenesis tests were conducted using human umbilical vein endothelial cells (HUVECs) and AFAP1-AS1- silenced Hs578T cells on 3D cell cultures. The presence of VM (CD31-/PAS+) in tumor tissues from TNBC patients with and without metastasis was assessed through immunohistochemistry using endothelial marker CD31 antibodies and periodic acid-Schiff (PAS) staining. Results Compared with normal mammary tissues, AFAP1-AS1 expression was higher in breast cancer tissues. Moreover, AFAP1-AS1 expression was upregulated in the TNBC subtype compared to receptor-positive breast tumors. In addition, the expression of AFAP1-AS1 was correlated with the expression of the thirteen genes characteristic of a previously reported hypoxia signature. Interestingly, AFAP1-AS1 was upregulated in primary TNBC tumors from patients who developed metastasis compared with the nonmetastatic group. Functional analysis revealed that the knockdown of AFAP1-AS1 in Hs578T cells significantly impaired the hypoxia-induced VM, accompanied by a decrease in the development of 3D channel networks. Similarly, AFAP1-AS1 knockdown counteracts the angiogenic potential of cancer cells, as indicated by a reduction in the number of polygons, sprouting cells, and nodes in HUVEC cells. Remarkably, an increase in CD31-/PAS + staining of 3D channel networks in primary breast tumors from metastatic patients was found compared with the nonmetastatic group. Finally, we found that the number of blood vessels increased in the nonmetastatic group more than in the metastatic cohort. Conclusions Our data suggested that AFAP1-AS1 controls both VM and angiogenesis in Hs578T breast cancer cells and that increased metastasis is associated with VM in TNBC patients.

Immune checkpoint inhibitors (ICI)-based combinations have become the standard first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). Despite significant improvements in survival and the achievement of sustained long-term responses, a subset of patients remains refractory to ICI, and most will eventually develop resistance. Thus, identifying predictive biomarkers for ICI efficacy and resistance is essential for optimizing therapeutic strategies. Up to now, tissue-based biomarkers have not been successful as predictive biomarkers in RCC. Circulating blood-based biomarkers offer a promising alternative. These biomarkers, including circulating immune cells, soluble factors, tumor-derived markers, and those based on metabolomics, are less invasive, offer reproducibility over time, and provide a comprehensive assessment of tumor biology and patient immune status, as well as allow dynamic monitoring during treatment. This review aims to evaluate the current evidence on the different candidate circulating biomarkers being investigated for their potential to predict ICI efficacy in RCC patients.

Abstract Background The natural light environment is far more complex than that experienced by animals under laboratory conditions. As a burrowing species, wild mice are able to self-modulate their light exposure, a concept known as light environment sampling behaviour. By contrast, under laboratory conditions mice have little opportunity to exhibit this behaviour. To address this issue, here we introduce a simple nestbox paradigm to allow mice to self-modulate their light environment. Dark nestboxes fitted with passive infrared sensors were used to monitor locomotor activity, circadian entrainment, decision making and light environment sampling behaviour. Results Under these conditions, mice significantly reduce their light exposure to an average of just 0.8 h across a 24 h period. In addition, mice show a distinct pattern of light environment sampling behaviour, with peaks at dawn and dusk under a ramped light dark cycle. Furthermore, we show that the timing of light environment sampling behaviour depends upon endogenous circadian rhythms and is abolished in mice lacking a circadian clock, indicating a feedback loop between light, the circadian clock and behaviour. Conclusions Our results highlight the important role of behaviour in modifying the light signals available for circadian entrainment under natural conditions.

Abstract Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified within the French National Multidisciplinary Tumor Board for CUP. This cohort strongly suggests that rCUP share similarities with common RCC subtypes and benefit from renal-tailored systemic treatment. This study highlights the importance of integrating clinical and molecular data for optimal diagnosis and management of CUP.

Abstract Objective To investigate the prevalence and natural history of POLG disease in the Norwegian population. Methods A national, population‐based, retrospective study using demographic, clinical, and genetic data of patients with genetically confirmed POLG disease. The patients were diagnosed between 2002 and 2022, and were included into the Norwegian POLG Patient Registry. Patients were stratified according to age at disease onset (early

The New World insect species Frankliniella minuta (Moulton, 1907) is reported from Asia for the first time. This is a member of the Order Thysanoptera and is placed in the subfamily Thripinae of the Thripidae. A total of 45 female and 14 male adults were found on Tridax procumbens (Asteraceae) at the Malaysian Agricultural Research and Development Institute (MARDI) in Selangor, Peninsular Malaysia. Both sexes were taken from the capitula of T. procumbens. The potential threat of this species to the horticultural industry is inconclusive, but the discovery will alert horticulturalists and quarantine entomologists to possible invasion pathways. Diagnostic characters, relevant figures and a key to Frankliniella species in Malaysia are provided.

Polycystic ovarian syndrome (PCOS), frequently associated to obesity, is the main reproductive disorder in women in age to procreate. Some evidence suggests that pesticides can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). Here, we detected two fungicides, Tebuconazole (Tb) and Epoxiconazole (Epox) in the soils and waters of French area. Our hypothesis is that these two triazoles could be associated to the etiology of PCOS. We used the human KGN cell line and primary human granulosa cells (hGCs) from different group of patients: normal weight non PCOS (NW), normal weight PCOS (PCOS NW), obese (obese) and obese PCOS (PCOS obese). We exposed in vitro these cells to Tb and Epox from 0 up to 10 mM for 24 and 48 h and analysed cell viability and steroidogenesis. In hGCs NW, cell viability was reduced from 12.5 µM for Tb and 75 µM for Epox. In hGCs NW, Epox decreased progesterone (Pg) and estradiol (E2) secretions and inhibited STAR, HSD3B and CYP19A1 mRNA expressions from 25 µM and increased AHR mRNA expression from 75 µM. Tb exposure also reduced steroid secretion and STAR and CYP19A1 mRNA expressions and increased AHR mRNA expression but at cytotoxic concentrations. Silencing of AHR in KGN cells reduced inhibitory effects of Tb and Epox on steroid secretion. Tb and Epox exposure decreased more steroid secretion in hGCs from obese, PCOS NW and PCOS obese groups than in NW group. Moreover, we found a higher gene expression of AHR within these three groups. Taken together, both Epox and Tb reduced steroidogenesis in hGCs through partly AHR and Tb was more cytotoxic than Epox. These triazoles alter more strongly PCOS and/or obese hGCs suggesting that human with reproductive disorders are more sensitive to triazoles exposure.

DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A, is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.

Background: The Penuma is a soft silicone penile implant designed for cosmetic enhancement of the flaccid penis in men who have normal erections. Objectives: The goal of this study is to report outcomes on patient satisfaction at least 6 months after Penuma subcutaneous penile implant for cosmetic enhancement of the penis, and to determine if modifications in surgical approach resulted in reduction in postoperative complications. Design: Penile measurements, adverse events, and patient satisfaction were compared between patients undergoing the new lateral scrotal incision versus the traditional infrapubic approach. Methods: A retrospective chart review was performed on all patients who underwent a Penuma implant by a single surgeon from April 2019 to December 2022. A 26-item non-validated device-specific questionnaire was sent to patients at least 6 months after the date of their initial surgery. Results: A total of 92 cases were performed by a single surgeon. The average increase in flaccid length was 2.5 cm (±2.2), representing a 44% increase ( p

La France est actuellement au premier rang des productions européennes de poulets biologiques. Cette production ne représente toutefois encore que quelques pourcents de la production nationale. L’élevage avicole biologique est souvent considéré comme respectueux du bien-être animal et de l’environnement. Cependant, au-delà de ces images positives que l’élevage avicole biologique et les produits biologiques véhiculent, certaines contraintes déjà identifiées limitent leur développement. Le contact avec la faune sauvage présentant un risque sanitaire, la gestion du parcours, les tensions sur l’environnement dues à une excrétion des déjections sur le parcours difficilement maîtrisables et la sensibilité au contexte économique et aux comportements de consommation sont autant d’obstacles. L’élevage biologique offre néanmoins des opportunités 1) pour l’animal : le parcours facilite l’expression de nombreux comportements et permet la consommation d’insectes et de plantes possédant diverses propriétés (nutritionnelle, médicinales…) ; 2) pour l’éleveur : une amélioration des conditions de travail ainsi qu’une plus grande satisfaction sont mises en avant ; 3) pour l’environnement : le parcours constitue une source de biodiversité. Après une présentation des conditions d’élevage des poulets biologiques en France et en Europe, nous proposons d’identifier les barrières à l’extension de l’élevage biologique et les leviers/opportunités pour les dépasser.

IntroductionIt is well established that child victims are some of the most challenging populations to interview. Indeed, children tend to feel ashamed, scared or in denial, leading to difficulties for law enforcement when gathering information, and subsequently with prosecuting offenders. Moreover, with crimes against children increasing, it is common for interviewed victims to have experienced several abuses (poly-victimization). Thus, the main goals of this study are to (1) identify the facets that are included in poly-victimization, in order to (2) provide a clear definition that can be used by law enforcement during child interviews, which could lead to (3) a better identification of cases of abuse to maximize safeguarding and protect children.Materials and methodsA systematic review was used to establish the differences in conceptualizations of poly-victimization as well as the measurements chosen by research to measure this concept. The current systematic review included research articles on childhood poly-victimization using a quantitative measuring instrument published as of 2007, that focused on populations under 18 years of age.ResultsThe findings were divided into (1) conceptual dimensions, (2) characteristics of studies’ populations and (3) measures and psychometrics properties. It was found that research used various terms for poly-victimization, yet with numerous definitions implying differences in number of abuses, time frame, and mental health aspects to be considered in the identification of poly-victimization. The included papers (n = 6) were from Europe, Asia, and the United States. Over half of the studies used the Juvenile Victimization Questionnaire (JVQ) but adapted either (i) to the study’s population, (ii) possible answers, (iii) wording of questions, or (iv) by the removal of questions.ConclusionOur findings highlight the need for a more theoretically coherent definition of childhood poly-victimization. Questions regarding number of abuses, time consideration (past year vs. lifetime), mental health and severity of abuse should be addressed to develop a unified definition of poly-victimization. Rapport-based interviews should be the focus to uncover the truth and to avoid a secondary trauma in the crisis of a child’s disclosure of abuse. A new definition of “Childhood Poly-Victimization” is proposed by the authors as well as a “Decision Tree for Identifying Childhood Poly-Victimization” designed to be used by law enforcement during child investigative interviews.

Abstract Background Vector control using insecticides is a key prevention strategy against malaria. Unfortunately, insecticide resistance in mosquitoes threatens all progress in malaria control. In the perspective of managing this resistance, new insecticide formulations are being tested to improve the effectiveness of vector control tools. Methods The efficacy and residual activity of Pirikool® 300 CS was evaluated in comparison with Actellic® 300 CS in experimental huts at the Tiassalé experimental station on three substrates including cement, wood and mud. The mortality, blood-feeding inhibition, exiting behaviour and deterrency of free-flying wild mosquitoes was evaluated. Cone bioassay tests with susceptible and resistant mosquito strains were conducted in the huts to determine residual efficacy. Results A total of 20,505 mosquitoes of which 10,979 (53%) wild female Anopheles gambiae were collected for 112 nights. Residual efficacy obtained from monthly cone bioassay was higher than 80% with the susceptible, laboratory-maintained An. gambiae Kisumu strain, from the first to the tenth study period on all three types of treated substrate for both Actellic® 300CS and Pirikool® 300CS. This residual efficacy on the wild Tiassalé strain was over 80% until the 4th month of study on Pirikool® 300CS S treated substrates. Overall 24-h mortalities of wild free-flying An. gambiae sensu lato which entered in the experimental huts over the 8-months trial on Pirikool® 300CS treatment was 50.5%, 75.9% and 52.7%, respectively, on cement wall, wood wall and mud wall. The positive reference product Actellic® 300CS treatment induced mortalities of 42.0%, 51.8% and 41.8% on cement wall, wood wall and mud wall. Conclusion Pirikool® 300CS has performed really well against resistant strains of An. gambiae using indoor residual spraying method in experimental huts. It could be an alternative product for indoor residual spraying in response to the vectors' resistance to insecticides.

