SUGAR: Spherical ultrafast graph attention framework for cortical surface registration.

Cortical surface registration plays a crucial role in aligning cortical functional and anatomical features across individuals. However, conventional registration algorithms are computationally inefficient. Recently, learning-based registration algorithms have emerged as a promising solution, significantly improving processing efficiency. Nonetheless, there remains a gap in the development of a learning-based method that exceeds the state-of-the-art conventional methods simultaneously in computational efficiency, registration accuracy, and distortion control, despite the theoretically greater representational capabilities of deep learning approaches. To address the challenge, we present SUGAR, a unified unsupervised deep-learning framework for both rigid and non-rigid registration. SUGAR incorporates a U-Net-based spherical graph attention network and leverages the Euler angle representation for deformation. In addition to the similarity loss, we introduce fold and multiple distortion losses to preserve topology and minimize various types of distortions. Furthermore, we propose a data augmentation strategy specifically tailored for spherical surface registration to enhance the registration performance. Through extensive evaluation involving over 10,000 scans from 7 diverse datasets, we showed that our framework exhibits comparable or superior registration performance in accuracy, distortion, and test-retest reliability compared to conventional and learning-based methods. Additionally, SUGAR achieves remarkable sub-second processing times, offering a notable speed-up of approximately 12,000 times in registering 9,000 subjects from the UK Biobank dataset in just 32 min. This combination of high registration performance and accelerated processing time may greatly benefit large-scale neuroimaging studies.

A highly sensitive fluorescent probe RN-NA reveals peroxynitrite as a novel biomarker for primary open angle glaucoma.

AIM: To directly quantify peroxynitrite (ONOO-) using a highly sensitive fluorescence resonance energy transfer probe RN-NA, investigate the association between ONOO- and primary open angle glaucoma (POAG), and clarify whether RN-NA could be used as a potential tool for POAG diagnosis. METHODS: Plasma and aqueous humor (AH) samples were collected from POAG patients (n=100, age: 59.70±6.87y) and age-related cataract (ARC) patients (n=100, age: 61.15±4.60y) admitted to our hospital. Next, RN-NA was used to detect ONOO- in plasma and AH samples, and the relationship between ONOO- level and POAG was analyzed using binary logistic regression. Besides, Pearson correlation analysis was applied to characterize the correlation of the levels of ONOO- with the patients' age, intraocular pressure (IOP), and mean deviation of visual field testing. The ONOO- scavenger MnTMPyP was employed to treat the 3-morpholinosyndnomine (SIN-1)-induced ocular hypertension in mice (n=7, 6-8wk). Finally, the IOP and ONOO- in both eyes were measured 30min after the last drug treatment. RESULTS: ONOO- levels of AH and plasma were significantly higher in the POAG group than in the ARC group (P<0.01). Additionally, ONOO- levels were closely correlated with POAG in a binary logistic regression analysis [odds ratio (OR)=1.008, 95% confidence interval (CI): 1.002-1.013, P<0.01 for AH; OR=1.004, 95%CI: 1.002-1.006, P<0.001 for plasma]. Pearson correlation analysis showed that ONOO- levels in AH or plasma were positively associated with visual field defects (R=0.51, P<0.01 for AH; R=0.45, P<0.001 for plasma), and ONOO- levels in plasma and AH were correlated in the POAG group (R=0.69, P<0.001). However, administering MnTMPyP to mouse eyes reversed the elevated IOP caused by SIN-1 (P<0.05). CONCLUSION: ONOO- levels in AH and plasma, detected by RN-NA, are significantly related to POAG and positively correlated with visual field defects in POAG patients. Hence, ONOO- is a potential biomarker of POAG, especially advanced POAG. Besides, anti-nitration compounds may be novel ocular hypotensive agents based on the animal study.

The correlation of anterior segment structures in primary congenital glaucoma by ultrasound biomicroscopy with disease severity and surgical outcomes.

PURPOSE: To evaluate the anterior segment structures using ultrasound biomicroscopy (UBM) in primary congenital glaucoma (PCG) and explore their correlation with disease severity and surgical outcomes. METHODS: Clinical information of PCG patients who underwent UBM prior to their first glaucoma surgeries from September 2014 to March 2021 were reviewed. The study included 214 UBM images of 154 PCG eyes and 60 fellow unaffected eyes. Anterior segment characteristics were analyzed. UBM parameters, including the iris thickness (IT) at variant distances from the pupil edge and iris root, anterior chamber depth (ACD), and pupil diameter (PD), were compared between two groups and their relationship with clinical factors and surgical outcomes were analyzed in PCG eyes. RESULTS: PCG eyes had unclear scleral spur, thin iris, wide anterior chamber angle, deep anterior chamber, rarefied ciliary body, elongated ciliary processes, and abnormal anterior iris insertion. ITs were thinner, ACD was deeper, and PD was larger in PCG eyes than fellow unaffected eyes (all P < 0.001). In PCG eyes, thinner ITs correlated with bilateral involvement and earlier age at presentation, and larger PD correlated with earlier age at presentation (P = 0.030) and higher intraocular pressure (P < 0.001). Thinner IT2 (P = 0.046) and larger PD (P = 0.049) were identified as risk factors for surgical failure. CONCLUSION: UBM is a powerful technique to exam anterior segment structures in PCG. The anatomical features are associated with disease severity and surgical outcomes, providing essential clinical insights.

