MICA

Mica is widely applied in cosmetics, construction, automotive, electronics, defense, and medical industries, particularly important in cosmetics as an ingredient in foundations, eyeshadows, lipsticks, and nail polishes for its pearlescent and shimmering effects. To evaluate the suitability of mica minerals from Bangladeshi river sands for cosmetic applications by investigating their chemical composition, heavy metal content, potential for skin irritation, and antimicrobial activity. The chemical composition, crystallographic structure, and heavy metal content of mica samples were analyzed using X-ray fluorescence, X-ray diffraction, and Atomic Absorption Spectroscopy. Non-carcinogenic and carcinogenic risks were evaluated using USEPA models (ADD, HQ, HI, LADD, ILTCR). Sensory evaluation was performed by 10 trained panelists, while primary skin irritation was tested on albino rabbits. Antimicrobial activity against bacterial and fungal strains was assessed using agar well diffusion and broth microdilution assays. Muscovite contained high Al 2 O 3 (30.46%) and SiO 2 (49.29%), whereas biotite and phlogopite were enriched in Fe 2 O 3 (43%) and MgO, supporting shimmer, color, and UV-protective properties. XRD confirmed high crystallinity and purity. Heavy metals were within safe dermal and inhalation exposure limits. Sensory evaluation showed a silky texture, strong adhesion, and a luminous finish. All samples were non-irritant (PII = 0.00). Biotite and phlogopite exhibited moderate antibacterial activity against Staphylococcus aureus, Salmonella typhi, and Bacillus megaterium, but no antifungal effects. Muscovite, biotite, and phlogopite mica exhibit low heavy metal content, non-irritant and non-carcinogenic behavior, moderate antibacterial activity, and favorable sensory properties, highlighting their potential as safe, effective, and multifunctional ingredients for cosmetic applications.

Macrophages and natural killer (NK) cells are innate immune components proven to be either pathogenic, protective, or both in autoimmune disorders. Nonetheless, the function of macrophages in the pathogenesis of pemphigus vulgaris (PV), an autoimmune skin disorder, is lacking. We aimed to investigate macrophages and their crosstalk with NK cells in PV, with a particular focus on how these interactions influence their functionalities. Flow cytometry and immunofluorescence was utilised to assess macrophage profile along with expression of receptors on NK cells and macrophages. In-vitro macrophage skewing, and NK-macrophage interactions (including F-actin accumulation, activation markers, cytotoxicity, IFNγ and perforin secretion, NOS2, CD86, CD206 expression, phagocytic activity, and arginase activity were examined. NKG2D blocking and related assays were performed to elucidate its role in crosstalk. Expression of NKG2D on NK cells and MICA/B on macrophages was upregulated. CD56 + NK cells and CD68 + macrophages co-localized in lesions. A significant increase in macrophages in both the periphery and lesional skin was observed. Both M1 and M2 macrophages were upregulated in blood, whereas M1 increased and M2 decreased in skin lesions. Macrophages displayed skewing toward an M2 phenotype in vitro . Upon co-culturing, F-actin accumulation increased during interaction. The interaction led to increased activation, cytotoxicity, and IFNγ and perforin secretion in NK cells when M1 stimulation and Dsg3 autoantigen were given. In macrophages, increased expression of iNOS and CD86 and higher phagocytic activity were noted, whereas arginase activity and expression along with CD206 were downregulated. NKG2D blockade on NK cells resulted in partial but significant decrease in NK cells activity including activation, perforin, cytotoxicity and IFNγ release. The reduction were prominent in M1 state. M1 like markers NOS2 and CD86 were reduced and arginase activity non significantly improved under M2 state post blockade. This study helped in comprehending functionally active NK- macrophage axis, where NK cells promote pro inflammatory M1 state, and dysregulate M2 macrophage functionality. NKG2D blockade resulted in partial reversal suggesting its critical, though not elusive, contribution indicating multifactorial crosstalk mechanism. Targeting NK cell activity or promoting M2 functionality could potentially lead to improvements in disease pathogenesis.

