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Abstract Salmonella utilizes a type 3 secretion system to translocate virulence proteins (effectors) into host cells during infection1. The effectors modulate host cell machinery to drive uptake of the bacteria into vacuoles, where they can establish an intracellular replicative niche. A remarkable feature of Salmonella invasion is the formation of actin-rich protuberances (ruffles) on the host cell surface that contribute to bacterial uptake. However, the membrane source for ruffle formation and how these bacteria regulate membrane mobilization within host cells remains unclear. Here, we show that Salmonella exploits membrane reservoirs for the generation of invasion ruffles. The reservoirs are pre-existing tubular compartments associated with the plasma membrane (PM) and are formed through the activity of RAB10 GTPase. Under normal growth conditions, membrane reservoirs contribute to PM homeostasis and are preloaded with the exocyst subunit EXOC2. During Salmonella invasion, the bacterial effectors SipC, SopE2, and SopB recruit exocyst subunits from membrane reservoirs and other cellular compartments, thereby allowing exocyst complex assembly and membrane delivery required for bacterial uptake. Our findings reveal an important role for RAB10 in the establishment of membrane reservoirs and the mechanisms by which Salmonella can exploit these compartments during host cell invasion.

Objective: Intracranial complications of pediatric sinusitis are uncommon but are often associated with significant morbidity, especially when appropriate care is delayed. The present study aimed to identify commonalities for the development and progression of these complications in the pediatric population. Data Sources: CENTRAL, CINAHL, Citation searching, ClinicalTrials.gov, Embase, Google Scholar, MEDLINE, PsycINFO, PubMed, Scopus, Web of Science, and World Health Organization. Review Methods: A comprehensive literature search was performed using Preferred Reporting Items for Systematic Reviews and Meta‐analyses scoping review guidelines. Studies describing intracranial infections secondary to sinusitis in the pediatric population (age <18 years) were included. Studies in which adult and pediatric data were not separated and studies in which the pediatric cohort was fewer than 10 cases were excluded. Ultimately, 33 studies describing 1149 unique patient cases were included for data collection and analysis. Results: Our analysis revealed intracranial complications were more common in adolescent males. Most children presented with over 1 week of vague symptoms, such as headache and fever. The majority of complications were diagnosed radiographically with computed tomography. Subdural empyema and epidural abscess were the most common intracranial complications reported. On average, patients were admitted for over 2 weeks. Most children were treated with a combination of antibiotics and surgical intervention. Complications were rare, but when present, were often associated with significant morbidity. Conclusion: This scoping review of the available literature has provided insight into commonalities among pediatric patients who develop intracranial complications of sinusitis, providing a foundation for further study to inform medical and surgical decision‐making in this population. [ABSTRACT FROM AUTHOR]

Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while latestage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies. [ABSTRACT FROM AUTHOR]

This document is a corrigendum published in the journal Frontiers in Immunology. It corrects an error in Figure 10 of a previously published article titled "Late-stage MC38 tumours recapitulate features of human colorectal cancer - implications for appropriate timepoint selection in preclinical studies." The error involved a duplicated density plot in the figure. The authors apologize for the mistake but state that it does not affect the scientific conclusions of the article. The original article has been updated. [Extracted from the article]

The National Hospital Insurance Fund (NHIF) of Kenya was upgraded to improve access to healthcare for impoverished households, expand universal health coverage, and boost the uptake of essential reproductive, maternal, newborn and child health (RMNCH) services. However, premiums may be unaffordable for the poorest households. The Innovative Partnership for Universal Sustainable Healthcare (i-PUSH) programme targets low-income women and their households to improve their access to and utilization of quality healthcare, including RMNCH services, by providing subsidized, mobile phone-based NHIF coverage in combination with enhanced, digital training of community health volunteers and upgrading of health facilities. This study evaluated whether expanded NHIF coverage increased the accessibility and utilization of quality basic RMNCH services in areas where i-PUSH was implemented using a longitudinal cluster randomized controlled trial in Kakamega, Kenya. A total of 24 pair-matched villages were randomly assigned either to the treatment or the control group. Within each village, 10 eligible households (i.e. with a woman aged 15-49 years who was either pregnant or with a child <4 years old) were randomly selected. The study applied a difference-in-difference methodology based on a pooled cross-sectional analysis of baseline, midline and endline data, with robustness checks based on balanced panels and Analysis of Covariance methods. The analysis sample included 346 women, of whom 248 had had a live birth in the 3 years prior to any of the surveys, and 424 children aged 0-59 months. Improved NHIF coverage did not have a statistically significant impact on any of the RMNCH outcome indicators at midline nor endline. Uptake of RMNCH services, however, improved substantially in both control and treatment areas at endline compared to baseline. For instance, significant increases were observed in the number of antenatal care visits from baseline to midline (mean = 2.62-2.92, P < 0.01) and delivery with a skilled birth attendant from baseline to midline (mean = 0.91-0.97, P < 0.01). Expanded NHIF coverage, providing enhanced access to RMNCH services of unlimited duration at both public and private facilities, did not result in an increased uptake of care, in a context where access to basic public RMNCH services was already widespread. However, the positive overall trend in RMNCH utilization indicators, in a period of constrained access due to the COVID-19 pandemic, suggests that the other components of the i-PUSH programme may have been beneficial. Further research is needed to better understand how the provision of insurance, enhanced community health volunteer training and improved healthcare quality interact to ensure pregnant women and young children can make full use of the continuum of care., (© The Author(s) 2024. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

