Cryo-EM images of phase-separated lipid bilayer vesicles analyzed with a machine-learning approach.

Lateral lipid heterogeneity (i.e., raft formation) in biomembranes plays a functional role in living cells. Three-component mixtures of low- and high-melting lipids plus cholesterol offer a simplified experimental model for raft domains in which a liquid-disordered (Ld) phase coexists with a liquid-ordered (Lo) phase. Using such models, we recently showed that cryogenic electron microscopy (cryo-EM) can detect phase separation in lipid vesicles based on differences in bilayer thickness. However, the considerable noise within cryo-EM data poses a significant challenge for accurately determining the membrane phase state at high spatial resolution. To this end, we have developed an image-processing pipeline that utilizes machine learning (ML) to predict the bilayer phase in projection images of lipid vesicles. Importantly, the ML method exploits differences in both the thickness and molecular density of Lo compared to Ld, which leads to improved phase identification. To assess accuracy, we used artificial images of phase-separated lipid vesicles generated from all-atom molecular dynamics simulations of Lo and Ld phases. Synthetic ground-truth data sets mimicking a series of compositions along a tieline of Ld + Lo coexistence were created and then analyzed with various ML models. For all tieline compositions, we find that the ML approach can correctly identify the bilayer phase with >90% accuracy, thus providing a means to isolate the intensity profiles of coexisting Ld and Lo phases, as well as accurately determine domain-size distributions, number of domains, and phase-area fractions. The method described here provides a framework for characterizing nanoscopic lateral heterogeneities in membranes and paves the way for a more detailed understanding of raft properties in biological contexts.

A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.

BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved Deutsche Forschungsgemeinschaft (DFG) motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

GST polymorphism as a predictive biomarker for modulating the susceptibility to chronic obstructive pulmonary disease: A North Indian study.

Chronic obstructive pulmonary disease (COPD) is commonly characterized by shortness of breath, coughing or expectoration. Smoking is the leading cause of COPD development, but only a small percentage of smokers develop symptoms, implying a genetic component. Glutathione S-transferase enzymes are responsible for detoxifying cigarette smoke components. The role of glutathione S-transferase T1 (GSTT1) and glutathione S-transferase M1 (GSTM1) gene polymorphism was assessed with COPD susceptibility and associated clinical parameters in the North Indian population. This was a cross-sectional study involving 200 COPD patients and 200 healthy individuals, with peripheral blood sampling and adequate questionnaires. Multiplex PCR was used for genotyping GSTT1 and GSTM1 gene polymorphism. Logistic regression was used to calculate the odds ratio and 95% confidence intervals to assess the COPD risk and GST polymorphisms. The GSTT1 gene deletion rate was higher in COPD cases (34.5%) than in healthy individuals (20.5%). A statistical relationship between the GSTT1(-) null genotype and COPD risk was observed (odds ratio = 2.04, 95% CI = 1.30-3.20, P = 0.0019). After adjusting for covariates like age, sex and smoking status, a significant association was found for GSTT1(-) null genotype and COPD risk (adjusted odds ratio = 2.90, 95% CI = 1.43-5.87, P = 0.003). The GSTT1(-) genotype was also significantly correlated with clinical parameters for COPD risk. Another primary observation was that females with the GSTT1(-) null genotype were more vulnerable to COPD than males with the same gene deletion. The GSTT1(-) null genotype strongly correlates with COPD development, while no association was observed in the GSTM1(-) null genotype in the North Indian population.

Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo.

GBA1 mutations that encode lysosomal ß-glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher disease (GD) and are strong risk factors for synucleinopathies, including Parkinson's disease and Lewy body dementia. Only a subset of subjects with GBA1 mutations exhibit neurodegeneration, and the factors that influence neurological phenotypes are unknown. We find that α-synuclein (α-syn) neuropathology induced by GCase depletion depends on neuronal maturity, the physiological state of α-syn, and specific accumulation of long-chain glycosphingolipid (GSL) GCase substrates. Reduced GCase activity does not initiate α-syn aggregation in neonatal mice or immature human midbrain cultures; however, adult mice or mature midbrain cultures that express physiological α-syn oligomers are aggregation prone. Accumulation of long-chain GSLs (≥C22), but not short-chain species, induced α-syn pathology and neurological dysfunction. Selective reduction of long-chain GSLs ameliorated α-syn pathology through lysosomal cathepsins. We identify specific requirements that dictate synuclein pathology in GD models, providing possible explanations for the phenotypic variability in subjects with GCase deficiency.

