Genome characterization of Rift Valley fever virus isolated from cattle, goats and sheep during interepidemic periods in Kenya.

Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phlebovirus genus in the phenuviridae family. Its genome is trisegmented with small (S), medium (M) and large (L) fragments. In nature, the virus exists as a single serotype that is responsible for outbreaks of Rift Valley fever (RVF), a zoonotic disease that often occurs in Africa and the Middle East. RVFV genomes are thought to undergo both recombination and reassortment and investigations of these events is important for monitoring the emergence of virulent strains and understanding the evolutionary characteristics of this virus. The aim of this study was to characterize the genomes of RVFV isolates from cattle, sheep, and goats collected during an interepidemic period in Kenya between June 2016 and November 2021. A total of 691 serum samples from cattle (n = 144), goats (n = 185) and sheep (n = 362) were analysed at the Central Veterinary Laboratories. The competitive IgM-capture ELISA, was used to screen the samples; 205 samples (29.67%) tested positive for RVFV. Of the 205 positive samples, 42 (20.5%) were from cattle, 57 (27.8%) from goats, and 106 (51.7%) from sheep. All the IgM-positive samples were further analyzed by qPCR, and 24 (11.71%) tested positive with Ct values ranging from 14.788 to 38.286. Two samples, 201808HABDVS from sheep and 201810CML3DVS from cattle, had Ct values of less than 20.0 and yielded whole genome sequences with 96.8 and 96.4 coverage, respectively. There was no statistically significant evidence of recombination in any of the three segments and also phylogenetic analysis showed no evidence of reassortment in the two isolated RVFV segments when compared with other isolates of different lineages from previous outbreaks whose genomes are deposited in the GenBank. No evidence of reassortment leaves room for other factors to be the most probable contributors of change in virulence, pathogenicity and emergence of highly virulent strains of the RVFV.

Evolution of Key Oxygen-Sensing Genes Is Associated with Hypoxia Tolerance in Fishes.

Low dissolved oxygen (hypoxia) is recognized as a major threat to aquatic ecosystems worldwide. Because oxygen is paramount for the energy metabolism of animals, understanding the functional and genetic drivers of whole-animal hypoxia tolerance is critical to predicting the impacts of aquatic hypoxia. In this study, we investigate the molecular evolution of key genes involved in the detection of and response to hypoxia in ray-finned fishes: the prolyl hydroxylase domain (PHD)-hypoxia-inducible factor (HIF) oxygen-sensing system, also known as the EGLN (egg-laying nine)-HIF oxygen-sensing system. We searched fish genomes for HIFA and EGLN genes, discovered new paralogs from both gene families, and analyzed protein-coding sites under positive selection. The physicochemical properties of these positively selected amino acid sites were summarized using linear discriminants for each gene. We employed phylogenetic generalized least squares to assess the relationship between these linear discriminants for each HIFA and EGLN and hypoxia tolerance as reflected by the critical oxygen tension (Pcrit) of the corresponding species. Our results demonstrate that Pcrit in ray-finned fishes correlates with the physicochemical variation of positively selected sites in specific HIFA and EGLN genes. For HIF2A, two linear discriminants captured more than 90% of the physicochemical variation of these sites and explained between 20% and 39% of the variation in Pcrit. Thus, variation in HIF2A among fishes may contribute to their capacity to cope with aquatic hypoxia, similar to its proposed role in conferring tolerance to high-altitude hypoxia in certain lineages of terrestrial vertebrates.

Estimating maximum oxygen uptake of fishes during swimming and following exhaustive chase - different results, biological bases and applications.

The maximum rate at which animals take up oxygen from their environment (MO2,max) is a crucial aspect of their physiology and ecology. In fishes, MO2,max is commonly quantified by measuring oxygen uptake either during incremental swimming tests or during recovery from an exhaustive chase. In this Commentary, we compile recent studies that apply both techniques to the same fish and show that the two methods typically yield different mean estimates of MO2,max for a group of individuals. Furthermore, within a group of fish, estimates of MO2,max determined during swimming are poorly correlated with estimates determined during recovery from chasing (i.e. an individual's MO2,max is not repeatable across methods). One explanation for the lack of agreement is that these methods measure different physiological states, each with their own behavioural, anatomical and biochemical determinants. We propose that these methods are not directly interchangeable but, rather, each is suited to address different questions in fish biology. We suggest that researchers select the method that reflects the biological contexts of their study, and we advocate for the use of accurate terminology that acknowledges the technique used to elevate MO2 (e.g. peak MO2,swim or peak MO2,recovery). If the study's objective is to estimate the 'true' MO2,max of an individual or species, we recommend that pilot studies compare methods, preferably using repeated-measures designs. We hope that these recommendations contribute new insights into the causes and consequences of variation in MO2,max within and among fish species.

