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.

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.

BACKGROUND: CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy. METHODS: We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging. RESULTS: Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice. CONCLUSIONS: Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.

Mesoscale networks and corresponding transitions from self-assembly of block copolymers.

A series of cubic network phases was obtained from the self-assembly of a single-composition lamellae (L)-forming block copolymer (BCP) polystyrene-block-polydimethylsiloxane (PS-b-PDMS) through solution casting using a PS-selective solvent. An unusual network phase in diblock copolymers, double-primitive phase (DP) with space group of [Formula: see text], can be observed. With the reduction of solvent evaporation rate for solution casting, a double-diamond phase (DD) with space group of [Formula: see text] can be formed. By taking advantage of thermal annealing, order-order transitions from the DP and DD phases to a double-gyroid phase (DG) with space group of [Formula: see text] can be identified. The order-order transitions from DP (hexapod network) to DD (tetrapod network), and finally to DG (trigonal planar network) are attributed to the reduction of the degree of packing frustration within the junction (node), different from the predicted Bonnet transformation from DD to DG, and finally to DP based on enthalpic consideration only. This discovery suggests a new methodology to acquire various network phases from a simple diblock system by kinetically controlling self-assembling process.

A global Slc7a7 knockout mouse model demonstrates characteristic phenotypes of human lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons 3 and 4. Perinatal lethality was observed in Slc7a7Lbu/Lbu and Slc7a7Bay/Bay mice on the C57BL/6 and C57BL/6NJ inbred genetic backgrounds, respectively. We noted improved survival of Slc7a7Lbu/Lbu mice on the 129 Sv/Ev × C57BL/6 F2 background, but postnatal growth failure occurred. Consistent with human LPI, these Slc7a7Lbu/Lbu mice exhibited reduced plasma and increased urinary concentrations of the cationic amino acids. Histopathological assessment revealed loss of brush border and lipid vacuolation in the renal cortex of Slc7a7Lbu/Lbu mice, which combined with aminoaciduria suggests proximal tubular dysfunction. Micro-computed tomography of L4 vertebrae and skeletal radiographs showed delayed skeletal development and suggested decreased mineralization in Slc7a7Lbu/Lbu mice, respectively. In addition to delayed skeletal development and delayed development in the kidneys, the lungs and liver were observed based on histopathological assessment. Overall, our Slc7a7Lbu/Lbu mouse model on the F2 mixed background recapitulates multiple human LPI phenotypes and may be useful for future studies of LPI pathology.

Nanonetwork Thermosets from Templated Polymerization for Enhanced Energy Dissipation.

Herein, we aim to develop a facile method for the fabrication of mechanical metamaterials from templated polymerization of thermosets including phenolic and epoxy resins using self-assembled block copolymer, polystyrene-polydimethylsiloxane with tripod network (gyroid), and tetrapod network (diamond) structures, as templates. Nanoindentation studies on the nanonetwork thermosets fabricated reveal enhanced energy dissipation from intrinsic brittle thermosets due to the deliberate structuring; the calculated energy dissipation for gyroid phenolic resins is 0.23 nJ whereas the one with diamond structure gives a value of 0.33 nJ. Consistently, the gyroid-structured epoxy gives a high energy dissipation value of 0.57 nJ, and the one with diamond structure could reach 0.78 nJ. These enhanced properties are attributed to the isotropic periodicity of the nanonetwork texture with plastic deformation, and the higher number of struts in the tetrapod diamond network in contrast to tripod gyroid, as confirmed by the finite element analysis.

Self-Assembly of Low-Molecular-Weight Asymmetric Linear Triblock Terpolymers: How Low Can We Go?

The synthesis of two (2) novel triblock terpolymers of the ABC type and one (1) of the BAC type, where A, B and C are chemically different segments, such as polystyrene (PS), poly(butadiene) (PB1,4) and poly(dimethylsiloxane) (PDMS), is reported; moreover, their corresponding molecular and bulk characterizations were performed. Very low dimensions are evident from the characterization in bulk from transmission electron microscopy studies, verified by small-angle X-ray data, since sub-16 nm domains are evident in all three cases. The self-assembly results justify the assumptions that the high Flory-Huggins parameter, χ, even in low molecular weights, leads to significantly well-ordered structures, despite the complexity of the systems studied. Furthermore, it is the first time that a structure/properties relationship was studied for such systems in bulk, potentially leading to prominent applications in nanotechnology and nanopatterning, for as low as sub-10 nm thin-film manipulations.

Telomere shortening triggers a feedback loop to enhance end protection.