Abstract Porosity affects key astromaterial processes from disruption in our atmosphere and impact with the ground, to the comminution of boulders by thermal and impact processes and slope mechanics on asteroid surfaces, to access and utilization of in-situ resources. Whereas the bulk porosity of clay-rich meteorites is well established, the magnitude of their surface area and nano-scale porosity is poorly known. Here we use N2 BET gas adsorption to measure the specific surface area and nanoscale pore distribution in several clay-rich meteorites. Two recent falls Tarda (C2-ung) and Aguas Zarcas (CM2) have specific surface areas of 72.5 and 16.5 m2/g, respectively. However, the specific surface area of Tarda ranges from 33.7 to 81.6 m2/g depending on outgassing conditions. The Tarda surface area is dominated by an interconnected network of ~ 3-nm-sized pores, whereas Aguas Zarcas shows a lower density of ~ 3 nm pores and broader size distribution around 40 nm. In contrast, Ivuna and Orgueil (CI1) have surface areas of ~ 15 to 18 m2/g: the low values compared to Tarda are likely due to the neoformation of pore-blocking minerals during atmospheric exposure. These data suggest that returned samples from asteroids Ryugu and Bennu, which are mineralogically and texturally similar to Tarda, also have interconnected nano-scale porosity with high surface area.

Abstract As an important immune stimulator and modulator, IFNγ is crucial for gut homeostasis and its dysregulation links to diverse colon pathologies, such as colitis and colorectal cancer (CRC). Here, we demonstrated that the epigenetic regulator, CBX3 (also known as HP1γ) antagonizes IFNγ signaling in the colon epithelium by transcriptionally repressing two critical IFNγ-responsive genes: STAT1 and CD274 (encoding Programmed death-ligand 1, PD-L1). Accordingly, CBX3 deletion resulted in chronic mouse colon inflammation, accompanied by upregulated STAT1 and CD274 expressions. Chromatin immunoprecipitation indicated that CBX3 tethers to STAT1 and CD274 promoters to inhibit their expression. Reversely, IFNγ significantly reduces CBX3 binding to these promoters and primes gene expression. This antagonist effect between CBX3 and IFNγ on STAT1/PD-L1 expression was also observed in CRC. Strikingly, CBX3 deletion heightened CRC cells sensitivity to IFNγ, which ultimately enhanced their chemosensitivity under IFNγ stimulation in vitro with CRC cells and in vivo with a syngeneic mouse tumor model. Overall, this work reveals that by negatively tuning IFNγ-stimulated immune genes’ transcription, CBX3 participates in modulating colon inflammatory response and CRC chemo-resistance.

Gout is highly prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), owing to impaired uric acid excretion. However, treating gout in this population is challenging due to concerns about medication safety and efficacy with reduced kidney function. This review examines the evidence of various pharmacologic and non-pharmacologic approaches to managing gout in CKD/ESRD. For acute gout flares, there is insufficient evidence to guide optimal dosing of NSAIDs, colchicine, and corticosteroids in advanced CKD. The risks generally outweigh the benefits of NSAIDs and colchicine. Corticosteroids appear safer but require individual risk-benefit assessments. Interleukin-1 inhibitors show promise, but larger studies are needed. For long-term urate lowering, xanthine oxidase inhibitors like allopurinol and febuxostat are preferred over probenecid and other uricosurics. However, studies specifically evaluating urate-lowering therapies in CKD are scarce, resulting in conflicting expert guidelines. Starting with low allopurinol doses and gradual titration can mitigate the risks. Higher allopurinol doses may be needed to reach urate targets in some CKD patients. Febuxostat’s safety in advanced CKD remains debated. Optimal gout management in dialysis patients is also unclear, including when to continue urate-lowering therapy. Overall, gout is often suboptimally treated in CKD/ESRD, highlighting the need for more research to guide therapy in this population. Improving management can significantly reduce the burden of these comorbid diseases.

Historical, nomenclatural, technical, and biological problems associated with the 42 species of Mesothrips are discussed. Type specimens have been re-examined of 14 of the 25 species that were described prior to 1930 and remain known only from imperfectly slide-mounted specimens. As a result, seven new synonyms are recognised. From China, six species of Mesothrips have been listed, but the records of M. alluaudi and M. manii are rejected, and three new species are described: M. jianfengi sp. nov., M. longistylus sp. nov., and M. vernicia sp. nov. These three species are divergent from other members of Mesothrips in lacking a prominent fore tarsal tooth and may indicate a possible generic relationship to the flower-living species in the Asian genus Dolichothrips. An illustrated key is provided to the seven Mesothrips species now known from China.

Clinical trials to establish the efficacy of new agents in the adjuvant cancer setting typically take many years to complete. During that time, external factors can impact recruitment and reporting plans. An example is a new standard of care becoming available during the recruitment period.In this paper we describe how we modified the design of the RAMPART trial (NCT03288532) which was set up to investigate immune checkpoint inhibitor therapy in the adjuvant renal cancer setting. The trial had been initiated when no globally accepted adjuvant strategy after nephrectomy existed. A subsequent change in the standard of care for many patients with early renal cancer meant it was no longer feasible to continue to recruit. We needed to find a way to maximise the contribution that RAMPART participants could make to the evidence base for immune checkpoint inhibitor therapy without introducing bias or detriment to the integrity of the trial results. We describe how we agreed and incorporated all design and timeline changes while remaining blinded to accumulating data within the trial, thus protecting the reliability of the future results. We share details of our design modifications to guide others who may have similar experiences, particularly as more agents and combinations of agents are developed and investigated in similar adjuvant settings.