Factors contributing to nurse resignation during COVID-19: A qualitative descriptive study.

AIMS: To explore and describe registered nurses' perceptions and experiences of work well-being extending from what inspired them to join the healthcare organization, what created a great day at work for them, through to what may have supported them to stay. DESIGN: Qualitative descriptive study. METHODS: Thirty-nine Australian nurses who resigned in 2021 from two metropolitan healthcare organizations in Victoria were interviewed in 2022, each for 30-60 min. The semi-structured interview transcripts were transcribed verbatim and analysed inductively and thematically. RESULTS: Four themes were constructed for each of the key research questions. Inspiration to join the organizations transpired through organizational reputation, recruitment experiences, right position and right time, fit and feel. A great day at work was created through relationships with colleagues, experiences with managers, adequate resourcing and delivering quality care. Factors contributing to nurses resigning included COVID-19, uncertainty of role, workload and rostering, and finally, not feeling supported, respected and valued. Factors that may have supported the nurses to stay included flexible work patterns and opportunities, improved workplace relationships, workload management and support, and supportive systems and environments. Cutting across these themes were five threads: (1) relationships, (2) communication, (3) a desire to learn and develop, (4) work-life balance and (5) providing quality patient care. CONCLUSIONS: Novel ways of working and supporting individuals, teams and organizations are needed to maintain and sustain nurses. The nurses' inspiration, what created a great day at work, and support needed to stay highlighted the importance of workplace initiatives to build nursing career pathways, provide equitable opportunities for professional development, workload and roster flexibility and implement professional relationship-enhancing actions to foster authentic civility. IMPACT: This study contributes an in-depth exploration of the perceptions and experiences of nurses who resigned from two healthcare organizations and provides a description of (1) what inspired these nurses to initially join the organization, (2) what they perceived created a great day at work for them, (3) the factors contributing to their resignation and (4) what may have supported them to stay. The reasons nurses resign from an organization were identified as complex and multi-factorial, with opportunities for promoting nursing career pathways, addressing equity in opportunities and implementing professional relationship-enhancing actions. These contributions add both context and opportunity to strengthen organizational initiatives to attract, sustain and retain nurses.

Association of IL4RA and IL-8 polymorphism in predicting susceptibility towards tuberculosis.

Mycobacterium tuberculosis is an infectious bacterial disease frequently affecting the lungs. With two fatalities from tuberculosis (TB) occurring every three minutes, India has the highest disease burden. The aetiology of tuberculosis has been linked to IL-8 and IL-4RA. Thus, the impact of the IL4RAQ576R and IL8 gene polymorphism on TB susceptibility was assessed. 301 healthy and 301 TB patients participated in a cross-sectional study. PCR RFLP was performed to identify the genotype of the IL4RAQ576R and IL-8 +781C/T gene polymorphism. The odds ratio and 95% confidence intervals were calculated using logistic regression to evaluate the risk of TB with IL4RAQ576R and IL-8 +781C/T polymorphism. A significant association was found between IL-4RA (p=0.04) and IL-8 +781 C/T (p= 0.03) in tuberculosis. Further, when clinical symptoms were compared with both polymorphisms, two of them, i.e., cough in IL-4RA576R (p=0.04) and breathlessness (p=0.01) in IL-8 +781C/T, showed a significant association. Moreover, different combinations of the SNPS were made, and the 3 risk allele shows a significant protective role (p=0.02). There is considerable evidence which shows that M. tuberculosis causes TB, an infectious disease that is genetically predisposed. The results of our study also showed that IL-4 RA Q576R and IL-8 +781 C/T played a significant protective function against tuberculosis, confirming the claim mentioned earlier. However, only the cough in IL-4RA576R and the dyspnea in IL-8 +781C/T exhibited a significant co-relation in TB patients when symptoms were examined. Additionally, the combined effects of the two SNPs were investigated, and it was discovered that the 3-risk allele has a strong association with tuberculosis. Therefore, the polymorphisms mentioned earlier, which may also be influenced by ethnicity, may significantly impact the chance of developing tuberculosis.