Telomere homeostasis is controlled by both telomerase machinery and end protection. Telomere shortening induces DNA damage sensing kinases ATM/ATR for telomerase recruitment. Yet, whether telomere shortening also governs end protection is poorly understood. Here we discover that yeast ATM/ATR controls end protection. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this regulation is stimulated by DNA damage and telomere shortening. Compromised Rap1 phosphorylation hampers the interaction between Rap1 and its interacting partner Rif1, which thereby disturbs the end protection. As expected, reduction of Rap1-Rif1 association impairs telomere length regulation and increases telomere-telomere recombination. These results indicate that ATM/ATR DNA damage checkpoint signal contributes to telomere protection by strengthening the Rap1-Rif1 interaction at short telomeres, and the checkpoint signal oversees both telomerase recruitment and end capping pathways to maintain telomere homeostasis.

Epidermoid cyst of the testis: An atypical sonographic appearance.

Epidermoid cysts are rare. They represent the most common benign tumor of the testis. The sonographic appearances of testicular epidermoid cysts usually include avascular, mostly lamellated, heterogeneous internal echotexture, with hypoechoic and hyperechoic concentric rings, accounting for the typical onion-ring appearance. On MRI, epidermoid cysts show a low-signal-intensity center, with internal concentric rings of alternating high- and low-signal intensity on T2-weighted images, which correlates with the onion-ring appearance. We report a patient with testicular epidermoid cyst with atypical ultrasound and MRI appearances that led to the erroneous initial diagnosis of "burned-out" tumor. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:448-451, 2016.

Percutaneous cryoablation for inoperable malignant lung tumors: midterm results.

OBJECTIVE: To retrospectively analyze the efficacy and short- to mid-term survival rate of cryoablation for malignant lung tumors. METHODS: Percutaneous CT-guided cryoablation for 45 malignant lung tumors in 26 patients during 41 sessions from 2009 to 2013 were performed. Follow up CT-scan were used to determine local tumor progression. Survival rate, local tumor control rate and associated risk factors were analyzed. RESULTS: The immediate during and short-term complications with CTCAE grade 2 or upper include pneumothorax (15%), pleural effusion (20%), pulmonary hemorrhage (24%), pneumonitis (15%), hemothorax (15%), hemoptysis (10%), pain (20%), bronchopleural fistula (n=1), and empyema (n=2). Life-threatening bleeding or hemodynamic instability was not observed. There was no procedural-related mortality. Overall survival rate of 1, 2, 3 years are 96%, 88%, 88%. For curative intent, local tumor control (LTC) rate of 1, 2, 3 years are 75%, 72%, 72%. CONCLUSION: Cryoablation for malignant lung tumors is effective and feasible in local control of tumor growth, with good short- to mid-term survival rate, as an alternative option for inoperable patients.

The immunologically active oligosaccharides isolated from wheatgrass modulate monocytes via Toll-like receptor-2 signaling.

Wheatgrass is one of the most widely used health foods, but its functional components and mechanisms remain unexplored. Herein, wheatgrass-derived oligosaccharides (WG-PS3) were isolated and found to induce CD69 and Th1 cytokine expression in human peripheral blood mononuclear cells. In particular, WG-PS3 directly activated the purified monocytes by inducing the expression of CD69, CD80, CD86, IL-12, and TNF-α but affected NK and T cells only in the presence of monocytes. After further purification and structural analysis, maltoheptaose was identified from WG-PS3 as an immunomodulator. Maltoheptaose activated monocytes via Toll-like receptor 2 (TLR-2) signaling, as discovered by pretreatment of blocking antibodies against Toll-like receptors (TLRs) and also determined by click chemistry. This study is the first to reveal the immunostimulatory component of wheatgrass with well defined molecular structures and mechanisms.

Evaluation of the extent of ketamine-induced uropathy: the role of CT urography.

BACKGROUND: With growing ketamine abuse, ketamine-induced uropathy (KIU) has become more prevalent in recent years. This research evaluates the presence, distribution and extent of KIU in the upper and lower urinary tracts by retrospectively reviewing CT urography (CTU) images. METHODS: Patients diagnosed with KIU who underwent CT scanning from 1 January 2006 to 31 December 2011 were recruited. The CT protocols included three-phase CTU in six patients, split-bolus CTU in 17, two-phase CT in one and unenhanced CT in three. The CT images were retrospectively reviewed by two radiologists. RESULTS: A total of 27 patients participated in this study. The common CT findings included diffuse bladder wall thickening (88.9%), small bladder volume (66.7%) and perivesical inflammation (44.4%). Twelve patients (44.4%) were diagnosed with hydronephrosis, including three patients with unilateral hydronephrosis and nine with bilateral hydronephrosis. Of these patients, nine had ureteral wall thickening (33.3%) and two (7.4%) had ureterovesical junction involvement (ie, they had hydronephrosis but no ureteral wall thickening). One patient had a ureteral obstruction because of a ureter stone. The correlation between upper urinary tract involvement and grading of the interstitial cystitis was statistically non-significant (p=0.33). Four patients (14.8%) had a vesicovaginal fistula which could be detected in the excretory phase only. CONCLUSIONS: Upper urinary tract involvement is common in patients with KIU. CTU might aid evaluation of the extent of KIU and prompt adequate management.