In this multicenter study conducted in France, we challenged the hypothesis of the transmission of pathogens other than Borrelia spp. in 22 patients developing erythema migrans following a tick bite. Using a combination of high-throughput microfluidic PCRs and agnostic metagenomics on skin biopsies and blood samples, no microorganisms other than Borrelia spp. was found.

AbstractThe purpose of this study was to ascertain the existing level of geographic understanding and the ability to integrate geographic considerations into investigations within the police (without prior training on geographic profiling) at two different levels of investigative experience, compared to professional geographic profilers. Three groups of investigative professionals - geographic profilers (geos), detective constables (DCs) and probationary police constables (PCs) - were given a simulation case that deals with a real series of potentially linked cases of arson. During these individual simulation interviews, qualitative data on participants’ verbal utterances and vocalised thought processes was recorded, then analysed and quantified. Both the quantity of investigative statements made as well as their content and quality were scrutinised. Quantitatively, the DC and geo groups were almost identical in terms of how many investigative considerations they made in relation to geographic and temporal (related to time of day, day of the week, etc.) aspects of a crime. However, qualitative analysis revealed a gap in the level of understanding of the importance of some geographic considerations between geos and the police. Overall, the research concludes that police investigators are a very fertile ground for receiving training on geographic profiling, as some of it is already naturally integrated into their investigations, and that increasing investigators’ understanding of geographic profiling could enhance their operational capabilities in the thousands of cases in which no expert geographic profiler is brought in to support them.

Abstract Background In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. Methods We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. Results Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. Conclusions Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

Biological synaptic transmission is unreliable, and this unreliability likely degrades neural circuit performance. While there are biophysical mechanisms that can increase reliability, for instance by increasing vesicle release probability, these mechanisms cost energy. We examined four such mechanisms along with the associated scaling of the energetic costs. We then embedded these energetic costs for reliability in artificial neural networks (ANNs) with trainable stochastic synapses, and trained these networks on standard image classification tasks. The resulting networks revealed a tradeoff between circuit performance and the energetic cost of synaptic reliability. Additionally, the optimised networks exhibited two testable predictions consistent with pre-existing experimental data. Specifically, synapses with lower variability tended to have (1) higher input firing rates and (2) lower learning rates. Surprisingly, these predictions also arise when synapse statistics are inferred through Bayesian inference. Indeed, we were able to find a formal, theoretical link between the performance-reliability cost tradeoff and Bayesian inference. This connection suggests two incompatible possibilities: evolution may have chanced upon a scheme for implementing Bayesian inference by optimising energy efficiency, or alternatively, energy-efficient synapses may display signatures of Bayesian inference without actually using Bayes to reason about uncertainty.

Background Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures.Methods Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method.Results At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs.Conclusions Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN.Trial registration number NCT02231749.

Background There are insufficient in vitro bone models that accommodate long-term culture of osteoblasts and support their differentiation to osteocytes. The increased demand for effective therapies for bone diseases, and the ethical requirement to replace animals in research, warrants the development of such models. Here we present an in-depth protocol to prepare, create and maintain three-dimensional, in vitro, self-structuring bone models that support osteocytogenesis and long-term osteoblast survival (>1 year). Methods Osteoblastic cells are seeded on a fibrin hydrogel, cast between two beta-tricalcium phosphate anchors. Analytical methods optimised for these self-structuring bone model (SSBM) constructs, including RT-qPCR, immunofluorescence staining and XRF, are described in detail. Results Over time, the cells restructure and replace the initial matrix with a collagen-rich, mineralising one; and demonstrate differentiation towards osteocytes within 12 weeks of culture. Conclusions Whilst optimised using a secondary human cell line (hFOB 1.19), this protocol readily accommodates osteoblasts from other species (rat and mouse) and origins (primary and secondary). This simple, straightforward method creates reproducible in vitro bone models that are responsive to exogenous stimuli, offering a versatile platform for conducting preclinical translatable research studies.

Ixodid (hard) ticks play important ecosystem roles and have significant impacts on animal and human health via tick-borne diseases and physiological stress from parasitism. Tick occurrence, abundance, activity, and key life-history traits are highly influenced by host availability, weather, microclimate, and landscape features. As such, changes in the environment can have profound impacts on ticks, their hosts, and the spread of diseases. Researchers recognize that spatial and temporal factors influence activity and abundance and attempt to account for both by conducting replicate sampling bouts spread over the tick questing period. However, common field methods notoriously underestimate abundance, and it is unclear how (or if) tick studies model the confounding effects of factors influencing activity and abundance. This step is critical as unaccounted variance in detection can lead to biased estimates of occurrence and abundance. We performed a descriptive review to evaluate the extent to which studies account for the detection process while modeling tick data. We also categorized the types of analyses that are commonly used to model tick data. We used hierarchical models (HMs) that account for imperfect detection to analyze simulated and empirical tick data, demonstrating that inference is muddled when detection probability is not accounted for in the modeling process. Our review indicates that only 5 of 412 (1 %) papers explicitly accounted for imperfect detection while modeling ticks. By comparing HMs with the most common approaches used for modeling tick data (e.g., ANOVA), we show that population estimates are biased low for simulated and empirical data when using non-HMs, and that confounding occurs due to not explicitly modeling factors that influenced both detection and abundance. Our review and analysis of simulated and empirical data shows that it is important to account for our ability to detect ticks using field methods with imperfect detection. Not doing so leads to biased estimates of occurrence and abundance which could complicate our understanding of parasite-host relationships and the spread of tick-borne diseases. We highlight the resources available for learning HM approaches and applying them to analyzing tick data.

