Hasil untuk "General. Including alchemy"

D. Osborn, G. Levy, I. Nazareth et al.

Hanan Jamal Mohamed, Wonwoo Jeong, Jiwon Choi et al.

Autologous adipose tissue (AT) grafting is often compromised by insufficient early vascularization, leading to ischemia, fibrosis, and inconsistent long-term volume retention. Incorporating platelet-rich plasma (PRP) into AT bioinks offers a clinically accessible means to enhance vascular recruitment, but the in vivo impact of PRP dosage remains unclear. Here, we investigated how PRP concentration, uniformly integrated into a previously reported clinically relevant AT bioink, regulates vascular infiltration, tissue remodeling, and overall graft survival. High-dose PRP markedly improved graft performance, including an 8-fold increase in highly perfused regions, a 3.8-fold enhancement in adipocyte survival, a 1.67-fold reduction in fibrosis, and a 2.51-fold increase in collagen III deposition compared with PRP-free AT grafts. Histological analysis further demonstrated that PRP mitigates the adverse effects of poor perfusion, reducing regional disparities in survival and extracellular matrix (ECM) remodeling. High-dose PRP also maximized graft retention, preserving 103% of graft mass relative to 50.6% in native AT. Together, these results establish a clear in vivo dose–response relationship for PRP-enhanced AT grafts and highlight platelet concentration as a key design parameter for soft-tissue reconstruction. This work provides a translational framework for optimizing PRP-functionalized bioinks to improve clinical outcomes in reconstructive surgery.

D. York

This Perspective provides a contextual explanation of the current state-of-the-art alchemical free energy methods and their role in drug discovery as well as highlights select emerging technologies. The narrative attempts to answer basic questions about what goes on “under the hood” in free energy simulations and provide general guidelines for how to run simulations and analyze the results. It is the hope that this work will provide a valuable introduction to students and scientists in the field.

Monika Šupová, Šárka Rýglová, Tomáš Suchý et al.

Collagen hydrogels serve as biomimetic scaffolds that closely resemble the natural extracellular matrix, thus providing an ideal 3D biocompatible environment for cells. However, based on our previous experience, not all collagen isolates are capable of gelling, which appears to depend on the type, origin, species, age and sex of the source animal and the collagen isolation method applied. We therefore decided to evaluate porcine collagen-rich materials isolated from two different porcine genotypes applying two different specific isolation methods, and to analyse other main components, i.e., lipids and glycosaminoglycans, as well as amino acid composition and structural and morphological properties. While all the collagen isolates obtained were subjected to the gelling process, only one of them successfully gelled. In addition, the gelling ability of this isolate was confirmed repeatedly on collagens that were isolated from other pigs of the same porcine genotype. The results revealed that the gelling process proceeds via cooperation between the composition and the structure of the collagen isolate. With respect to the composition, one of the most important factors in terms of the success of the gelation process of collagen isolates concerns elevated glycosaminoglycan contents. The structural factors that characterise collagen isolates, i.e., cross-links (immature and mature) and their mutual ratio, as well as the presence of telopeptides, strongly impact the progress of the gelling process and the resulting character of the hydrogel structure. All these factors are influenced by the isolation procedure.

Mustafa Erdem Sagsoz, Ozlem Korkut, Salvatore Gallo

Tissue-equivalent hydrogel dosimeters represent a class of tools that hold significant promise, particularly in the precise measurement of three-dimensional dose distributions in radiotherapy. Due to their physical properties closely resembling those of human soft tissue, these dosimeters effectively replicate the energy transfer phenomena resulting from radiation interactions, such as atomic ionization and scattering by nuclei or electrons. Consequently, tissue-equivalent dosimeters, characterized by their linear energy transfer properties, have been extensively applied in medical physics, radiation oncology, and nuclear safety. Future advancements focusing on developing more stable, less toxic, normoxic, and cost-effective dosimeters could enable their broader adoption. This review provides a comprehensive overview of the key characteristics that make hydrogel dosimeters tissue-equivalent, highlighting their benefits, limitations, and primary application areas. Additionally, it explores current advancements in polymeric gel technology and discusses future directions aimed at optimizing their performance and accessibility for broader adoption.