Fistula component of cerebral arteriovenous malformations: morphologic change after stereotactic radiosurgery and outcome of embolisation.

BACKGROUND: The angioarchitecture of arteriovenous fistulas (AVFs) of cerebral arteriovenous malformation (CAVM) after stereotactic radiosurgery (SRS) remain unclear. The purpose of this study is to report the angiographic change of AVF components of CAVMs after SRS and outcomes of endovascular embolisation. METHODS: From 2002 to 2012, a total of 523 CAVMs had been treated primarily by SRS with more than 3-year latency. Among these databases, there were 19 patients with 21 AVFs undergoing embolization after SRS. We retrospectively analyzed the angioarchitecture of the CAVM to identify AVFs, morphologic change and outcomes of AVFs after SRS and embolisation. RESULTS: Eight AVFs were in the periphery of CAVMs, the other 13 were in a central location. Eighteen of 21 AVFs remained constant in morphology after SRS, while three feeders of AVFs were associated with radiation arteritis. The causes of failure to identify AVFs before SRS were overlooked (n = 7) or there was superimposition with feeders, nidus and/or venous drains of CAVMs (n = 14). Total fistula occlusion was achieved in all 21 AVFs; residual CAVMs was totally obliterated by embolisation and/or additional SRS in 12 patients. One patient had a small procedure-related intracerebral hemorrhage. Mean follow-up period was 26 months. CONCLUSIONS: Early detection of AVF components of CAVMs prior to SRS may be difficult, particularly those in a central location. However, most AVFs became evident and showed consistency in angiographic morphology after obliteration of the majority nidus parts of CAVMs. Endovascular embolisation is effective in managing these AVF components.

Thyroid metastasis from breast cancer presenting with diffuse microcalcifications on sonography: a case report.

Microcalcifications are frequently associated with papillary thyroid cancers. Metastatic nodules from extrathyroid malignancies may mimic primary thyroid neoplasm on sonography, but do not present with microcalcifications. We report the case of a 45-year-old woman with a history of invasive ductal carcinomas of bilateral breasts, status post surgery and neoadjuvant chemotherapy. Four years after surgery, thyroid sonography revealed diffuse microcalcifications without nodular component. Core needle biopsy confirmed thyroid metastasis from primary breast cancer.

Frank-Kasper-like network phase from self-assembly of high-χ star-block copolymers.

By taking advantage of the effects of solvent selectivity and topology on high-χ block copolymer (BCP) for self-assembly, network phases with high packing frustration can be formed in self-assembled polystyrene-b-polydimethylsiloxane (PS-b-PDMS). Apart from gyroid with trigonal structure and diamond with tetrahedral structure, a peculiar network phase with space group of [Formula: see text] (Frank-Kasper structure) can be found in six-arm star-block PS-b-PDMS as evidenced by small-angle x-ray scattering. Electron tomography results reveal the network phase with alternating connection of three and four struts. The observed phase behaviors suggest that the network formation is built from the bisectors of dispersive spheres in the Frank-Kasper phase, instead of building connections among them, and thus decipher the origins of complex phase formation due to the adaptive character of malleable mesoatoms.

Topology Effect on Order-Disorder Transition of High-χ Block Copolymers.

This work aims to systematically examine the topology effect on the self-assembly of block copolymers. Compositionally, symmetric polystyrene-block-polydimethylsiloxane block copolymers (BCPs) with different chain topologies (diblock, three-arm star-block, and four-arm star-block) and various molecular weights are synthesized. These purposely designed block copolymers are used as a model system to investigate the topology effect on order-to-disorder transition temperature (T ODT) by temperature-resolved small-angle X-ray scattering experiments. An increase of the T ODT is observed when the arm number of BCPs with equivalent arm length (i.e., molecular weight) is increased from one to four. Based on the random-phase approximation (RPA), Flory-Huggins interaction parameter (χ) is determined from the regression of the measured T ODT. The observation by differential scanning calorimetry also demonstrates the shifting of the endothermic peak from the order-to-disorder transition of star-blocks to the higher temperature region, consistent with the scattering experiments and the RPA prediction.

MAGE-A4-Responsive Plasma Cells Promote Non-Small Cell Lung Cancer.