Abstract Beyond ecological and health impacts, invasive alien plant species can generate indirect and direct costs, notably through reduced agricultural yields, restoration, and management of the invaded environment. Acacia dealbata and Ailanthus altissima are invasive plant species that cause particularly significant damage to the railway network in the Mediterranean area. The allelopathic properties of Mediterranean plant species could be used as nature‐based solutions to slow down the spread of such invasive plant species along railway borders. In this context, a mesocosm experiment was set‐up: (i) to test the potential allelopathic effects of Cistus ladanifer, Cistus albidus, and Cotinus coggygria leaf aqueous extracts on seed germination and seedling growth of A. dealbata and A. altissima; (ii) to evaluate whether these effects depend on the extract dose; and finally, (iii) to estimate whether these effects are modified by soil amendment. Leaf aqueous extracts of the three native plant species showed negative effects on both seed germination and seedling growth of the two invasive species. Our results show that the presence of allelochemicals induces a delay in seed germination (e.g., A. dealbata germination lasted up to 269% longer in the presence of high‐dose leaf aqueous extracts of C. coggygria), which can lead to a decrease in individual recruitment. They also highlight a decrease in seedling growth (e.g., high‐dose C. coggygria leaf aqueous extracts induced a 26% decrease in A. dealbata radicle growth), which can alter the competitiveness of invasive species for resource access. Our results also highlight that compost addition limits the inhibitory effect of native Mediterranean plants on the germination of invasive alien plants, suggesting that soil organic matter content can counteract allelopathic effects on invasive alien plants. Thus, our findings revealed that the allelopathic potential of certain Mediterranean plant species could be a useful tool to manage invasive plant species.

Multi-temporal Synthetic Aperture Radar Interferometry (MT-InSAR) is the only geodetic technique allowing to measure ground deformation down to mm/yr over continuous areas. Vegetation cover in equatorial regions favors the use of L-band SAR data to improve interferometric coherence. However, the electron content of ionosphere, affecting the propagation of the SAR signal, shows particularly strong spatio-temporal variations near the equator, while the dispersive nature of the ionosphere makes its effect stronger on low-frequencies, such as L-band signals. To tackle this problem, range split-spectrum method can be implemented to compensate the ionospheric phase contribution. Here, we apply this technique for time-series of ALOS-PALSAR data, and propose optimizations for low-coherence areas. To evaluate the efficiency of this method to retrieve subtle deformation rates in equatorial regions, we compute time-series using four ALOS-PALSAR datasets in contexts of low to medium coherence, showing slow deformation rates (mm/yr to cm/yr). The processed tracks are located in Ecuador, Trinidad and Sumatra, and feature 15 to 19 acquisitions including very high, dominating ionospheric noise, corresponding to equivalent displacements of up to 2 m. The correction method performs well and allows to reduce drastically the noise level due to ionosphere, with significant improvement compared with a simple plane fitting method. This is due to frequent highly non-linear patterns of perturbation, characterizing equatorial TEC distribution. We use semivariograms to quantify the uncertainty of the corrected time-series, highlighting its dependence on spatial distance. Thus, using ALOS-PALSAR-like archive, one can expect a detection threshold on the Line-of-Sight velocity ranging between 3 and 6 mm/yr, depending on the spatial wavelength of the signal to be observed. These values are consistent with the accuracy derived from the comparison of velocities between two tracks in their overlapping area. In the case studies that we processed, the time-series corrected from ionosphere allows to retrieve accurately fault creep and volcanic signal but it is still too noisy for retrieving tiny long-wavelength signals such as slow (mm/yr) interseismic strain accumulation.

The short-circuit (SC) immunity of power silicon carbide (SiC) MOSFETs is critical for high-reliability applications, where robust monitoring and protection strategies are essential to ensure system safety. Despite their superior voltage blocking capabilities and high energy efficiency, SiC MOSFETs exhibit greater sensitivity to SC-induced degradation compared to their silicon counterparts. This increased vulnerability necessitates the precise assessment of the key SC performance metrics, such as short-circuit withstand time (TSCWT), as well as a deeper understanding of the failure mechanisms. In this study, a comprehensive experimental methodology for evaluating the SC behavior of SiC MOSFETs is presented and validated using industrial references. The investigation further explores the concept of a Safe Operating Area (SOA) under SC conditions, highlighting the significant impact of quasi-simultaneous SC events on device lifetime. Additionally, an application case study demonstrates how these events can drastically reduce the device’s lifespan.