Ana Carla Kuneski, Hima Haridevan, Elena Ninkovic et al.

Hydrogels are widely known for their ability to increase soil water retention and for their potential slow nutrient release mechanism. They have been constantly improved to meet the growing demand for sustainability in agriculture. Research focused on the development of biodegradable hydrogels, produced from industrial cellulose waste, are an ecological and efficient alternative soil ameliorant for the improvement of agricultural land. The objective of this study was to evaluate the impacts of two types of hydrogel (processed in a glass reactor versus a twin-screw extruder) on soils with different textures (clay and sandy loam), testing their water retention capacity, nitrogen leaching, and effects on seed germination. The methodology included the evaluation of water retention capacity at different pressures with different hydrogel addition rates in the soil, leaching tests in columns filled with soil and hydrogel layers, and germination tests of sorghum and corn. The results indicated that the addition of hydrogel significantly improved water retention, especially in sandy loam soils. The hydrogels also reduced nitrogen leaching, acting as nitrification inhibitors and limiting the conversion of ammonium to nitrate, with greater effectiveness in clayey soils. In the tested formulations, it was observed that the hydrogel doses applied to the columns favored nitrogen retention in the region close to the roots, directly influencing the initial stages of germination. This behavior highlights the potential of hydrogels as tools for directing nutrients in the soil profile, indicating that adjustments to the C:N ratio, nutrient release rate, and applied doses can optimize their application for different crops.

Yiqing Yuan, Yilong Zhang, Haiyang Duan et al.

Electronic skins (E-skins) are the integration of intelligent wearable sensors that can collect human physiological, motion, or environmental parameters in real-time through flexible, sensitive materials. The performance of E-skins depends on the selection of materials to a large extent. Hydrogel materials are an excellent candidate for E-skin preparation due to their tissue-like softness and biocompatibility. However, their low electrical conductivity, weak mechanical strength, and environmental instability seriously hinder high-fidelity signal acquisition and reliable operation in practical applications. To overcome these bottlenecks, conductive composite hydrogels have emerged as a promising alternative material. The unique properties of conductive composite hydrogels, such as high stretchability, self-healing ability, and adjustable electrical conductivity, address the relevant issues of traditional hydrogels in wearable applications. This review focuses on conductive composite hydrogels for wearable E-skins. Firstly, the types, characteristics, and preparation strategies of hydrogel matrix materials are introduced. Subsequently, the performance regulation mechanisms of key conductive fillers on composite hydrogels are discussed. Then, the application progress in electrophysiological signal monitoring, human–machine interaction, and human motion monitoring is reviewed. Finally, the current challenges and future development directions of hydrogel-based E-skins are prospected, aiming to provide comprehensive material and fabrication references for the practical application of composite hydrogel in electronic skins.

C. Schreck

Katharina Schmalstieg-Bahr, David J Gladstone, E. Hummers et al.

Abstract Background Atrial fibrillation (AF) is a common treatable risk factor for stroke. Screening for paroxysmal AF in general practice is difficult, but biomarkers might help improve screening strategies. Objectives We investigated six blood biomarkers for predicting paroxysmal AF in general practice. Methods This was a pre-specified sub-study of the SCREEN-AF RCT done in Germany. Between 12/2017-03/2019, we enrolled ambulatory individuals aged 75 years or older with a history of hypertension but without known AF. Participants in the intervention group received active AF screening with a wearable patch, continuous ECG monitoring for 2x2 weeks and usual care in the control group. The primary endpoint was ECG-confirmed AF within six months after randomisation. High-sensitive Troponin I (hsTnI), brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), N-terminal pro atrial natriuretic peptide (NT-ANP), mid-regional pro atrial natriuretic peptide (MR-pro ANP) and C-reactive protein (CRP) plasma levels were investigated at randomisation for predicting AF within six months after randomisation. Results Blood samples were available for 291 of 301 (96.7%) participants, including 8 with AF (3%). Five biomarkers showed higher median results in AF-patients: BNP 78 vs. 41 ng/L (p = 0.012), NT-pro BNP 273 vs. 186 ng/L (p = 0.029), NT-proANP 4.4 vs. 3.5 nmol/L (p = 0.027), MR-pro ANP 164 vs. 125 pmol/L (p = 0.016) and hsTnI 7.4 vs. 3.9 ng/L (p = 0.012). CRP levels were not different between groups (2.8 vs 1.9 mg/L, p = 0.1706). Conclusion Natriuretic peptide levels and hsTnI are higher in patients with AF than without and may help select patients for AF screening, but larger trials are needed. KEY MESSAGES BNP, NT-pro BNP, NT-ANP and MR-pro ANP and hsTnI levels are higher in patients with AF than without AF With a sensitivity at 100%, BNP had the highest specificity of 60% (BNP level 50.1ng/L), followed by NT-pro BNP with a specificity of 53% (179ng/l)

