Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization.

Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.

Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil.

Ribosome quality control (RQC) resolves collided ribosomes, thus preventing their cytotoxic effects. The chemotherapeutic agent 5-Fluorouracil (5FU) is best known for its misincorporation into DNA and inhibition of thymidylate synthase. However, while a major determinant of 5FU's anticancer activity is its misincorporation into RNAs, the mechanisms by which cancer cells overcome the RNA-dependent 5FU toxicity remain ill-defined. Here, we report a role for RQC in mitigating the cytotoxic effects of 5FU. We show that 5FU treatment results in rapid induction of the mTOR signalling pathway, enhanced rate of mRNA translation initiation, and increased ribosome collisions. Consistently, a defective RQC exacerbates the 5FU-induced cell death, which is mitigated by blocking mTOR pathway or mRNA translation initiation. Furthermore, 5FU treatment enhances the expression of the key RQC factors ZNF598 and GIGYF2 via an mTOR-dependent post-translational mechanism. This adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment.

Tubulointerstitial nephropathy is the predominant finding in men in a review of more than 3000 renal biopsies over a 10-year period from Sri Lanka.

BACKGROUND: Chronic kidney disease (CKD) is a significant clinical challenge in Sri Lanka. The present study presents histopathological diagnoses from native renal biopsies in Kandy District, 2011-2020. METHODS: Reports of 5,014 renal biopsies principally performed at Kandy Teaching Hospital over 2011-2020 were reviewed. After exclusions for post-kidney transplant biopsies (1,572) and those without evident pathology (347), 3,095 biopsies were included. The predominant histopathological entities were grouped and categorised according to diagnosis and stratified by age and sex. RESULTS: The main histopathological entities (all biopsies) were tubulointerstitial nephropathy (TIN) 25% (n = 760), glomerulonephritis (GN) 15% (467), lupus nephropathy 14% (429), focal segmental glomerular sclerosis (FSGS) 10% (297), and IgA nephropathy (IgAN) 8% (242). For adult women ≥ 15 years, the main histopathological entities were lupus nephropathy 24% (325), TIN 17% (228), and GN 16% (217). For adult men ≥ 15 years, the main histopathological entities were TIN 34% (449), GN 14% (180), and IgAN 10% (125). The proportion of TIN in the present study was higher than international studies of a similar size. CONCLUSION: This is the largest study of renal biopsies reported from Sri Lanka to date. TIN was the most common diagnosis in adults ≥ 15 years at 25%. Notable sex differences showed TIN was the most common histopathology in men (34%) but not in women (17%). No previously published similar study of this size has found TIN as the predominant diagnosis amongst renal biopsies in men. Further research is required into the possible causes of these observations in Sri Lanka. CLINICAL TRIAL NUMBER: Not applicable.

Translation initiation in cancer at a glance.

Cell division, differentiation and function are largely dependent on accurate proteome composition and regulated gene expression. To control this, protein synthesis is an intricate process governed by upstream signalling pathways. Eukaryotic translation is a multistep process and can be separated into four distinct phases: initiation, elongation, termination and recycling of ribosomal subunits. Translation initiation, the focus of this article, is highly regulated to control the activity and/or function of eukaryotic initiation factors (eIFs) and permit recruitment of mRNAs to the ribosomes. In this Cell Science at a Glance and accompanying poster, we outline the mechanisms by which tumour cells alter the process of translation initiation and discuss how this benefits tumour formation, proliferation and metastasis.

Contrast-Enhanced In-Phase Dixon Sequence: Impact on Biopsy Clip Detection on Breast MRI.