Adaptive immunity is critical to eliminate malignant cells, while multiple tumor-intrinsic factors can alter this protective function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in several solid tumors and correlates with poor survival in non-small cell lung cancer (NSCLC), but its role in altering antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN , a tumor suppressor, in human NSCLC. Here we show that constitutive expression of human MAGE-A4 combined with the loss of Pten in mouse airway epithelial cells results in metastatic adenocarcinoma enriched in CD138 + CXCR4 + plasma cells, predominantly expressing IgA. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138 + IgA + plasma cell density surrounding tumors. The abrogation of MAGE-A4-responsive plasma cells (MARPs) decreased tumor burden, increased T cell infiltration and activation, and reduced CD163 + CD206 + macrophages in mouse lungs. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA + MARPs in the lungs.

How far can the radiation dose be lowered in head CT with iterative reconstruction? Analysis of imaging quality and diagnostic accuracy.

OBJECTIVE: To evaluate the imaging quality of head CT at lowered radiation dose by combining filtered back projection (FBP) and iterative reconstruction (IR) algorithms. METHODS: Experimental group A (n = 66) underwent CT with 43 % tube current reduction, and group B (n = 58) received an equivalent reduced dose by lowering the tube voltage. An age- and sex-matched control group (n = 72) receiving the conventional radiation dose was retrospectively collected. Imaging for the control group was reconstructed by FBP only, while images for groups A and B were reconstructed by FBP and IR. The signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs), sharpness, number of infarcts and severity of subcortical arteriosclerotic encephalopathy (SAE) were compared to assess imaging quality and diagnostic accuracy. RESULTS: There were no significant differences in SNRs and CNRs between group A and the control group. There were significantly decreased SNRs and increased CNRs in group B. Image sharpness decreased in both groups. Correlations between detected infarcts and severity of SAE across FBP and IR were high (r = 0.73-0.93). Head diameter was the only significant factor inversely correlated with infratentorial imaging quality. CONCLUSION: Head CT with 43 % reduced tube current reconstructed by IR provides diagnostic imaging quality for outpatient management. KEY POINTS: • Cranial CT using iterative reconstruction provides diagnostic images with 43 % mAs reduction. • Blurring of infratentorial images becomes evident using low-radiation head CT. • Head diameter was inversely correlated with imaging quality in the infratentorium. • Lowering tube kilovoltage requires a higher radiation dose to maintain image quality.

Prediction of lymphovascular invasion in rectal cancer by preoperative CT.

OBJECTIVE: The purpose of this study was to investigate whether the diameter of superior hemorrhoidal vein on preoperative CT can predict the presence of lymphovascular invasion (LVI). SUBJECTS AND METHODS: This study recruited 102 patients with treatment-naive rectal cancers. The diameters of superior hemorrhoidal vein and inferior mesenteric vein (IMV) on pretreatment CT and postoperative pathologic reports were reviewed. Univariate analysis and receiver operating characteristic curve analysis were applied to determine the correlation between clinical factors and pathologic features and the diameters of superior hemorrhoidal vein and IMV. RESULTS: The diameter of superior hemorrhoidal vein was significantly higher in patients with LVI than in those without (mean diameter, 44 vs 30 mm, respectively; p < 0.001) and was significantly higher in patients with distant metastases than in those without (p = 0.044). There was no significant difference between IMV diameter in LVI and that in distant metastasis (p = 0.521). CONCLUSION: Patients having rectal cancers with LVI showed a significantly increased mean superior hemorrhoidal vein diameter at presentation, which could be identified with pretreatment CT and help to direct the application of neoadjuvant treatment strategies.

Alveolar macrophages in lung cancer: opportunities challenges.

Alveolar macrophages (AMs) are critical components of the innate defense mechanism in the lung. Nestled tightly within the alveoli, AMs, derived from the yolk-sac or bone marrow, can phagocytose foreign particles, defend the host against pathogens, recycle surfactant, and promptly respond to inhaled noxious stimuli. The behavior of AMs is tightly dependent on the environmental cues whereby infection, chronic inflammation, and associated metabolic changes can repolarize their effector functions in the lungs. Several factors within the tumor microenvironment can re-educate AMs, resulting in tumor growth, and reducing immune checkpoint inhibitors (ICIs) efficacy in patients treated for non-small cell lung cancer (NSCLC). The plasticity of AMs and their critical function in altering tumor responses to ICIs make them a desirable target in lung cancer treatment. New strategies have been developed to target AMs in solid tumors reprograming their suppressive function and boosting the efficacy of ICIs. Here, we review the phenotypic and functional changes in AMs in response to sterile inflammation and in NSCLC that could be critical in tumor growth and metastasis. Opportunities in altering AMs' function include harnessing their potential function in trained immunity, a concept borrowed from memory response to infections, which could be explored therapeutically in managing lung cancer treatment.

Corrigendum: Alveolar macrophages in lung cancer: opportunities and challenges.

[This corrects the article DOI: 10.3389/fimmu.2023.1268939.].