Intestinal barrier (IB) dysfunction contributes to metabolic endotoxemia and associated diseases. Specifically, intestinal inflammation upregulates natural killer cell receptor 2D ligands (NKG2DLs) in intestinal epithelial cells (IECs), which triggers excessive immune responses and exacerbates IB injury. The prebiotic xylooligosaccharides (XOS) hold promise for ameliorating such injury by regulating NKG2DLs, yet the underlying mechanisms remain elusive. This study aimed to investigate the efficacy of XOS in improving IB injury and explore its role and molecular mechanisms in mitigating IB damage via NKG2DLs modulation. IB injury models were established in differentiated Caco-2 and MODE-K cells by treatment with 20 ng/mL tumor necrosis factor-α (TNF-α), followed by XOS intervention at concentrations of 50, 100, 150, and 200 μg/mL. Tight junction (TJ) proteins (ZO-1, Occludin) were detected using Western blotting (WB) and immunofluorescence, while barrier permeability was evaluated via transepithelial electrical resistance (TEER), phenol red permeability assay, and transmission electron microscopy (TEM). Additionally, the RhoA/ROCK/MLCK signaling pathway, apoptosis-related factors (Caspase-3, Bcl-2), and the expression of human NKG2DLs (MICA, MICB, ULBP-1) and murine NKG2DLs (Rae-1ε, H60, MULT-1) were analyzed by quantitative real-time PCR (qRT-PCR) or WB, and apoptotic cells were labeled using the TUNEL assay. To further investigate the involvement of NKG2DLs in the protective effect of XOS, RNA interference (RNAi) was performed to knock down NKG2DLs in Caco-2 and MODE-K cells. This conserved mechanism relies on Argonaute (Ago) family proteins that associate with small RNAs to mediate sequence-specific degradation of complementary target RNAs. Subsequently, both cell lines were treated with TNF-α and XOS, and the expression levels of NKG2DLs, ZO-1, and Occludin were determined by qRT-PCR or WB. Compared with TNF-α treatment alone, XOS at the concentrations used in this study significantly attenuated the downregulation and mislocalization of ZO-1 and Occludin in both Caco-2 and MODE-K cells (p < 0.05), increased TEER in Caco-2 cell (p < 0.05), reduced phenol red permeability (p < 0.05), and improved the ultrastructure of TJs and the integrity of microvilli. XOS at the tested concentrations also inhibited the activation of the RhoA/ROCK/MLCK signaling pathway (p < 0.05), suppressed Caspase-3 (p < 0.05) and the number of TUNEL-positive apoptotic cells, and alleviated TNF-α-induced overexpression of both human and murine NKG2DLs (p < 0.05). Notably, RNAi-mediated knockdown of Rae-1ε or H60 in MODE-K cells abrogated the XOS-induced restoration of ZO-1 and Occludin expression under TNF-α challenge. Collectively, under the experimental conditions of this study, XOS mitigate IB injury by inhibiting apoptosis, RhoA/ROCK/MLCK signaling and NKG2DLs in IECs.

Accurate high-resolution genotyping of HLA genes for hematopoietic cell transplant (HCT) recipients provides critical information for matching and donor selection. We describe unusual family typing for a pediatric transplant candidate which revealed that the patient and mother did not share a common HLA-B allele, although all other class I and class II HLA alleles inherited on the maternal haplotype were detected. Copy number analysis of hybrid capture next generation sequencing data showed 2 copies each of HLA-A, C, MICA, MICB, DRB1, DQA1, DQB1, DPA1, and DPB1, but revealed HLA-B allele hemizygosity in both the patient and mother. Binary alignment mapping to the HLA-B consensus sequence showed a drop in coverage in the 5' untranslated region, approximately 300 base pairs upstream of exon 1. Germline whole genome sequencing performed on DNA from a skin punch biopsy from the patient confirmed an ∼ 85 kb deletion spanning the entire HLA-B gene locus. This case highlights the importance of family/haplotype studies and copy number analysis in workup for HCT and suggests that HLA locus deletions, although rare, may be underappreciated. Furthermore, haplotypes with deleted alleles may not be accurately reflected in population frequencies and donor search algorithms.