A Three-Dimensional Scale for the Qualitative and Quantitative Assessments of Secondary Alveolar Bone Grafting (SABG) in Unilateral Cleft Lip and Palate Patients Using Cone-Beam Computed Tomography (CBCT).

Background The objective of our study was to derive an objective assessment scale for three-dimensional (3D) qualitative and quantitative evaluation of secondary alveolar bone grafting (SABG) using cone-bone computed tomography (CBCT) in patients with unilateral cleft lip and palate (UCLP). Methods CBCT scans for pre- and 3-month post-SABG were reviewed for bone volume, height, width, and density of the bony bridge formed in the cleft defect in 20 patients with UCLP. Basic descriptive and principal component analysis was used to extract the various sub-components of the scale. Spearman's correlation was used to check the validity of the scale, and intra-class coefficient (ICC) and Cronbach's α were calculated to establish the reliability and retest applicability of the scale. Results Each CBCT scan was assessed in five areas: cementoenamel junction (CEJ), root apex, root midpoint, 3 and 6 mm below CEJ, and tabulated in percentiles of 20, 25, 40, 50, 60, and 75 for all the parameters (bone volume, density, and width). These scores were validated when correlated to the scale given by Kamperos et al. Cronbach's α for the domains demonstrated acceptable to excellent internal consistency. The ICC showed good test-retest reliability having a range of scores from 0.89 to 0.94. Conclusion The proposed scale for the 3D assessment of SABG in patients with UCLP provides gradation for the objective assessment of the bony bridge. This gradation enables the qualitative and quantitative assessments of the bony bridge, thus allowing each clinician to judge SABG more conclusively.

Evaluation of Alt-RAMEC With Facemask in Patients With Unilateral Cleft lip and Palate (UCLP) Using Cone Beam Computed Tomography (CBCT) and Finite Element Modeling-A Clinical Prospective Study.

OBJECTIVE: Evaluate the effects of alternate rapid maxillary expansion and constriction (Alt-RAMEC) protocol on patients with unilateral cleft lip and palate (UCLP) along with maxillary protraction using cone beam computed tomography (CBCT) records and a finite element modeling (FEM) model. MATERIALS AND METHODS: Twenty-five patients (aged 9-13 years) with UCLP having a GOSLON score 3 were selected for this prospective single-arm cohort study after obtaining necessary informed consent. A 9-week Alt-RAMEC protocol using a custom-made fan-shaped expansion screw was initiated, which was followed by 6-month facemask wear. Pre (T1) and posttreatment (T2) records including CBCT were taken and were evaluated for treatment changes in all 3 dimensions using paired t test. Additionally, a FEM model (ANSYS 15.0) using the Alt-RAMEC protocol was also analyzed for the displacement and stress on various craniofacial structures. RESULTS: Significant forward movement of the maxilla along with clockwise rotation of mandible along with statistically significant increase in lower molar height and upper incisor proclination (P < .05) was observed. CBCT evaluation showed a statistical significant decrease in buccal alveolar bone thickness and increase in molar inclination (P < .05). Finite element modeling analysis highlighted that the maximum displacement occurred at the anterior region with stresses radiating till the anterior nasal spine, zygomatic arch, and sphenoid bone. CONCLUSION: Alt- RAMEC protocol combined with facemask protraction can lead to significant maxillary advancement, with some transient decrease in buccal bone thickness noted thereby warranting long-term studies to further assess its effect on the dentofacial apparatus.

A New Frame for Orienting Infants With Cleft Lip and Palate During 3-Dimensional Facial Scanning.