Oleg Petuhov, Nina Timbaliuc, Irina Ceban et al.

Activated carbons have great applicability in the conditioning of wines: discoloration, removal of foreign taste and smell, correction of organoleptic parameters, etc. The purpose of this work was to compare the structural and sorption characteristics of local vegetal activated carbon obtained from apricot stones (AC-C, Republic of Moldova) with that of commercial activated carbons (Granucol® BI/GE/FA, Germany). The physico-chemical characteristics of studied activated carbons have been evaluated by standard methods (nitrogen sorption isotherms, IR spectroscopy, pH value of activated carbons suspension etc.) and the adsorption capacity by using methylene blue dye as a reference substance. Experimental data were analysed by theoretical models: Langmuir and Equilibrium isotherm models, and pseudo-first-order, and pseudo-second-order kinetic models. The adsorption capacity of the local activated carbon (AC-C, 690 mg/g) is higher by 30% than that of activated carbons from Granucol® series (approx. 535 mg/g).

Mansuri M. Tosif, Aarti Bains, Kandi Sridhar et al.

Taro mucilage is a cost-effective, eco-friendly, and water-soluble edible viscous polysaccharide, which possesses diverse techno-functional properties including gelling and anti-microbial. Therefore, the objective of this study was to formulate and evaluate the efficacy of taro mucilage nanohydrogel for the shelf-life enhancement of fresh-cut apples. Taro mucilage was extracted using cold water extraction, and the yield of mucilage was found to be 2.95 ± 0.35% on a dry basis. Different concentrations of mucilage (1, 2, 3, 4, and 5%) were used to formulate the nanohydrogel. A smaller droplet size of 175.61 ± 0.92 nm was observed at 3% mucilage, with a zeta potential of −30.25 ± 0.94 mV. Moreover, FTIR data of nanohydrogel revealed the functional groups of various sugars, uronic acids, and proteins. Thermal analysis of nanohydrogel exhibited weight loss in three phases, and maximum weight loss occurred from 110.25 °C to 324.27 °C (65.16%). Nanohydrogel showed shear-thinning fluid or pseudo-plastic behavior. Coating treatment of nanohydrogel significantly reduced the weight loss of fresh-cut apples (8.72 ± 0.46%) as compared to the control sample (12.25 ± 0.78%) on the 10th day. In addition, minor changes were observed in the pH for both samples during the 10 days of storage. Titrable acidity of control fresh-cut apples measured 0.22 ± 0.05% on day 0, rising to 0.42 ± 0.03% on the 10th day, and for coated fresh-cut apples, it was observed to be 0.24 ± 0.07% on the 0th day and 0.36 ± 0.06% on 10th day, respectively. Furthermore, the total soluble solids (TSS) content of both control and coated fresh-cut apples measured on the 0th day was 11.85 ± 0.65% and 12.33 ± 0.92%, respectively. On the 10th day, these values were significantly increased (<i>p</i> < 0.05) to 16.38 ± 0.42% for the control and 14.26 ± 0.39% for the coated sliced apples, respectively. Nanohydrogel-coated fresh-cut apples retained antioxidant activity and vitamin C content as compared to the control sample. Taro mucilage nanohydrogel-based edible coating showed distinct anti-microbial activity against psychrotrophic, aerobic, and yeast molds. In summary, taro mucilage nanohydrogel can be used as a cost-effective natural coating material for the shelf-life enhancement or freshness maintenance of fresh-cut apples.