Method dependency of maximum oxygen uptake rate and its repeatability in the Gulf killifish, Fundulus grandis.

The maximum rate at which fish can take up oxygen from their environment to fuel aerobic metabolism is an important feature of their physiology and ecology. Methods to quantify maximum oxygen uptake rate (MO2), therefore, should reliably and reproducibly estimate the highest possible MO2 by an individual or species under a given set of conditions (peak MO2). This study determined peak MO2 and its repeatability in Gulf killifish, Fundulus grandis, subjected to three methods to elevate metabolism: swimming at increasing water speeds, during recovery after an exhaustive chase, and after ingestion of a large meal. Estimates of peak MO2 during swimming and after an exhaustive chase were repeatable across two trials, whereas peak MO2 after feeding was not. Peak MO2 determined by the three methods was significantly different from one another, being highest during swimming, lowest after an exhaustive chase, and intermediate after feeding. In addition, peak MO2 during recovery from an exhaustive chase depended on the length of time of recovery: in nearly 60% of the trials, values within the first hour of the chase were lower than those measured later. A novel and important finding was that an individual's peak MO2 was not repeatable when compared across methods. Therefore, the peak MO2 estimated for a group of fish, as well as the ranking of individual MO2 within that group, depends on the method used to elevate aerobic metabolism.

XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies.

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment-associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial.

Hypoxia-inducible factor 1 alpha protein increases without changes in mRNA during acute hypoxic exposure of the Gulf killifish, Fundulus grandis.

The hypoxia inducible factor 1 (HIF1) is a central regulator of the molecular responses of animals to low oxygen. While the hypoxia-responsiveness of HIF1 is generally attributed to the stabilization of the alpha protein subunit (HIF1α) at low oxygen, several studies on fish report increased tissue levels of HIF1A mRNA during hypoxia, suggesting transcriptional regulation. In the current study, HIF1α protein and HIF1A mRNA were determined in parallel in tissues of Gulf killifish, Fundulus grandis, exposed to short-term hypoxia (24 h at 1 mg O2 l-1). HIF1α protein was higher in brain, ovary, and skeletal muscle from fish exposed to hypoxia compared with normoxic controls by 6 h, and it remained elevated in brain and ovary at 24 h. In contrast, HIF1A mRNA levels were unaffected by hypoxia in any tissue. Moreover, HIF1α protein and HIF1A mRNA levels in the same tissues were not correlated with one another during either normoxia or hypoxia. Hence, an increase in HIF1α protein does not depend upon an increase in HIF1A mRNA during acute exposure to low oxygen in this species. The results support the widely accepted mechanism of post-translational protein stabilization, rather than new transcription, during the initial response of fish to hypoxia.

Primary Hyperparathyroidism Causing Psychosis: A Case Report.

New-onset psychotic symptoms presenting late in life can be caused by various medical and psychiatric conditions. The index of suspicion for an organic cause for psychotic symptoms in an elderly person should be high, and every presenting patient should undergo a detailed history-taking and evaluation before attributing these symptoms to a primary psychiatric condition. Hyperparathyroidism is one condition that can present with psychiatric symptoms such as low mood and anxiety. While psychiatric symptoms are not uncommon in hyperparathyroidism, acute psychosis is rare. This case report highlights the importance of a thorough evaluation of an elderly person presenting with a new onset of psychosis.

Genomic analysis of hypoxia inducible factor alpha in ray-finned fishes reveals missing Ohnologs and evidence of widespread positive selection.

As aquatic hypoxia worsens on a global scale, fishes will become increasingly challenged by low oxygen, and understanding the molecular basis of their response to hypoxia may help to better define the capacity of fishes to cope with this challenge. The hypoxia inducible factor (HIF) plays a critical role in the molecular response to hypoxia by activating the transcription of genes that serve to improve oxygen delivery to the tissues or enhance the capacity of tissues to function at low oxygen. The current study examines the molecular evolution of genes encoding the oxygen-dependent HIFα subunit (HIFA) in the ray-finned fishes (Actinopterygii). Genomic analyses demonstrate that several lineages retain four paralogs of HIFA predicted from two rounds of genome duplication at the base of vertebrate evolution, broaden the known distribution of teleost-specific HIFA paralogs, and provide evidence for salmonid-specific HIFA duplicates. Evolution of the HIFA gene family is characterized by widespread episodic positive selection at amino acid sites that potentially mediate protein stability, protein-protein interactions, and transcriptional regulation. HIFA transcript abundance depends upon paralog, tissue, and fish lineage. A phylogenetically-informed gene nomenclature is proposed along with avenues for future research on this critical family of transcription factors.