BACKGROUND: Nonradiographic 3-D assessment of soft tissue facial structures is an ideal tool to measure 3-D facial change and smartphone apps like Bellus 3D have brought these technologies to our doorsteps. Although this app works well for adults, it doesn't do so well with infants as their stabilization is difficult thus proper alignment becomes problematic often leading to distortion. This seriously hampers the repeatability and reliability of the whole process. MATERIAL AND METHOD: A stainless steel rod of 150-cm length is curved into a semicircle of a radius of 42.5 cm. Bases are fabricated at both the ends to firmly hold the stand on the table. A Teflon ring of one inch is made for adjusting the diameter of the camera holder. A camera holder is then attached to the Teflon ring. The mobile holder mounted is free to move within the arc. A 3-D facial scan of a single patient was carried out with the camera mounted on the frame and once without the frame. The same was compared using side-by-side comparison and superimposition of the .STL files from the frontal, profile, and worm's eye view. RESULT AND CONCLUSION: It was found that considerable distortion was noted around the nasal and paranasal areas when the scan was performed without the frame as compared to the one that was taken with the frame. This technique avoided distortion and the difficulty in turning the baby's head to record the lateral portion of the face.

PATIENT-REPORTED OUTCOME MEASURES FOR PEDIATRIC DENTAL PATIENTS: A METHODOLOGICAL REVIEW AND MAPPING EXERCISE.

OBJECTIVES: The most important dental patient-reported outcome (dPRO) is oral health-related quality of life (OHRQoL) which was commonly based on the following four dimensions: Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact. However, until now, analyses linking dPROSs to the four dimensions have only been done in adults. We therefore examined if the existing dental patient-reported outcome measures (dPROMS) for pediatric patients could also be mapped to these four domains. METHODS: We performed a literature search to identify generic dPROMs administered in children and adolescents. Two researchers independently assessed titles, abstracts and full texts and extracted pediatric dPROMs and items. dPROM items were then mapped to the four OHRQoL dimensions. RESULTS: We identified 701 articles. After abstract screening, 118 articles were reviewed in full text. Fifteen articles met the inclusion criteria. Twelve instruments were identified, including 6 modified versions of the questionnaires. All questionnaires and their included items could be mapped to the four dimensions. In some cases, items were linked to two dimensions. CONCLUSIONS: The four OHRQoL dimensions (Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact) are also applicable for existing dPROMs in pediatric dental patients. These dimensions should therefore be considered when measuring OHRQoL in children and adolescents in future studies.

Comparative Study of Presurgical Infant Orthopedics by Modified Grayson Method and Dynacleft With Nasal Elevators in Patients With Unilateral Cleft Lip and Palate-A Clinical Prospective Study.

OBJECTIVE: To compare the effects of presurgical infant orthopedics using 2 different methods, that is, the Dynacleft with Nasal elevator system versus the modified Grayson's technique in patients with complete unilateral cleft lip and palate. DESIGN: Prospective comparative cohort study. MATERIALS AND METHODS: Twenty-eight patients were divided into 2 groups, that is, Group A consisting of 14 patients who underwent correction with DynaCleft with Nasal elevator system and Group B consisting of 14 patients undergoing correction using the modified Grayson technique. Maxillary cast measurements were taken at 2-time intervals (pre- and posttreatment) to assess various parameters using a laser scanning machine (C500 Solutionix) and 3D software (GOM Inspect). Similarly, standardized anterior-posterior and worm's-eye view photographs using a custom box were taken and imported to Adobe Photoshop CS6 for measurements. Paired t test and independent t test were used to compare intra- and intergroup changes, respectively. RESULTS: The analysis of cast (primary outcome) and photographic (secondary outcome) measurements showed improved nasal asymmetry and alveolar correction in both groups which showed no significant intergroup difference when assessed using the independent t test (P > .05). Group A showed higher chances (42.8%) of causing a T-shaped defect (due to excessive mesial-inward rotation of the minor segment) when compared to the Group B possibly due to a more controlled molding vector (P < .05). CONCLUSION: Both methods proved effective in improving the nasal asymmetry, reducing the alveolar cleft gap, and approximating the lips together; but care must be taken when applying the alveolar molding vector in the Dynacleft system.

Association of cycle threshold values of CBNAAT with severity and outcome in COVID-19.