Chong Liu, Longwang Yue, Yu Fu et al.

Flexible sensors can measure various stimuli owing to their exceptional flexibility, stretchability, and electrical properties. However, the integration of multiple stimuli into a single sensor for measurement is challenging. To address this issue, the sensor developed in this study utilizes the natural biopolymers sodium alginate and carboxymethyl cellulose to construct a dual interpenetrating network, This results in a flexible porous sponge that exhibits a dual-modal response to strain and magnetic stimulation. The dual-mode flexible sensor achieved a maximum tensile strength of 429 kPa and elongation at break of 24.7%. It also exhibited rapid response times and reliable stability under both strain and magnetic stimuli. The porous foam sensor is intended for use as a wearable electronic device for monitoring joint movements of the body. It provides a swift and stable sensing response to mechanical stimuli arising from joint activities, such as stretching, compression, and bending. Furthermore, the sensor generates opposing response signals to strain and magnetic stimulation, enabling real-time decoupling of different stimuli. This study employed a simple and environmentally friendly manufacturing method for the dual-modal flexible sensor. Because of its remarkable performance, it has significant potential for application in smart wearable electronics and artificial electroskins.

Ping Wu, Wei Shang, Jiaqi Shao et al.

Gliadin nanoparticle (GNP) is a promising foaming agent, but its application is hindered by the limited foam stability under low acidic conditions. Herein, we attempted to tune the foam stability of GNP by coating it with flaxseed gum (FG) and investigated the structure, interfacial behaviors, and foam functionality of gliadin-FG (GFG) particles at pH 4.5. Results showed that the formation of GFG complex particles was driven by an electrostatic interaction between positive charge patches on the surface of GNP (~17 mV) and negative charges in FG molecule (~−13 mV) at all tested ratios. The addition of appropriate amounts of FG (1:0.05) effectively improved the foam stability of GNP. This was because GFG with larger sizes and lower surface charge possessed higher rigidity after coating with FG. When they adsorbed at the air/water interface, their deformation process was slower than that of GNP, as indicated by interfacial dilatational rheology and cryo-SEM, and the covered particles seemed to be more closely distributed to form solid-like and dense interfacial films. Notably, the addition of FG at a higher ratio (1:0.3) promoted the foam stability of GNP by about five folds because the larger GFG with suitable flexibility and wettability could form a stiff interface layer with more significant elastic response, and the unabsorbed particles and FG could form a gel-like network structure in the continuous phase. These characteristics effectively prevented foam disproportionation and coalescence, as well as retard the drainage. Our findings demonstrate that coating GNPs with FG is an effective approach to improve their application in foamed foods.

M. Neimark, V. V. Shmelev, A. A. Rakhmonov et al.

Impairment of higher mental functions can complicate the course of the postoperative period even after short and minimally invasive, including laparoscopic, surgical procedures. Postoperative cognitive dysfunction significantly challenges patients’ quality of life, negating real success of surgical intervention and anesthetic support. In some cases, early postoperative cognitive dysfunction may be one of the main predictors of persistent cognitive impairment.The purpose of the review. To contemplate etiology, pathogenesis and the current perspective of postoperative cognitive dysfunction.We analyzed 96 publications in various databases (PubMed, Medline, RSCI and others), including 67 papers published over the past 5 years.The review provides an overview of current definitions and classification of postoperative cognitive dysfunction, data on the prevalence, polyethyology and risk factors, potential impact of the type of anesthesia and surgical intervention on the development of postoperative cognitive dysfunction. Various pathogenetic mechanisms of higher mental functions impairment alongside with available effective pharmacotherapies to correct them were considered.Conclusion. Numerous adverse factors of the perioperative period, such as neurotoxic effects of general anesthetics, neuroinflammation in response to operational stress and surgical trauma, impaired autoregulation of the cerebral blood flow, imperfect oxygen homeostasis, interactions of neurotransmitter, etc., can potentially cause postoperative cognitive dysfunction. Further deeper insights into etiology and pathogenesis of early postoperative cognitive dysfunction are relevant and necessary to improve prevention strategies and identify most effective pharmacotherapies to correct such disorders.