The Role of Interventional Radiology in the Diagnosis and Treatment of Pulmonary Arteriovenous Malformations.

Pulmonary arteriovenous malformations (PAVMs) are uncommon, predominantly congenital direct fistulous connections between the pulmonary arteries and pulmonary veins, resulting in a right to left shunt. Patients with PAVMs are usually asymptomatic with lesions detected incidentally when radiological imaging is performed for other indications. In this review, we discuss the classification and radiological features of PAVMs as well as their treatment and follow-up options, with a particular focus on percutaneous endovascular techniques and the evolution of the available equipment for treatment.

Interindividual variation in maximum aerobic metabolism varies with gill morphology and myocardial bioenergetics in Gulf killifish.

This study asked whether interindividual variation in maximum and standard aerobic metabolic rates of the Gulf killifish, Fundulus grandis, correlates with gill morphology and cardiac mitochondrial bioenergetics, traits reflecting critical steps in the O2 transport cascade from the environment to the tissues. Maximum metabolic rate (MMR) was positively related to body mass, total gill filament length and myocardial oxygen consumption during maximum oxidative phosphorylation (multiple R2=0.836). Standard metabolic rate (SMR) was positively related to body mass, total gill filament length and myocardial oxygen consumption during maximum electron transport system activity (multiple R2=0.717). After controlling for body mass, individuals with longer gill filaments, summed over all gill arches, or greater cardiac respiratory capacity had higher whole-animal metabolic rates. The overall model fit and the explanatory power of individual predictor variables were better for MMR than for SMR, suggesting that gill morphology and myocardial bioenergetics are more important in determining active rather than resting metabolism. After accounting for body mass, heart ventricle mass was not related to variation in MMR or SMR, indicating that the quality of the heart (i.e. the capacity for mitochondrial metabolism) was more influential than heart size. Finally, the myocardial oxygen consumption required to offset the dissipation of the transmembrane proton gradient in the absence of ATP synthesis was not correlated with either MMR or SMR. The results support the idea that interindividual variation in aerobic metabolism, particularly MMR, is associated with variation in specific steps in the O2 transport cascade.

The Fibronectin-ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells.

Suppressive myeloid cells inhibit antitumor immunity by preventing T-cell responses. Immunoglobulin-like transcript 3 (ILT3; also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. However, the ligand that engages ILT3 within the tumor microenvironment and renders tumor-associated myeloid cells suppressive is unknown. Using a screening approach, we identified fibronectin as a functional ligand for ILT3. The interaction of fibronectin with ILT3 polarized myeloid cells toward a suppressive state, and these effects were reversed with an ILT3-specific antibody that blocked the interaction of ILT3 with fibronectin. Furthermore, ex vivo treatment of human tumor explants with anti-ILT3 reprogrammed tumor-associated myeloid cells toward a stimulatory phenotype. Thus, the ILT3-fibronectin interaction represents a "stromal checkpoint" through which the extracellular matrix actively suppresses myeloid cells. By blocking this interaction, tumor-associated myeloid cells may acquire a stimulatory phenotype, potentially resulting in increased antitumor T-cell responses.

[Role of stereotactic radiotherapy in the treatment of oligometastatic colorectal cancer]. / Place de la radiothérapie (cancer primitif, métastases) dans la prise en charge des patients atteints d'un cancer oligométastatique : cancer colorectal.

Stereotactic radiotherapy is used for patients with oligometastases from colorectal cancer. It results in good local tumour control, especially for hepatic and pulmonary metastases, subject to a sufficiently high biologically effective dose, and is well-tolerated. It can be associated with other local treatments such as surgery or radiofrequency as part of combined treatments, in order to increase patient survival.

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation.

The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing ß cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.

The Great ESKAPE: Exploring the Crossroads of Bile and Antibiotic Resistance in Bacterial Pathogens.

Throughout the course of infection, many pathogens encounter bactericidal conditions that threaten the viability of the bacteria and impede the establishment of infection. Bile is one of the most innately bactericidal compounds present in humans, functioning to reduce the bacterial burden in the gastrointestinal tract while also aiding in digestion. It is becoming increasingly apparent that pathogens successfully resist the bactericidal conditions of bile, including bacteria that do not normally cause gastrointestinal infections. This review highlights the ability of Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter (ESKAPE), and other enteric pathogens to resist bile and how these interactions can impact the sensitivity of bacteria to various antimicrobial agents. Given that pathogen exposure to bile is an essential component to gastrointestinal transit that cannot be avoided, understanding how bile resistance mechanisms align with antimicrobial resistance is vital to our ability to develop new, successful therapeutics in an age of widespread and increasing antimicrobial resistance.

Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice.

Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2-4. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer5-8, and a GDNF family receptor alpha like (GFRAL)-Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described9-12. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL-RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.