Determination of viral load through cycle threshold (Ct) values may act as a predictor of severity and outcomes in patients with corona virus disease 2019 (COVID-19). However, variable literature is available regarding this relationship. Our study attempted to explore this association and the effect of various socio-demographic and clinical parameters on severity and outcome of COVID-19. Retrospective analysis of records of 731 patients whose nasopharyngeal/oropharyngeal swabs were subjected to cartridge based nucleic acid amplification (CBNAAT) on Cepheid Xpert Xpress SARS-CoV-2 was done. Ct values of N2 and E genes were studied in relation to severity and outcome of COVID-19. The viral load as determined by Ct values was classified as high (<25), medium (25.1-32) and low (>32). Association of socio-demographic and clinical parameters with respect to severity and outcome was also studied. Severity and mortality were significantly more in elder individuals, those belonging to the rural background, those with symptoms >7 days in duration before presentation and those with increasing number of co-morbidities (severity: p<0.001; mortality: p<0.001, 0.005, 0.006 and <0.001, respectively). The Ct values of gene N2 and E inversely correlated with severity and mortality from the disease (N2 gene: p=0.001 for both severity and mortality, E gene: severity: p<0.001, mortality: p=0.016, respectively). The severity of the illness and chances of mortality were significantly lesser when the CT value of N2 gene was >32, in comparison when it was upto 25, and when between 25.1 and 32 (severity: p=0.032 and 0.003, respectively; mortality: p=0.018 and <0.001, respectively). Almost similar trends were seen with respect to E gene (severity: p<0.001 and 0.067, respectively; mortality p=0.175 and 0.005, respectively). Viral load as determined by Ct values of N2 and E genes can act as surrogate markers for prediction of severity and disease outcomes in COVID-19.

Another rare presentation of allergic bronchopulmonary aspergillosis in a high burden tuberculosis country.

Mediastinal lymphadenopathy is often associated with tuberculosis, especially in a high burden country like India. We present a case of an asymptomatic female, who had mediastinal lymphadenopathy and middle lobe collapse, both of which pointed towards a diagnosis of tuberculosis. Patient was later diagnosed as a case of allergic bronchopulmonary aspergillosis (ABPA) on basis of clinical, radiological and serological findings. Hence, even in a high burden country and in background of bronchial asthma, ABPA should be kept as a differential diagnosis in patients presenting with mediastinal lymphadenopathy.

A comparative assessment of transfer accuracy of two indirect bonding techniques in patients undergoing fixed mechanotherapy: A randomised clinical trial.

OBJECTIVES: To assess the transfer accuracy of three-dimensional (3D) printed transfer trays and compare them with transfer trays made up of polyvinyl siloxane (PVS) for use in indirect bonding. DESIGN: This was a two-arm parallel prospective randomised controlled trial. SETTING: The trial was undertaken at the outpatient department of a dental college. PARTICIPANTS: A total of 30 patients (18 men, 12 women) were randomly allocated to two groups. METHODS: The inclusion criteria included patients with permanent and fully erupted dentition (age range = 17-24 years), Angles class I malocclusion with crowding <3 mm requiring non-extraction treatment, good oral hygiene and no previous history of orthodontic treatment. Blinding was applicable only for outcome assessment. Indirect bonding was performed by the primary investigator for both the groups. Digital images of the pre-transfer and post-transfer brackets were obtained by means of an intra-oral scanner and compared using software. Superimpositions of pre- and post-transfer images were done to determine the transfer error for linear and angular variables for all tooth types. RESULTS: A total of 600 teeth were bonded, 300 each for both groups. Statistically significant differences were observed in all dimension between the two groups, with 3D-printed trays being more accurate than PVS trays except in the vertical dimension (P < 0.05). The prevalence of clinically unacceptable transfer errors revealed that most of the transfer errors were in the vertical dimensions for 3D-printed trays. CONCLUSION: 3D-printed trays are more accurate than PVS trays except for transfers in vertical dimension.

Can modified DNA base pairs with chalcogen bonding expand the genetic alphabet? A combined quantum chemical and molecular dynamics simulation study.