To avoid the critical problems of effective drugs not being carried to their targeted cancers and their quantity and location not being sensed in situ, this work presents a completely new innovative strategy to achieve both smart cancer targeting (SCT) and super-sensitive sensing (SSS), where one drug carrier works for effective drug loading and release. Herein, malignant melanoma treatment is used as an example of reliable detection and effective therapy. We report two characteristic dumbbell-like nano-micelles and spherical-like nano-micelles of hyaluronan induced by the Eu3+/Tb3+ complexes for effective drug loading and release, respectively. These special Eu3+/Tb3+-loaded nano-micelles (marked as ENM and TNM) have strong and sharp red/green luminescence that can sensitively detect the malignant melanoma drug dacarbazine through changes in fluorescence intensity. Cytotoxicity experiments confirmed that both ENM and TNM are not toxic to normal cells at very high concentrations of 4 mM. However, when loaded with cancer drugs (D-ENM and D-ENM), they both killed cancer cells with more than 40% efficacy at this concentration. The in vivo experiments confirmed that D-ENM and D-TNM can effectively target cancer cells in tissue and effectively impede cancer growth. The detection limits of ENM and TNM in sensing cancer drugs can reach 0.456 μg/mL and 0.139 μg/mL, respectively. Therefore, the reported Eu3+/Tb3+-induced hyaluronan nano-micelles (ENM and TNM) are distinguished carriers of this cancer drug and excellent in situ sensors, and they have highly therapeutic effects with extremely low toxicity to normal cells.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Background: Cardiac sarcoidosis can cause a wide range of symptoms, including shortness of breath, chest pain, oedema, and fatal arrhythmias such as ventricular tachycardia (VT). Because the symptoms can be nonspecific, diagnosing cardiac sarcoidosis can be challenging. Treatment options may include corticosteroids to reduce inflammation, immunosuppressive drugs to prevent further damage, medications to control symptoms, ablation procedures, and defibrillators to prevent cardiac arrest. Case: A 60-year-old woman who has sarcoidosis affecting multiple organs including cardiac sarcoidosis, non-ischemic cardiomyopathy with reduced ejection fraction, and hypertension, was admitted with tachycardia, shortness of breath, and a recently fired automatic implantable cardioverter defibrillator (AICD). Three months prior, the patient was admitted for a syncopal episode and diagnosed with cardiac sarcoidosis through cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET), which demonstrated active inflammation, and an AICD was implanted. During this admission, the patient had an episode of ventricular tachycardia and was treated with amiodarone and lidocaine. The patient received steroids, sacubitril/valsartan, and methotrexate. After 48 hours of observation, the patient was discharged without further events. Conclusion: Cardiac sarcoidosis is a rare but serious disease that can lead to life-threatening cardiac complications such as ventricular tachycardia. Early diagnosis and aggressive management are crucial for improving outcomes and preventing sudden cardiac death. AICD implantation as a secondary prevention in cardiac sarcoidosis might prevent cardiac arrest.

Abstract This study provides a comprehensive characterization of various hydrothermal systems in Southern Peru ranging from the faulted Precordillera's steep topography up to the volcanic High Cordillera (>4,000 m asl). The objective is to investigate thermal anomalies that may potentially serve as new geothermal resources. Our integrated approach combines: (a) geochemistry from 14 hot springs sampled throughout the Tacna region, and (b) 3D numerical modeling of coupled groundwater and heat transfer considering topography and faults embedded in homogeneous permeability. Water and gas analysis indicates that the springs located near volcanoes discharge Na‐K‐Cl waters with high temperatures (>87°C), high Total Dissolved Solid concentrations (TDS >3,452 mg/L), and free gases dominated by CO2 (>90 vol%). Springs located along the regional faults in the Precordillera discharge Ca‐SO4 and Na‐K‐Cl waters with moderate temperatures (27–53°C), intermediate TDS concentrations (464–2,458 mg/L), radiocarbon ages between 1.4 and 7.9 kyr, and free gases dominated by N2 (>95 vol%). The Aruma springs, which are located at the transition between the High and the Precordillera, display intermediate characteristics. Numerical models accurately replicate the locations and temperatures of the fault‐related springs only for permeable faults (>10−14 m2), revealing the creation of 100‐km long thermal plumes along faults, locally rising up the 150°C‐isotherm to about ∼1,000 m below the surface. This approach clearly distinguishes the spring origins, which are volcanic in High Cordillera and tectonic in Precordillera. Moreover, we highlight that steep topographic gradient and permeable reverse faults in the Andean forearc may generate considerable thermal anomalies, opening perspectives for the geothermal exploration.

Abstract In this research, a 3D brain organoid model is developed to study POLG‐related encephalopathy, a mitochondrial disease stemming from POLG mutations. Induced pluripotent stem cells (iPSCs) derived from patients with these mutations is utilized to generate cortical organoids, which exhibited typical features of the diseases with POLG mutations, such as altered morphology, neuronal loss, and mitochondiral DNA (mtDNA) depletion. Significant dysregulation is also identified in pathways crucial for neuronal development and function, alongside upregulated NOTCH and JAK‐STAT signaling pathways. Metformin treatment ameliorated many of these abnormalities, except for the persistent affliction of inhibitory dopamine‐glutamate (DA GLU) neurons. This novel model effectively mirrors both the molecular and pathological attributes of diseases with POLG mutations, providing a valuable tool for mechanistic understanding and therapeutic screening for POLG‐related disorders and other conditions characterized by compromised neuronal mtDNA maintenance and complex I deficiency.

Background There are insufficient in vitro bone models that accommodate long-term culture of osteoblasts and support their differentiation to osteocytes. The increased demand for effective therapies for bone diseases, and the ethical requirement to replace animals in research, warrants the development of such models. Here we present an in-depth protocol to prepare, create and maintain three-dimensional, in vitro, self-structuring bone models that support osteocytogenesis and long-term osteoblast survival (>1 year). Methods Osteoblastic cells are seeded on a fibrin hydrogel, cast between two beta-tricalcium phosphate anchors. Analytical methods optimised for these self-structuring bone model (SSBM) constructs, including RT-qPCR, immunofluorescence staining and XRF, are described in detail. Results Over time, the cells restructure and replace the initial matrix with a collagen-rich, mineralising one; and demonstrate differentiation towards osteocytes within 12 weeks of culture. Conclusions Whilst optimised using a secondary human cell line (hFOB 1.19), this protocol readily accommodates osteoblasts from other species (rat and mouse) and origins (primary and secondary). This simple, straightforward method creates reproducible in vitro bone models that are responsive to exogenous stimuli, offering a versatile platform for conducting preclinical translatable research studies.