Plasticity, repeatability and phenotypic correlations of aerobic metabolic traits in a small estuarine fish.

Standard metabolic rate (SMR), maximum metabolic rate (MMR), absolute aerobic scope (AAS) and critical oxygen tension (Pcrit) were determined for the Gulf killifish, Fundulus grandis, an ecologically dominant estuarine fish, acclimated to lowered salinity, elevated temperature and lowered oxygen concentration. Acclimation to low salinity resulted in a small, but significant, elevation of Pcrit (suggesting lower tolerance of hypoxia); acclimation to elevated temperature increased SMR, MMR, AAS and Pcrit; acclimation to low oxygen led to a small increase in SMR, but substantial decreases in MMR, AAS and Pcrit Variation in these metabolic traits among individuals was consistent and repeatable when measured during multiple control exposures over 7 months. Trait repeatability was unaffected by acclimation condition, suggesting that repeatability of these traits is not context dependent. There were significant phenotypic correlations between specific metabolic traits: SMR was positively correlated with MMR and Pcrit; MMR was positively correlated with AAS; and AAS was negatively correlated with Pcrit In general, within-individual variation contributed more than among-individual variation to these phenotypic correlations. The effects of acclimation on these traits demonstrate that aerobic metabolism is plastic and influenced by the conditions experienced by these fish in the dynamic habitats in which they occur; however, the repeatability of these traits and the correlations among them suggest that these traits change in ways that maintain the rank order of performance among individuals across a range of environmental variation.

Publisher Correction: GDF15 mediates the effects of metformin on body weight and energy balance.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

GDF15 mediates the effects of metformin on body weight and energy balance.

Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.

Efficacy of Carragelose® Nasal Spray Impregnated Versus Mupirocin Ointment Impregnated Nasal Packs on Mucosal Healing after Endoscopic Sinus Surgery: A Double-Blind, Non-Randomized, Right-Left Side Comparison

@#Objective: To determine the efficacy of carragelose® nasal spray versus mupirocin ointment impregnated nasal packs on postoperative mucosal healing among chronic rhinosinusitis with nasal polyposis (CRSwNP) patients after endoscopic sinus surgery (ESS). Methods: Design: Double-Blind, Non-Randomized, Right-Left Side Comparison Setting: Tertiary Government Training Hospital Participants: Fifteen (15) patients diagnosed with chronic rhinosinusitis with nasal polyposis (CRSwNP) who had ESS were included in the study. Nasal packs (Netcell®) impregnated with carragelose® nasal spray or mupirocin ointment were respectively applied in right and left nostrils. Postoperative mucosal healing was graded by a blinded consultant using the Lund-Kennedy Endoscopic Scoring System and Perioperative Sinus Endoscopy (POSE) scoring system. Results: Six patients (12 nasal sides) completed the study. Comparing nasal packs impregnated with carragelose® nasal spray mupirocin ointment, the carragelose® group had lower Lund- Kennedy median scores than the mupirocin group on the 7th post-operative day; and this was statistically significant (p = .027). There were no significant differences in Lund-Kennedy postoperative scores on days 4 (p = .217), 14 (p = .171) and 28 (p = .151). Conclusion: Carragelose® nasal spray impregnated nasal packs may be comparable with, and may be an alternative to mupirocin ointment impregnated nasal packs in terms of postoperative mucosal healing among ESS patients with CRSwNP.

Intestinal helminth infection enhances bacteria-induced recruitment of neutrophils to the airspace.

Intestinal helminth infections elicit Th2-type immunity, which influences host immune responses to additional threats, such as allergens, metabolic disease, and other pathogens. Th2 immunity involves a shift of the CD4+ T-cell population from type-0 to type-2 (Th2) with increased abundance of interleukin (IL)-4 and IL-13. This study sought to investigate if existing gut-restricted intestinal helminth infections impact bacterial-induced acute airway neutrophil recruitment. C57BL/6 mice were divided into four groups: uninfected; helminth-Heligmosomoides polygyrus infected; Pseudomonas aeruginosa infected; and coinfected. Mice infected with H. polygyrus were incubated for 2 weeks, followed by P. aeruginosa intranasal inoculation. Bronchial alveolar lavage, blood, and lung samples were analyzed. Interestingly, infection with gut-restricted helminths resulted in immunological and structural changes in the lung. These changes include increased lung CD4+ T cells, increased Th2 cytokine expression, and airway goblet cell hyperplasia. Furthermore, coinfected mice exhibited significantly more airspace neutrophil infiltration at 6 hours following P. aeruginosa infection and exhibited an improved rate of survival compared with bacterial infected alone. These results suggest that chronic helminth infection of the intestines can influence and enhance acute airway neutrophil responses to P. aeruginosa infection.