BACKGROUND. Identification of breast biopsy clips using conventional MRI sequences may be challenging. A contrast-enhanced in-phase Dixon sequence may have greater conspicuity for areas of susceptibility compared with standard clinical sequences. OBJECTIVE. The purpose of this article is to compare detection of breast biopsy clips on MRI between the contrast-enhanced in-phase Dixon sequence and three routine clinical sequences. METHODS. This retrospective study included 164 patients (mean age, 50.3 years) with a total of 281 breast biopsy clips who underwent contrast-enhanced breast MRI between January 2, 2019, and April 16, 2020. Three radiologists, blinded to the clip location and sequence used, independently annotated biopsy clip locations on three clinical sequences (T1-weighted non-fat-suppressed [NFS], STIR, and first phase from dynamic contrast-enhanced T1-weighted fat-suppressed [FS]) and on a contrast-enhanced in-phase Dixon sequence and then recorded confidence scores (1-4 scale). A study coordinator used all available imaging and reports to localize clips on MRI, which served as the reference standard. A physicist measured clip CNR. Sequences were compared using the McNemar test and two-tailed Wilcoxon signed rank tests. RESULTS. Among the three readers, pooled sensitivity and PPV were 78.2% and 96.2% for T1-weighted NFS, 26.6% and 92.7% for STIR, 61.7% and 95.9% for contrast-enhanced T1-weighted FS, and 85.1% and 95.1% for contrast-enhanced in-phase Dixon sequence. Pooled sensitivity was higher for contrast-enhanced in-phase Dixon sequence than for the other sequences (all p < .05); pooled PPV was not significantly different between contrast-enhanced in-phase Dixon and the other sequences (all p > .05). Mean confidence scores (pooled across readers for true-positive assessments) and mean CNR were 3.0 ± 0.9 (SD) and 1.21 ± 0.61 for T1-weighted NFS, 1.7 ± 0.9 and 0.57 ± 0.69 for STIR, 2.5 ± 1.0 and 0.54 ± 0.61 for contrast-enhanced T1-weighted FS, and 3.5 ± 0.8 and 4.05 ± 2.6 for the contrast-enhanced in-phase Dixon sequence. Pooled mean confidence scores and CNR were higher for contrast-enhanced in-phase Dixon than for the other sequences (all p < .001). CONCLUSION. Compared with clinical sequences, the contrast-enhanced in-phase Dixon sequence had higher sensitivity for detecting breast biopsy clips on MRI and higher reader confidence and CNR, without change in PPV. CLINICAL IMPACT. The contrast-enhanced in-phase Dixon sequence may help address a current challenge in clinical breast MRI interpretation.

Dental health status, dentist visiting, and dental insurance of Asian immigrants in Canada.

OBJECTIVE: This study examined the dental care utilization and self-preserved dental health of Asian immigrants relative to non-immigrants in Canada. Factors associated with oral health-related disparities between Asian immigrants and other Canadians were further examined. METHODS: We analyzed 37,935 Canadian residents aged 12 years and older in the Canadian Community Health Survey 2012-2014 microdata file. Factors (e.g., demographics, socioeconomic status, lifestyles, dental insurance coverage, and year of immigration) associated with disparities in dental health (e.g., self-perceived teeth health, dental symptoms during past one month, and teeth removed due to decay in past one year) and service utilization (e.g., visiting dentist within the last three years, visiting dentist more than once per year) between Asian immigrants and other Canadians were examined using multi-variable logistic regression models. RESULTS: The frequency of dental care utilization was significantly lower in Asian immigrants than their non-immigrant counterparts. Asian immigrants had lower self-perceived dental health, were less likely to be aware of recent dental symptoms, and more likely to report tooth extractions due to tooth decay. Low education (OR = 0.42), male gender(OR = 1.51), low household income(OR = 1.60), non-diabetes(OR = 1.87), no dental insurance(OR = 0.24), short immigration length (OR = 1.75) may discourage Asian immigrants from dental care utilization. Additionally, a perceived lack of necessity to dentist-visiting was a crucial factor accounting for the disparities in dental care uptake between Asian immigrants and non-immigrants. CONCLUSION: Asian immigrants showed lower dental care utilization and oral health than native-born Canadians.

A common polymorphism in the 5' UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy.

We show that a common polymorphic variant in the ERCC5 5' untranslated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of this protein and its ability to be synthesized following exposure to agents that cause bulky adduct DNA damage. Individuals that harbor uORF1 have a marked resistance to platinum-based agents, illustrated by the significantly reduced progression-free survival of pediatric ependymoma patients treated with such compounds. Importantly, inhibition of DNA-PKcs restores sensitivity to platinum-based compounds by preventing uORF1-dependent ERCC5 expression. Our data support a model in which a heritable 5' noncoding mRNA element influences individuals' responses to platinum-based chemotherapy.

Two decades of chronic kidney disease of unknown aetiology (CKDu) research: Existing evidence and persistent gaps from epidemiological studies in Sri Lanka.