In the last 2 decades, there has been an increase in the geographic range and frequency of vector-borne diseases. Management of mosquito populations has become challenging due to increasing rates of resistance to existing insecticidal products and formulations. Several alternative tools have emerged to suppress or replace mosquito populations. One of these tools is the In2Care Mosquito Station (In2Care station). This dual-action station contains the insect growth regulator pyriproxyfen which disrupts the development of immatures and the entomopathogenic fungus Beauveria bassiana (B. bassiana) strain GHA which kills exposed adult mosquitoes. The In2Care stations have previously been shown to effectively control Aedes aegypti in field settings at a density of 6 stations/acre rather than the label-recommended 10 stations/acre. To further test the efficacy of low station density deployment, we deployed In2Care stations in the Pleasant Street Historic District of Gainesville, Florida, at a density of 3 stations/acre over a period of 2 years in the presence or absence of ground larvicidal applications. The deployment of stations resulted in no measurable impact on Ae. aegypti and Culex quinquefasciatus adult or immature abundance suggesting that the low-density deployment of In2Care stations is insufficient to reduce Ae. aegypti and Cu. quinquefasciatus abundance within treatment areas., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In mice, intraperitoneal (ip) contrast agent (CA) administration is convenient for mapping microvascular parameters over a long-time window. However, continuous quantitative MRI of CA accumulation in brain over hours is still missing., Purpose: To validate a quantitative time-resolved MRI technique for mapping the CA kinetics in brain upon ip administration., Study Type: Prospective, animal model., Specimen: 25 C57Bl/6JRj mice underwent MRI., Field Strength/sequence: 7-T, gradient echo sequence., Assessment: Gd-DOTA concentration was monitored by MRI (25 s/repetition) over 135 minutes with (N = 15) and without (N = 10) ip mannitol challenge (5 g/kg). After the final repetition, the brains were sampled to quantify gadolinium by mass spectrometry (MS). Upon manual brain segmentation, the average gadolinium concentration was compared with the MS quantification in transcardially perfused (N = 20) and unperfused (N = 5) mice. Precontrast T 1 -maps were acquired in 8 of 25 mice., Statistical Tests: One-tailed Spearman and Pearson correlation between gadolinium quantification by MRI and by MS, D'Agostino-Pearson test for normal distribution, Bland-Altman analysis to evaluate the agreement between MRI and MS. Significance was set at P-value <0.05., Results: MRI showed that ip administered CA reached the blood compartment (>5 mM) within 10 minutes and accumulated continuously for 2 hours in cerebrospinal fluid (>1 mM) and in brain tissue. The MRI-derived concentration maps showed interindividual differences in CA accumulation (from 0.47 to 0.81 mM at 2 hours) with a consistent distribution resembling the pathways of the glymphatic system. The average in-vivo brain concentration 2 hours post-CA administration correlated significantly (r = 0.8206) with the brain gadolinium quantification by MS for N = 21 paired observations available., Data Conclusion: The presented experimental and imaging protocol may be convenient for monitoring the spatiotemporal pattern of CA uptake and clearance in the mouse brain over 2 hours. The quantification of the CA from the MRI signal in brain is corroborated by MS., Evidence Level: N/A TECHNICAL EFFICACY: Stage 1., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. Merkel cell polyomavirus causes 80% of MCCs, encoding the viral oncogenes small T and truncated large T (tLT) antigens. These proteins impair the RB1-dependent G1/S checkpoint blockade and subvert the host cell epigenome to promote cancer. Whole-proteome analysis and proximal interactomics identified a tLT-dependent deregulation of DNA damage response (DDR). Our investigation revealed, to our knowledge, a previously unreported interaction between tLT and the histone methyltransferase EHMT2. T antigen knockdown reduced DDR protein levels and increased the levels of the DNA damage marker γH2Ax. EHMT2 normally promotes H3K9 methylation and DDR signaling. Given that inhibition of EHMT2 did not significantly change the MCC cell proteome, tLT-EHMT2 interaction could affect the DDR. With tLT, we report that EHMT2 gained DNA damage repair proximal interactors. EHMT2 inhibition rescued proliferation in MCC cells depleted for their T antigens, suggesting impaired DDR and/or lack of checkpoint efficiency. Combined tLT and EHMT2 inhibition led to altered DDR, evidenced by multiple signaling alterations. In this study, we show that tLT hijacks multiple components of the DNA damage machinery to enhance tolerance to DNA damage in MCC cells, which could explain the genetic stability of these cancers., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of multicellular tissues requires both local and global coordination of cell polarization, however, the mechanisms underlying their interplay are poorly understood. In Arabidopsis, leaf epidermal pavement cells (PC) develop a puzzle-piece shape locally coordinated through apoplastic auxin signaling. Here we show auxin also globally coordinates interdigitation by activating the TIR1/AFB-dependent nuclear signaling pathway. This pathway promotes a transient maximum of auxin at the cotyledon tip, which then moves across the leaf activating local PC polarization, as demonstrated by locally uncaged auxin globally rescuing defects in tir1;afb1;afb2;afb4;afb5 mutant but not in tmk1;tmk2;tmk3;tmk4 mutants. Our findings show that hierarchically integrated global and local auxin signaling systems, which respectively depend on TIR1/AFB-dependent gene transcription in the nucleus and TMK-mediated rapid activation of ROP GTPases at the cell surface, control PC interdigitation patterns in Arabidopsis cotyledons, revealing a mechanism for coordinating a local cellular process with the development of whole tissues.