The study investigated whether selected genetic polymorphisms are linked to adverse reactions after Pfizer-BioNTech BNT162b2 vaccination. A prospective observational cohort of 354 hospital employees who received two doses of BNT162b2 vaccination was analysed. Adverse effects were recorded after each dose using standardized surveys and graded by severity. Genotyping was performed for variants in ACE2, TMPRSS2, HLA-E, IFNG, MICA, NKG2A, NKG2C, TLR4, and TLR7. Statistical analyses included Fisher's exact test and proportional odds logistic regression with Bonferroni correction. The KLRC2/NKG2C del/del genotype was associated with higher frequencies of selected reactions. After the first dose , skin redness occurred in 100% (5/6) of del/del carriers versus 32% (35/110) of wt/del and 31% (72/229) of wt/wt (p = 0.0105 and p = 0.0129, respectively); swelling in 100% (5/5) versus 33% (36/109) and 35% (8/229) (p = 0.0153; p = 0.0177); and headache in 100% (5/5) versus 26% (29/110) and 36% (82/229) (p = 0.0054; p = 0.0198). After dose 2, diarrhea occurred in 40% (2/5) of del/del carriers versus 2% (2/110) of wt/del and 2% (4/227) of wt/wt (OR 34.85, 95% CI 3.35-300.59; p = 0.0264). Severity was associated with NKG2C del/del (dose 1 OR 0.16, 95% CI 0.04-0.71; p = 0.0371; dose 2 OR 0.07, 0.01-0.59; p = 0.0323) and showed a borderline association for TLR4 rs4986790 AG versus AA (OR 0.38, 0.16-0.87; p = 0.0508). No significant associations were observed for the remaining variants. Genetic variability in KLRC2/NKG2C and TLR4 may influence the risk and severity of adverse events following mRNA COVID-19 vaccination, supporting a role for host genetics in vaccine reactogenicity.

Major histocompatibility complex class I chain-related gene A (MICA) is a non-classical MHC-I molecule essential for immune surveillance, yet its intracellular maturation remains poorly understood. We show that MICA is predominantly retained intracellularly in melanoma cells and colocalizes with the endoplasmic reticulum chaperone calreticulin (CRT). Notably, MICA also colocalizes with CRT in healthy skin. Immunoprecipitation assays reveal that CRT preferentially associates with a low-molecular-weight form of MICA. Recombinant protein assays and in silico analyses support direct interaction between CRT and non-glycosylated MICA, but not with fully glycosylated eukaryotic MICA. These findings identify CRT-dependent retention of MICA as a physiological checkpoint that may be dysregulated in melanoma to promote immune evasion.

Although regulatory T cells (Tregs) control autoimmune diseases, the role of evolutionarily older Foxp3 + γδTregs is much less understood. We noted that both lesional and nonlesional skin of patients with alopecia areata (AA), one of the most common autoimmune diseases, contains significantly more Vδ1 + /Foxp3 + γδTregs than healthy scalp skin. Therefore, we investigated how human γδTregs impact experimentally induced AA in human scalp skin xenotransplants on SCID/beige mice in vivo. Peripheral autologous human Vδ2 + /Foxp3 + γδTregs were expanded and preactivated in vitro and then injected intradermally into scalp skin xenografts before or after induction of AA. These γδTregs reduced the perifollicular lymphocytic infiltrate, restored hair follicle immune privilege, prevented AA onset, and promoted hair regrowth in established AA lesions. In parallel, γδTregs cocultured with organ-cultured, MICA/B-overexpressing human scalp hair follicles suppressed pathogenic CD8 + /NKG2D + T-cell activity and counteracted all AA hallmarks ex vivo-including hair follicle immune privilege collapse, hair follicle dystrophy, and premature IFNγ-induced catagen-through IL-10 and TGF-β1 secretion, contact-dependent inhibition, and adenosine generation through CD39/CD73. These findings in a model human autoimmune disease introduce human γδTregs as clinically important regulatory lymphocytes and invite the use of autologous peripheral Vδ2 + /Foxp3 + γδTregs as a cell-based therapy for AA and possibly other CD8 + T cell-dependent autoimmune diseases characterized by immune privilege collapse.

Fibril-forming tropocollagens (TCs) play an essential role in tissue biomechanics. They are ubiquitous in mammals and other animal tissues, where they provide passive mechanical functions. While molecular dynamics simulations have targeted the mechanics of individual TCs, experimental data on their tensile mechanical properties remain scarce. As a consequence, the link between the unique triple-helix structure of the collagen molecule and macro-mechanical properties of collagenous tissues is not well understood. To close this gap, we have investigated isolated TCs grafted on the tip of atomic force microscopy (AFM) probes as well as adsorbed TC films using a surface force apparatus (SFA). AFM force spectroscopy showed that an individual TC can be stretched without failing to a contour length of up to 900 nm─nearly three times its native length─over thousands of stretching cycles. The molecule was retracted from a strongly adhering mica surface by pulling on one of the α-chains, forcing the triple-helix to unravel. During this process, the α-chains slipped progressively, irreversibly, and almost entirely past each other before being caught by strong physical interactions between overlapping chain ends. SFA measurements showed that strong electrostatic interactions bind TC to mica and prevent TC aggregation, supporting the AFM results. These findings indicate that a controlled slippage mechanism underpins the exceptional toughness of TCs, collagen fibrils, and collagen-rich tissues such as tendons and skin.