Background: Studies have shown major cardiovascular effects associated with ketamine use disorder including dose-dependent negative inotropic effects. Preoperative ketamine use has been linked to ketamine-induced stress cardiomyopathy. Case presentation: A 28-year-old female with a history of recurrent cystitis and ketamine use disorder (twice weekly for 14 years) presented with bilateral lower extremity oedema and shortness of breath for 3 months. She was tachycardic with a troponin level of 0.07 ng/ml and a B-type natriuretic peptide (BNP) level of 2511 pg/ml. Electrocardiogram showed normal sinus rhythm and transthoracic echocardiography (TTE) showed left ventricular ejection fraction (EF) of 15%, dilated left ventricle, and severe tricuspid and mitral regurgitation. Computed tomography (CT) scan of the chest and abdomen showed bilateral pleural effusions with congestive hepatopathy and ascites. The patient was started on intravenous furosemide, metoprolol, and sacubitril/valsartan. Rheumatological workup including complement levels, and antinuclear anti-double-stranded DNA was negative. A repeat TTE 2 weeks later revealed an EF of 25% and moderate tricuspid regurgitation. Four months later, the EF was 54% with normal left ventricular cavity size. Conclusion: Although ketamine use disorder is increasing, data on long-term side effects is minimal. Screening for ketamine use disorders should be considered in patients presenting with acute systolic heart failure. Long-term studies are needed to evaluate the benefits of adding ketamine screening to standard urine toxicology.

Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection.

Background: The increasing popularity of the silicone sleeve penile implant has been accompanied by concerns over potential risks and adverse events. Objectives: To provide multi-institutional data on safety outcomes in patients undergoing silicone sleeve penile implant surgery across high-volume implant surgeons. In addition, we discuss preventative techniques to minimize postoperative complications and the management of these events. Design and methods: We performed a retrospective analysis of men undergoing penile silicone sleeve implants between November 2020 and November 2022 with four surgeons, each from a separate institution. Perioperative and postoperative adverse events, including unsatisfactory cosmetic outcomes requiring revision, were determined by physician follow-up. Flaccid penile length and girth were measured preoperatively and postoperatively. Results: A total of 299 male patients underwent silicone sleeve implant surgery, with an average age of 42.5 ± 10.5 years and an average body mass index of 28.5 ± 4.0. The patient cohort exhibited minimal comorbidities, with 5% having hyperlipidemia, 2% being smokers, 2% having cardiovascular disease, and 1% having diabetes. Patients experienced an average increase of 4.1 ± 1.5 cm in their flaccid penile length (a 50% increase) and an average increase of 3.4 ± 1.5 cm in their flaccid girth (a 37% increase) ( p

IntroductionEndocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing’s syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT.MethodsRetrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus.ResultsAfter adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites – 18 in PPGL, 15 in CS, and 23 in PA – were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites.DiscussionsOur study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL’s metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

Objective: Systematically review evidence on using GLP-1RAs for reducing BEB in BED and BN. Methods: Comprehensive literature search (PubMed and Google Scholar) conducted for studies evaluating GLP-1Ras for BEB. Extracted data on study characteristics, efficacy, and safety. Results: Studies show that GLP-1RAs (liraglutide and dulaglutide) reduce BE frequency and comorbidities in addition to favorable psychiatric side effect profile compared to current options. However, large-scale, blinded placebo-controlled trials are lacking. Conclusion: Early findings suggest promising effects of GLP-1RAs on BEB. However, rigorous clinical trials are needed to firmly establish efficacy, dosing, safety, and comparative effectiveness before considering GLP-1RAs a viable novel approach.

Azaleothrips, a genus of fungus-feeding Phlaeothripinae , is easily recognized by the complex sculpture on the body surface. It is species-rich in the Oriental region, with 10 species here recognized from China, including A. sphaericus sp. nov. and four new records. An illustrated key to the species from China is provided.

Abstract SARS-CoV-2 infection requires Spike protein-mediated fusion between the viral and cellular membranes. The fusogenic activity of Spike depends on its post-translational lipid modification by host S-acyltransferases, predominantly ZDHHC20. Previous observations indicate that SARS-CoV-2 infection augments the S-acylation of Spike when compared to mere Spike transfection. Here, we find that SARS-CoV-2 infection triggers a change in the transcriptional start site of the zdhhc20 gene, both in cells and in an in vivo infection model, resulting in a 67-amino–acid-long N-terminally extended protein with approx. 40 times higher Spike acylating activity, resulting in enhanced fusion of viruses with host cells. Furthermore, we observed the same induced transcriptional change in response to other challenges, such as chemically induced colitis and pore-forming toxins, indicating that SARS-CoV-2 hijacks an existing cell damage response pathway to optimize it fusion glycoprotein.

Species of the Oriental subtropical and tropical genus Phylladothrips of fungus-feeding thrips exhibit some diagnostic character states, usually with abdominal tergite VIII bearing two pairs of wing-retaining setae and male tergite IX setae S2 about as long as S1. These species are quite small, and the maxillary stylets unusually broad for Phlaeothripinae. Phylladothrips trisetae sp. nov. from Xizang, China and P. selangor sp. nov. from Selangor, Malaysia are described, and P. fasciae is newly recorded from China. All 11 species in this genus are revised with an illustrated key.

Abstract The invasion of reticulocytes by Plasmodium vivax merozoites is dependent on the interaction of the Plasmodium vivax Duffy Binding Protein (PvDBP) with the Duffy antigen receptor for chemokines (DARC). The N-terminal cysteine-rich region II of PvDBP (PvDBPII), which binds DARC, is a leading P. vivax malaria vaccine candidate. Here, we have evaluated the immunogenicity of recombinant PvDBPII formulated with the adjuvants Matrix-M and GLA-SE in mice. Analysis of the antibody responses revealed comparable ELISA recognition titres as well as similar recognition of native PvDBP in P. vivax schizonts by immunofluorescence assay. Moreover, antibodies elicited by the two adjuvant formulations had similar functional properties such as avidity, isotype profile and inhibition of PvDBPII-DARC binding. Furthermore, the anti-PvDBPII antibodies were able to block the interaction of DARC with the homologous PvDBPII SalI allele as well as the heterologous PvDBPII PvW1 allele from a Thai clinical isolate that is used for controlled human malaria infections (CHMI). The cross-reactivity of these antibodies with PvW1 suggest that immunization with the PvDBPII SalI strain should neutralize reticulocyte invasion by the challenge P. vivax strain PvW1.