Brian F. Yagi, Jamie E. Luster, A. Scherer et al.

Given increasing numbers of people experiencing transitions in health insurance due to declines in employer-sponsored insurance and changes in health policy, the understanding and application of health insurance terms and concepts (health insurance literacy) may be important for navigating use of health care. The study objective was to systematically review evidence on the relationship between health insurance literacy and health care utilization. Medline, SCOPUS, Web of Science, CINAHL, PsychInfo, Cochrane Library, and reference lists of published literature were searched in August 2019. Quantitative, qualitative, and intervention studies that assessed the association of health insurance literacy as the exposure and health care utilization as the outcome were identified, without language or date restrictions. Outcomes were independently assessed by 2–3 reviewers. Twenty-one studies including a total of 62,416 subjects met inclusion criteria: three interventional trials, two mixed-methods studies, and sixteen cross-sectional studies. Ten of thirteen preventive care studies suggested that higher health insurance literacy was associated with greater utilization of primary care and other preventive services. Eight of nine studies of care avoidance demonstrated that individuals with lower health insurance literacy were more likely to delay or avoid care. A few studies had mixed results regarding the utilization of emergency department, inpatient, and surgical care. The emerging literature in this area suggests that health insurance literacy is an important factor that can enable effective utilization of health care, including primary care and preventive services. However, the literature is limited by a paucity of studies using validated tools that broadly measure health insurance literacy (rather than testing knowledge of specific covered services). Improving health insurance literacy of the general public and increasing plain language communication of health insurance plan features at the point of health care navigation may encourage more effective and cost-conscious utilization.

W. Lourenço

Abstract This synoptic review aims to bring some general information on fossil scorpions, namely those trapped in amber - fossilized resin - ranging from Lower Cretaceous through the Palaeocene and up to the Miocene. The question to be addressed is how the study of these fossils can be connected with possible present scorpionism problems. A precise knowledge of these ancient lineages provides information about the evolution of extant lineages, including the buthoids, which contain most known noxious species. Among the Arthropods found trapped in amber, scorpions are considered rare. A limited number of elements have been described from the Late Tertiary Dominican and Mexican amber, while the most ancient Tertiary amber from the Baltic region produced more consistent results in the last 30 years, primarily focusing on a single limited lineage. Contrarily, the Cretaceous amber from Myanmar, also called Burmite, has yielded and continues to yield a significant number of results represented by several distinct lineages, which attest to the considerable degree of diversity that existed in the Burmese amber-producing forests. As in my previous similar contributions to this journal, the content of this note is primarily addressed to non-specialists whose research embraces scorpions in various fields such as venom toxins and public health. An overview knowledge of at least some fossil lineages can eventually help to clarify why some extant elements associated with the buthoids represent dangerous species while others are not noxious.

Chandra Sekhar Beera, B. Dhanalakshmi, D. Nirmala Devi et al.

Chromium (Cr)-doped cobalt ferrite nanoparticles were synthesized using a sol–gel autocombustion method, with the chemical formula CoCr_xFe_2xO₄. The value of x ranged from 0.00 to 0.5 in 0.1 increments. X-ray diffraction analysis confirmed the development of highly crystalline cubic spinel structures for all samples, with an average crystallite size of approximately 40 to 45 nm determined using the Scherrer equation. Pellets were prepared using a traditional ceramic method. The magnetic and magnetostrictive properties of the samples were tested using strain gauge and VSM (vibrating sample magnetometer) techniques. The results of the magnetic and magnetostrictive tests showed that the chromium-substituted cobalt ferrites exhibited higher strain derivative magnitudes than pure cobalt ferrite. These findings indicated that the introduction of chromium into the cobalt ferrite structure led to changes in the material’s magnetic properties. These changes were attributed to anisotropic contributions, resulting from an increased presence of Co²⁺ ions at B-sites due to the chromium substitutions. In summary, this study concluded that introducing chromium into the cobalt ferrite structure caused alterations in the material’s magnetic properties, which were explained by changes in the cationic arrangement within the crystal lattice. This study successfully explained these alterations using magnetization and coercivity data and the probable cationic dispersion.