BACKGROUND: Chronic Kidney Disease of unknown origin (CKDu) excludes known primary renal conditions or systemic disease (such as diabetes mellitus or hypertension). Prominence of CKDu has been noted for some decades in Sri Lanka, especially among men in particular rural areas, prompting many studies directed towards environmental causation. This article critically reviews relevant primary studies. METHODS: Articles for this literature review (n = 86) were found by searching Medline, Embase, Global Health and ProQuest databases over 2000-2020 utilizing a standard algorithm. Articles were critiqued according to criteria for diagnosis of CKDu, aetiological agents investigated, analytic methods employed and findings. RESULTS: Criteria for diagnosis of CKDu varied significantly, including pre-selection by proteinuria, eGFR and biopsy proven interstitial nephritis. Prevalence studies have been largely conducted in the North Central Province, with recent studies demonstrating the presence of CKDu in other regions. Aetiological factors investigated in primary studies included water source, use of agrochemicals, agricultural work, heavy metals, snake bites, ayurvedic medication, heat stress, infectious diseases and usage of tobacco and betel leaf. There is no conclusive evidence for any one aetiological agent despite consistent evidence of distal factors such as male sex, rural residence and farming. CONCLUSIONS: The current body of evidence for any aetiological agent as the cause of CKDu in Sri Lanka is limited. Further research with stronger study designs is necessary to increase knowledge of aetiology of CKDu in Sri Lanka to identify and eliminate exposure to possible causative agent(s) prior to concluding that the disease is multifactorial.

Plant-Based Milk Alternatives and Risk Factors for Kidney Stones and Chronic Kidney Disease.

OBJECTIVE: Patients with kidney stones are counseled to eat a diet low in animal protein, sodium, and oxalate and rich in fruits and vegetables, with a modest amount of calcium, usually from dairy products. Restriction of sodium, potassium, and oxalate may also be recommended in patients with chronic kidney disease. Recently, plant-based diets have gained popularity owing to health, environmental, and animal welfare considerations. Our objective was to compare concentrations of ingredients important for kidney stones and chronic kidney disease in popular brands of milk alternatives. DESIGN AND METHODS: Sodium, calcium, and potassium contents were obtained from nutrition labels. The oxalate content was measured by ion chromatography coupled with mass spectrometry. RESULTS: The calcium content is highest in macadamia followed by soy, almond, rice, and dairy milk; it is lowest in cashew, hazelnut, and coconut milk. Almond milk has the highest oxalate concentration, followed by cashew, hazelnut, and soy. Coconut and flax milk have undetectable oxalate levels; coconut milk also has comparatively low sodium, calcium, and potassium, while flax milk has the most sodium. Overall, oat milk has the most similar parameters to dairy milk (moderate calcium, potassium and sodium with low oxalate). Rice, macadamia, and soy milk also have similar parameters to dairy milk. CONCLUSION: As consumption of plant-based dairy substitutes increases, it is important for healthcare providers and patients with renal conditions to be aware of their nutritional composition. Oat, macadamia, rice, and soy milk compare favorably in terms of kidney stone risk factors with dairy milk, whereas almond and cashew milk have more potential stone risk factors. Coconut milk may be a favorable dairy substitute for patients with chronic kidney disease based on low potassium, sodium, and oxalate. Further study is warranted to determine the effect of plant-based milk alternatives on urine chemistry.

Sicyopterus garra Hora, 1925, a valid species of sicydiine goby from the Andaman Islands, India.

Sicyopterus garra Hora, 1925 from the insular streams of South Andaman Islands was synonymized with Sicyopterus microcephalus described from Java, South East Asia and has retained this taxonomic status since then. Recent collections of Sicyopterus from the type locality of S. garra and the examination of syntypes of this species revealed significant morphological and genetic differences from S. microcephalus and the other Sicyopterus species with papillae on upper lip. S. garra is thus a valid species and not a synonym of S. microcephalus. S. garra differs from S. microcephalus in having fewer lateral scales 53-59 vs. 57-68, fewer zigzag series (12-14 vs. 13-16), a longer caudal peduncle length (16-21 vs. 13-17), and by having a high percentage of divergence in COI gene (5.5%-5.8%).