Treatment-free survival (TFS; time spent free of systemic anticancer therapy) is increasingly used to support traditional endpoints. TFS was previously evaluated in patients with advanced melanoma treated with nivolumab plus ipilimumab. This analysis compared TFS for nivolumab plus relatlimab and nivolumab monotherapy in patients with advanced melanoma. Data were from 714 patients in the phase 2/3 RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). TFS was defined as the difference in restricted mean event times between the Kaplan-Meier curves for time to protocol therapy cessation and time to subsequent systemic anticancer therapy initiation or death. TFS was further partitioned into time with and time without grade ≥3 treatment-related adverse events (TRAEs). Subgroup analysis based on tumor BRAF mutational status and tumor programmed death ligand 1 (PD-L1) expression level was conducted. Between-treatment group differences were calculated with bootstrapped 95% CIs. At 48 months from randomization, Kaplan-Meier estimates of overall survival were 52% and 43% for patients in the nivolumab plus relatlimab and nivolumab groups, respectively; 38% and 33% of patients in these respective groups were free of subsequent systemic therapy. The 48-month mean TFS was 2.9 months (95% CI 1.0 to 4.9) longer with nivolumab plus relatlimab than with nivolumab (9.7 vs 6.8 months, respectively). Mean TFS represented 20% and 14% of the 48-month period after initiating nivolumab plus relatlimab and nivolumab, respectively. Considering only time without grade ≥3 TRAEs, the 48-month mean TFS was 2.6 months (95% CI 0.8 to 4.5) longer with nivolumab plus relatlimab than with nivolumab (9.1 vs 6.5 months, respectively). The 48-month mean total TFS was consistently longer with nivolumab plus relatlimab than with nivolumab in the BRAF mutant (9.4 vs 6.5 months), BRAF wild-type (9.9 vs 6.9 months), PD-L1 ≥1% (12.3 vs 7.7 months), and PD-L1<1% (7.9 vs 6.2 months) subgroups. This analysis demonstrated TFS benefit during the 48 months since initiating nivolumab plus relatlimab compared with nivolumab alone in patients with advanced melanoma. A direct comparison between nivolumab plus relatlimab and nivolumab plus ipilimumab is needed to determine the differences between the regimens in TFS and those in traditional endpoints.

Background : Worldwide, the number of cases of parasitic diseases has been increasing; however, available treatments have variable adverse effects and low efficacy, mainly in Neglected Tropical Diseases such as Chagas disease and Leishmaniasis. Therefore, the development of new and more effective antiparasitic drugs is important. Natural products are the source of secondary metabolites with different biological activities, such as antibacterial, anticancer, anti-inflammatory, and antiparasitic. Objectives : In this work, secondary metabolites (phenols and terpenes) from natural products were selected to be evaluated against the epimastigotes of NINOA and A1 strains of Trypanosoma cruzi and the promastigotes of M379 strain and FCQEPS native isolate of Leishmania mexicana . Additionally, their cytotoxicity and selectivity index were determined. Methods : Eighteen secondary metabolites were evaluated in vitro against T. cruzi epimastigotes and L. mexicana promastigotes; additionally, their cytotoxicity on the J774.2 macrophage cell line was determined. Results : The compounds l-(-)-menthol (14, IC 50 = 24.52 µM) and β-citronellol (11, IC 50 = 21.54 µM) had higher trypanocidal activity than the reference drug (benznidazole) against NINOA and A1 strains of T. cruzi , respectively. On the other hand, para -anisyl alcohol (4, IC 50 = 34.89 µM) had higher leishmanicidal activity than the reference drug (glucantime ® ) against M379 and the FCQEPS native isolate of L. mexicana . Finally, in silico, the determination of their pharmacokinetic and toxicological properties showed that they are promising candidates for oral and topical uses. Conclusions : This study opens the possibility of using secondary metabolites as scaffolds for access to the development of new molecules for the treatment of parasite diseases.