Vicente Leafar Peña García, Pablo Héctor Di Chenna, María Laura Uhrig

The self-assembly of carbohydrate-based amphiphiles can lead to colloidal soft materials such as supramolecular gels featuring highly desirable characteristics like biodegradability and biocompatibility. The report herein presents the synthesis, characterization and supramolecular self-assembly, physical gelation and wheat lectin binding of two structurally related amphiphilic compounds having β-<i>S</i>-<i>N</i>-acetylglucosamine residues linked to a 2,3-diacyl-<i>N</i>,<i>N</i>′-dipropargylated-<span style="font-variant: small-caps;">l</span>-tartaric diamide. A 1-thio-β-<i>N</i>-acetyl-<span style="font-variant: small-caps;">d</span>-glucosamine precursor attached to a conveniently functionalized linker with an azido group was synthesized by means of a one-pot procedure followed by deprotection. A click reaction successfully led to the two amphiphiles, which differed in length of the fatty acid attached to the tartaric acid scaffold. Although both compounds are poorly soluble in water and organic solvents, the difference in terms of hydrophilic moieties provided them with distinct supramolecular gelation properties. While the presence of an octadecyl chain produced a hydrogelator, the dodecadecyl homologue would only form weak gels in DMSO. SEM and rheology experiments confirmed the characteristic fibrillar morphology and viscoelastic properties, in agreement with the presence of physical gels. Both amphiphiles were able to interact reversibly with wheat germ agglutinin (WGA), a lectin that specifically recognizes GlcNAc residues, indicating a potential use in the food industry, as a gluten sensitivity manager, as well as in health-related industries, for example, for drug delivery systems.

A. S. Begin, M. Hidrue, S. Lehrhoff et al.

Physicians need to learn and work amidst a plethora of uncertainties, which may drive burnout. Understanding differences in tolerance of uncertainty is an important research area. To examine factors associated with tolerance of uncertainty, including well-being metrics such as burnout. Online confidential survey. The Massachusetts General Physicians Organization (MGPO). All 2172 clinically active faculty in the MGPO. We examined associations for tolerance of uncertainty with demographic information, personal and professional characteristics, and physician well-being metrics. Two thousand twenty (93%) physicians responded. Multivariable analyses identified significant associations of lower tolerance of uncertainty with female gender (OR, 1.23; 95% CI, 1.03–1.48); primary care practice (OR, 1.56; 95% CI, 1.22–2.00); years since training (OR, 0.99; 95% CI, 0.98–0.995); and lacking a trusted advisor (OR, 1.25; 95% CI, 1.03–1.53). Adjusting for demographic and professional characteristics, physicians with low tolerance of uncertainty had higher likelihood of being burned-out (OR, 3.06; 95% CI, 2.41–3.88), were less likely to be satisfied with career (OR, 0.37; 95% CI, 0.26–0.52), and less likely to be engaged at work (RR, 0.87; 95% CI, 0.84–0.90). At a time when concern about physician well-being is high, with much speculation about causes of burnout, we found a strong relationship between tolerance of uncertainty and physician well-being, across specialties. Particular attention likely needs to be paid to those with less experience, those in specialties with high rates of undifferentiated illness and uncertainty, such as primary care, and ensuring all physicians have access to a trusted advisor. These results generate the potential hypothesis that efforts focused in understanding and embracing uncertainty could be potentially effective for reducing burnout. This concept should be tested in prospective trials.

K. Pollard, D. Cauvi, C. Toomey et al.

BACKGROUND Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease. SCOPE OF THE REVIEW In this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models. MAJOR CONCLUSIONS Although subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity. GENERAL SIGNIFICANCE Mercury exposure likely contributes to the pathogenesis of autoimmunity.