Forty Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist.

Oxalobacter formigenes, a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by O. formigenes plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants. The role of O. formigenes in reducing the risk of calcium oxalate kidney stone disease and oxalate nephropathy in humans is less clear, in part due to difficulties in culturing this organism and the lack of studies which have utilized diets in which the oxalate content is controlled. Herein, we review the literature on the 40th anniversary of the discovery of O. formigenes, with a focus on its biology, its role in gut oxalate metabolism and calcium oxalate kidney stone disease, and potential areas of future research. Results from ongoing clinical trials utilizing O. formigenes in healthy volunteers and in patients with primary hyperoxaluria type 1 (PH1), a rare but severe form of calcium oxalate kidney stone disease, are also discussed. Information has been consolidated on O. formigenes strains and best practices to culture this bacterium, which should serve as a good resource for researchers.

Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide.

BACKGROUND: Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). METHODS: C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 µg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined. RESULTS: In comparison to mice challenged only with A. niger, addition of LPS (1 µg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies. CONCLUSIONS: In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Sequential assessment of bowel function and anorectal physiology after anterior resection for cancer: a prospective cohort study.

AIM: The aim of this study was to investigate changes in bowel function and anorectal physiology (ARP) after anterior resection for colorectal cancer. METHOD: Patients were recruited from November 2006 to September 2008. Cleveland Clinic Incontinence (CCI) scores and stool frequency were determined by patient questionnaires before surgery (t0 ) and at three (t3 ), six (t6 ), nine (t9 ) and 12 (t12 ) months after restoration of intestinal continuity. ARP measurements were recorded at T0 , T3 and T12 . Endoanal ultrasound was performed at T0 and T12 . RESULTS: Eighty-nine patients were included. CCI score increased postoperatively then normalized, whereas stool frequency did not change. Patients who had neoadjuvant radiotherapy or a lower anastomosis had increased incontinence and stool frequency in the postoperative period, whereas those with defunctioning stomas or open surgery had increased stool frequency alone. Maximum resting pressure, volume at first urge and maximum rectal tolerance were reduced throughout the postoperative period. Radiotherapy, lower anastomosis and defunctioning stoma (but not operative approach) altered manometric parameters postoperatively. Maximum rectal tolerance correlated with incontinence and first urge with stool frequency. The length of the anterior internal anal sphincter decreased postoperatively. CONCLUSIONS: Incontinence recovers in the first year after anterior resection. Radiotherapy, lower anastomosis, defunctioning stoma and open surgery have a negative influence on bowel function. ARP may be useful if bowel dysfunction persists beyond 12 months.

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

TAp73 contributes to the oxidative stress response by regulating protein synthesis.

TAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellular metabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis.

Adolescent Gender and Age Differences in Religiously and Spiritually Motivated Types of Forgiveness and the Relationship to Depressive Symptoms.

We examined three religiously/spiritually motivated forgiveness types, forgiveness of self, others, and divine forgiveness, and their association with depressive symptoms, across adolescent gender and age groups. Twelve- to 18-year-old patients arriving for primary care completed a 3-item Forgiveness measure and the Beck Depression Inventory-II. Girls reported a higher tendency to forgive others compared to boys, and self-forgiveness and divine forgiveness tended to decline with age in both genders. We found no significant associations between forgiveness and depression among boys. Among girls, higher self-forgiveness was associated with fewer depressive symptoms. Forgiveness of others was associated with less depression only among 17-18-year-old girls. Divine forgiveness showed no association with depression in either gender. Forgiveness of self and others appears to be protective factors for depression among adolescent girls.

Future treatments for hyperoxaluria.

PURPOSE OF REVIEW: The review of potential therapies in the treatment of hyperoxaluria is timely, given the current excitement with clinical trials and the mounting evidence of the importance of oxalate in both kidney stone and chronic kidney disease. RECENT FINDINGS: Given the significant contribution of both endogenous and dietary oxalate to urinary oxalate excretions, it is not surprising therapeutic targets are being studied in both pathways. This article covers the existing data on endogenous and dietary oxalate and the current targets in these pathways. SUMMARY: In the near future, there will likely be therapies targeting both endogenous and dietary oxalate, especially in subsets of kidney stone formers.

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells.

Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.