Intersurface forces mediated by polymer films are important in a range of technological and industrial situations. In cosmetics, applications such as hair conditioning typically rely on the adsorption of polyelectrolyte films onto the charged surface of hair fibers, whose contact mechanics and tribological properties are central to determining the final sensorial perceptions associated with the cosmetic treatment. A major current challenge to be tackled by the cosmetic industry is to design high-performance products employing biosourced polyelectrolytes, with the aim of achieving ecosustainable processes and products. In this context, the present study focuses on the mechanical properties of thin films obtained by adsorption from a solution of fungal chitosan onto negatively charged mica surfaces. We use a Surface Forces Apparatus, allowing for the simultaneous measurement of film thickness and friction force as a function of the applied normal load and shear velocity. We show that, in aqueous medium at an ionic strength of 40 mM, adsorbed films of chitosan give rise to repulsive intersurface forces whose range, comparable to the Flory radius of the macromolecules, increases with the polymer molecular weight. In addition, the adsorbed layers are found to behave, under compressive forces, as pseudobrushes of neutral polymers. Finally, we show that under shear forces, chitosan layers exhibit a transition from a low to a high friction regime under increasing confinement.

The major histocompatibility complex class I chain-related gene A ( MICA ), a component of the human leukocyte antigen ( HLA ) gene complex, is involved in the pathogenesis of various diseases including cancers and autoimmune disorders. Rosacea, a chronic inflammatory skin disease with a complex pathogenesis, potentially influenced by genetic and autoimmune factors. This study aims to investigate the relationship among MICA gene polymorphisms, single nucleotide polymorphisms (SNPs), and susceptibility to rosacea, thereby offering new insights into the disease mechanism. Peripheral blood DNA samples were collected from 84 patients with rosacea (rosacea group) and 223 healthy volunteers (control group) who visited the Dermatology Outpatient Department of Xiangya Hospital of Central South University between November 2017 and November 2019. MICA genotyping was performed using polymerase chain reaction-sequencing-based typing (PCR-SBT) and the next-generation sequencing (NGS), and the accuracy of the 2 methods was compared. The frequency distributions of MICA alleles between the 2 groups were analyzed. Amino acid clustering and SNP site analyses were conducted to identify haplotype-linked SNPs and to classify MICA polymorphic variants. Distribution differences of these classifications between groups were also examined. Blood tests in rosacea patients showed mildly elevated, with no significant changes in lymphocyte counts. Both PCR-SBT and NGS accurately identified MICA alleles. The most common alleles in the rosacea group were MICA*010:01 , MICA*008:04 , and MICA*019:01 . The frequencies of MICA*002:01 and MICA*027 were significantly lower in the rosacea group compared to controls (6.55% vs 18.16% and 1.19% vs 5.38%, respectively), while and MICA*010:01 were significantly higher (7.74% vs 3.36% and 31.55% vs 18.61%, respectively; all P <0.05). Five short tandem repeat (STR) alleles were identified. Frequencies of MICA-A4 and MICA-A9 were lower in the rosacea group than in the control group (16.07% vs 23.32% and 7.74% vs 17.26%, respectively), whereas MICA-A6 was higher (10.12% vs 4.03%; all P <0.05). Clustering and SNP analysis identified 6 linked SNP sites, classifying MICA variants into Type I (C 36 +M 129 +K 173 +G 206 +W 210 +S 215 ) and Type II (Y 36 +V 129 +E 173 +S 206 +R 210 +T 215 ). Type I MICA variants were significantly associated with rosacea susceptibility. MICA gene polymorphisms are associated with susceptibility to rosacea, and there are 6 linked SNP sites within the MICA gene. Based on this, MICA polymorphic variants are classified into Type I and Type II, with Type I being more closely associated with disease development of rosacea. 目的 : 主要组织相容性复合体I类链相关基因A(major histocompatibility complex class I chain-related gene A， MICA )是人类白细胞抗原(human leukocyte antigen， HLA )基因的重要组成部分，其基因多态性与肿瘤、自身免疫性疾病等多种疾病的发生和发展密切相关。玫瑰痤疮是一种慢性炎症性皮肤病，其发病机制复杂，与遗传、自身免疫异常等因素有关。本研究分析 MICA 基因多态性及其单核苷酸多态性(single nucleotide polymorphism，SNP)位点与玫瑰痤疮易感性的关系&