PurposePyridoxine-dependent epilepsy due to ALDH7A1 variants (PDE-ALDH7A1) is a rare disorder, presenting typically with severe neonatal, epileptic encephalopathy. Early diagnosis is imperative to prevent uncontrolled seizures. We have explored the role of EEG in the diagnosis and management of PDE.MethodsA total of 13 Norwegian patients with PDE-ALDH7A1 were identified, of whom five had reached adult age. Altogether 163 EEG recordings were assessed, 101 from the 1st year of life.ResultsMedian age at seizure onset was 9 h (IQR 41), range 1 h-6 days. Median delay from first seizure to first pyridoxine injection was 2 days (IQR 5.5). An EEG burst suppression pattern was seen in eight patients (62%) during the first 5 days of life. Eleven patients had recordings during pyridoxine injections: in three, immediate EEG improvement correlated with seizure control, whereas in six, no change of epileptiform activity occurred. Of these six, one had prompt clinical effect, one had delayed effect (< 1 day), one had no effect, one had uncertain effect, and another had more seizures. A patient without seizures at time of pyridoxine trial remained seizure free for 6 days. Two patients with prompt clinical effect had increased paroxysmal activity, one as a conversion to burst suppression. Autonomic seizures in the form of apnoea appeared to promote respiratory distress and were documented by EEG in one patient. EEG follow-up in adult age did not show signs of progressing encephalopathy.ConclusionA neonatal burst suppression EEG pattern should raise the suspicion of PDE-ALDH7A1. Respiratory distress is common; isolated apnoeic seizures may contribute. EEG responses during pyridoxine trials are diverse, often with poor correlation to immediate clinical effect. Reliance on single trials may lead to under-recognition of this treatable condition. Pyridoxine should be continued until results from biomarkers and genetic testing are available.

The mangrove pens were modified to produce mud crab (Scylla serrata) and milkfish (Chanos chanos) in a polyculture system. The modification of mangrove pens was done by adding excavations inside the pen. The water quality parameters (dissolved oxygen (DO), pH, salinity, and temperature) were monitored, and the recovery and production rates in each pen were evaluated. The experiment was conducted for a rearing period of 143 days in nine mangrove pens, each having an area of 32 m2 and an average net enclosure height of 3 m from the soil surface. The three different pens constructed (existing design: canal only, 43% excavation by area, and 54% excavation by area) were designated as T1, T2, and T3, respectively. The water quality parameters recorded in the pens were favorable for the growth and recovery of the mud crab and milkfish, except for DO. For mud crab, the highest mean recovery was recorded in T2, followed by T3, and the lowest in T1. The production rate followed the same pattern as the recovery, with T2 having the highest, followed by T3, and T1 having the lowest. The statistical analysis revealed that the variations in mud crab recovery were not significant, while in terms of production rate, modified mangrove pens were found to be more effective than the existing design. Due to the total mortality of the cultured milkfish, the current set-up of modified mangrove pens was found to be unsuitable for the polyculture system of milkfish and mud crab production.

Evidence is beginning to emerge of the serious negative effects online only child sexual abuse (OOCSA) can have on victims. Establishing the scale and nature of the problem could assist police in prioritizing suspects. In study 1, scoping review identified eleven studies that examined OOCSA's impact on victims. Five themes emerged from narrative review; definitional issues, a new normal, OOCSA grooming processes, comparisons with offline CSA, mechanisms between OOCSA and harm. In study 2, OOCSA national prevalence was estimated by applying 2.9% rate of OOCSA observed from original police data to a lower bound (“sexual communication with a child” crimes recorded by the police), middle (scaling up to estimate undetected offenses) and upper bound estimate of the national offender pool (self-reported sexual solicitation offenders). Recent UK Home Office figures were adapted to establish economic costs. Lifetime costs estimates attributable to OOCSA are £7.4 million (police reports), £59.6 million (including undetected offenders) and £1.4 billion (national prevalence estimates). Over 75% of this is non-financial costs borne by victims in terms of emotional harm and lost output. Government bears around 20% of the cost burden, mostly non-financial costs for police forces. Findings are discussed in relation to evidence-led recommendations for prioritization and wider police actions that can be taken to avoid the considerable economic and social burden associated with OOCSA offenses.

Collaborative management has developed as a main approach to solving complex environmental problems such as diffuse water pollution from agriculture. This paper aims to understand the drivers of farmers’ participation in collaborative water quality management. The role of farm characteristics, farmers’ profiles and farmers’ social networks is more particularly investigated while taking into account transaction costs. The study relies on a statistical analysis of data collected in two drinking water catchments in France. The results show that larger, more profitable farms with more equipment and access to off-farm income are more likely to participate in collaborative processes for water quality management. Furthermore, farmers’ involvement in agricultural and nonagricultural networks has a strong positive influence on their participation. These results suggest that significant costs, including transaction costs, are associated with farmers’ participation in collaborative management. Targeted support for smaller, financially constrained farms and less-connected farmers could enhance the effectiveness of the collaborative approach to diffuse pollution control.

The cellular thermal shift assay (CETSA®) has increasingly been used in early drug discovery to provide a measure of cellular target engagement. Traditionally, CETSA has been employed for bespoke questions with small to medium throughput and has predominantly been applied during hit validation rather than in hit identification. Using a CETSA screen versus the kinase CRAF, we assessed 3 key questions: (1) technical feasibility – could the CETSA methodology technically be applied at truly high throughput scale? (2) relevance – could hits suitable for further optimisation be identified? (3) reliability – would the approach identify known chemical equity. Here, we describe the first large scale AlphaLISA SureFire based CETSA (Alpha CETSA) approach allowing us to screen a large library of almost 0.5 million compounds. We discuss the issues overcome in automating and executing the screen and describe the resulting screen output.