Introduction: Given the current global cancer epidemic across the world, the need for healthcare professionals in this field is crucial. Little is known about the factors that drive medical students toward oncology., Method: We conducted a systematic review of the literature (from 1980 to the present), using several search equations and selecting original articles written in English based on qualitative or quantitative surveys, to understand what motivates medical students to choose oncology., Results: We identified only seven articles that reported quantitative surveys; no qualitative surveys were found. These seven surveys are composed of closed-ended questions and are pragmatic questionnaires based on field knowledge, but without an underlying theory. These studies most often interrogate students already oriented towards oncology. The following five concepts associated with the choice of oncology had the highest recurrence among these seven surveys, which had been conducted in different countries and at various times: interest in cancer management, initiation of the specialty during the 2nd cycle, job opportunities, low working hours, and quality of life., Discussion: The literature on this topic is particularly scarce. No qualitative studies have been published in the English language. The limited data in the literature do not allow us to fully comprehend the problem., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Reference genome assemblies have been created from multiple lineages within the Canidae family; however, despite its phylogenetic relevance as a basal genus within the clade, there is currently no reference genome for the gray fox (Urocyon cinereoargenteus). Here, we present a chromosome-level assembly for the gray fox (U. cinereoargenteus), which represents the most contiguous, non-domestic canid reference genome available to date, with 90% of the genome contained in just 34 scaffolds and a contig N50 and scaffold N50 of 59.4 and 72.9 Megabases, respectively. Repeat analyses identified an increased number of simple repeats relative to other canids. Based on mitochondrial DNA, our Vermont sample clusters with other gray fox samples from the northeastern United States and contains slightly lower levels of heterozygosity than gray foxes on the west coast of California. This new assembly lays the groundwork for future studies to describe past and present population dynamics, including the delineation of evolutionarily significant units of management relevance. Importantly, the phylogenetic position of Urocyon allows us to verify the loss of PRDM9 functionality in the basal canid lineage, confirming that pseudogenization occurred at least 10 million years ago., Competing Interests: Conflicts of interest. The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Mosquito-borne diseases represent a significant threat to human and animal health in the United States. Several viruses, including West Nile, Saint Louis encephalitis, and Eastern equine encephalitis are endemic. In humans, the disease is typically detected during the summer months, but not during the winter months. The ability of these viruses to reemerge year after year is still not fully understood, but typically involves persistence in a reservoir host or vector during periods of low transmission. Mosquito species are known to overwinter at different life stages (adults, larvae, or eggs) in manufactured or natural sites. Gopher tortoise burrows are known to serve as refuge for many vertebrate and invertebrate species in pine savannas. In this study, we surveyed the interior of gopher tortoise burrows for overwintering mosquitoes. We identified 4 species (Anopheles crucians s.l., Culex erraticus, Mansonia dyari, and Uranotaenia sapphirina). Cx. erraticus was the most abundant, and its presence and abundance increased in winter months, implying that this species utilized gopher tortoise burrows for overwintering. Bloodfed Cx. erraticus and An. crucians s.l. females were detected. While An. crucians s.l. fed exclusively on the white-tailed deer, Cx. erraticus had a more diverse host range but fed primarily on the gopher tortoise. Tortoises and other long-lived reptiles like the American alligator have been shown to sustain high viremia following West Nile virus (WNV) and Eastern equine encephalitis virus (EEEV) infection and therefore could play a role in the maintenance of these viruses. In addition, Cx. erraticus is naturally infected with WNV and is a known bridge vector for EEEV. As such, these overwintering sites may play a role in perpetuating over-winter arboviral activity in Florida., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America.)