A comprehensive (DFT and MD) computational study is presented with the goal to design and analyze model chalcogen-bonded modified nucleobase pairs that replace one (i.e., AXY:T, G:CXY, GXY:C) or two (GXY:CX'Y', X/X' = S, Se and Y/Y' = F, Cl, Br) Watson-Crick (WC) hydrogen bonds of the canonical A:T or G:C pair with chalcogen bond(s). DFT calculations on 18 base pair combinations that replace one WC hydrogen bond with a chalcogen bond reveal that the bases favorably interact in the gas phase (binding strengths up to -140 kJ mol-1) and water (up to -85 kJ mol-1). Although the remaining hydrogen bond(s) exhibits similar characteristics to those in the canonical base pairs, the structural features of the (Y-XO) chalcogen bond(s) change significantly with the identity of X and Y. The 36 doubly-substituted (GXY:CX'Y') base pairs have structural deviations from canonical G:C similar to those of the singly-substituted modifications (G:CXY or GXY:C). Furthermore, despite the replacement of two strong hydrogen bonds with chalcogen bonds, some GXY:CX'Y' pairs possess comparable binding energies (up to -132 kJ mol-1 in the gas phase and up to -92 kJ mol-1 in water) to the most stable G:CXY or GXY:C pairs, as well as canonical G:C. More importantly, G:C-modified pairs containing X = Se (high polarizability) and Y = F (high electronegativity) are the most stable, with comparable or slightly larger (by up to 13 kJ mol-1) binding energies than G:C. Further characterization of the chalcogen bonding in all modified base pairs (AIM, NBO and NCI analyses) reveals that the differences in the binding energies of modified base pairs are mainly dictated by the differences in the strengths of their chalcogen bonds. Finally, MD simulations on DNA oligonucleotides containing the most stable chalcogen-bonded base pair from each of the four classifications (AXY:T, G:CXY, GXY:C and GXY:CX'Y') reveal that the singly-modified G:C pairs best retain the local helical structure and pairing stability to a greater extent than the modified A:T pair. Overall, our study identifies two (G:CSeF and GSeF:C) promising pairs that retain chalcogen bonding in DNA and should be synthesized and further explored in terms of their potential to expand the genetic alphabet.

Comparison of rate of tooth movement and pain perception during accelerated tooth movement associated with conventional fixed appliances with micro-osteoperforations - a randomised controlled trial.

OBJECTIVES: To investigate the influence of micro-osteoperforation (MOP) on rate of orthodontic tooth movement and pain perception with fixed appliances. DESIGN: 2 arm parallel randomized controlled trial with an allocation ratio of 1:1. SETTING: The outpatient department of a dental college. PARTICIPANTS: 105 patients were screened, out of which 60 met the inclusion criteria and consented to participate; consisting of 33 females and 27 males requiring en-masse retraction following first premolar extractions. METHODS: The experimental group consisted of patients bonded with a fixed appliance (Gemini 3M) who received MOP distal to canines throughout the period of retraction every 28 days. These were compared with a control group treated with identical brackets without MOP and were assessed for rate of tooth movement (canine retraction) and pain perception using a Visual Analogue Scale (VAS) of 10 mm. RESULTS: Prior to commencement, all baseline parameters were matched between the two groups (p>0.05). A statistically significant increase in rate of tooth movement in the MOP group (p<0.05). CONCLUSION: MOP appears to enhance the rate of tooth movement with no differences in pain perception.

Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells.

Binding of particulate antigens by antigen-presenting cells is a critical step in immune activation. Previously, we demonstrated that uric acid crystals are potent adjuvants, initiating a robust adaptive immune response. However, the mechanisms of activation are unknown. By using atomic force microscopy as a tool for real-time single-cell activation analysis, we report that uric acid crystals could directly engage cellular membranes, particularly the cholesterol components, with a force substantially stronger than protein-based cellular contacts. Binding of particulate substances activated Syk kinase-dependent signaling in dendritic cells. These observations suggest a mechanism whereby immune cell activation can be triggered by solid structures via membrane lipid alteration without the requirement for specific cell-surface receptors, and a testable hypothesis for crystal-associated arthropathies, inflammation, and adjuvanticity.