The morphology of angle dysgenesis assessed by ultrasound biomicroscopy and its relationship with glaucoma severity and mutant genes in Axenfeld-Rieger syndrome.

Background: Axenfeld-Rieger syndrome (ARS), a developmental disorder, involves anterior segment abnormalities and can lead to glaucoma. However, limited research has addressed the ultrasound biomicroscopy (UBM) characteristics of ARS. This study aimed to assess the anterior chamber angle features using UBM in ARS and determine their correlation with glaucoma severity and mutant genes. Methods: UBM examination was conducted for 42 patients diagnosed with ARS and glaucoma. The morphology of the anterior chamber angle was classified into 6 types (type A, pure high iris insertion; type B, posterior embryotoxon; type C, iris process; type D, trabecular-iris synechia; type E, peripheral iridocorneal adhesion; type F, goniodysgenesis). Candidate genes were sequenced with next-generation sequencing. Correlations of clinical characteristics with angle dysgenesis types and mutant genes were analyzed. Results: Among the 42 patients recruited, 6 eyes were excluded for poor quality UBM images or lack of glaucoma development. The remaining 78 eyes were categorized into 6 groups according to their dominant type of anterior chamber angle (>2 quadrants). There were statistically significant differences in onset age of glaucoma (P<0.001), untreated intraocular pressure (IOP) (P=0.016), vertical cup to disc ratio (P=0.001), and age at surgery (P<0.001) among the groups. Eyes in the type C and D groups developed glaucoma and underwent surgery at an earlier age, while eyes in the type B, E, and F groups developed glaucoma at a relatively later age. Eyes in type A group developed glaucoma and underwent surgery at the latest age, and had the lowest untreated IOP compared to the other groups. Patients with FOXC1 defects were more likely to have angle type B, type C, and type D (accounting for 93.8% of the total), whereas patients with PITX2 defects were more likely to have angle type A, type E, and type F (accounting for 92.1% of the total). Conclusions: UBM is powerful for evaluating the anterior segment abnormalities in ARS. Combined with genetic testing results, the morphological classification helps to assess the severity of glaucoma.

Highly accurate and large-scale collision cross sections prediction with graph neural networks.

The collision cross section (CCS) values derived from ion mobility spectrometry can be used to improve the accuracy of compound identification. Here, we have developed the Structure included graph merging with adduct method for CCS prediction (SigmaCCS) based on graph neural networks using 3D conformers as inputs. A model was trained, evaluated, and tested with >5,000 experimental CCS values. It achieved a coefficient of determination of 0.9945 and a median relative error of 1.1751% on the test set. The model-agnostic interpretation method and the visualization of the learned representations were used to investigate the chemical rationality of SigmaCCS. An in-silico database with 282 million CCS values was generated for three different adduct types of 94 million compounds. Its source code is publicly available at https://github.com/zmzhang/SigmaCCS . Altogether, SigmaCCS is an accurate, rational, and off-the-shelf method to directly predict CCS values from molecular structures.

Comparison of Clinical Outcomes of Endovascular Therapy and Hybrid Surgery in the Treatment of Trans-Atlantic Inter-Society Consensus II D Aortoiliac Occlusive Disease.

Purpose: To study and compare the clinical outcomes of endovascular therapy with those of hybrid surgery in the treatment of Trans-Atlantic Inter-Society Consensus II (TASC II) D aortoiliac occlusive disease (AIOD). Patients and Methods: Patients with TASC II D-type AIOD who underwent their first surgical treatment at our hospital between March 2018 and March 2021 were enrolled and followed up to evaluate the improvement in symptoms, complications, and primary patency. The Kaplan-Meier method was used to compare the differences in primary patency between the treatment groups. Results: In total, 132 of 139 enrolled patients (94.96%) achieved technical success following treatment. The perioperative mortality rate was 1.44% (2/139), and postoperative complications occurred in two patients. Among the patients who successfully underwent surgery, 120 underwent endovascular treatment (110 patients with stenting and 10 patients with thrombolysis before stenting), 10 underwent hybrid surgery, and 2 underwent open surgery. The follow-up data were compared between the endovascular and hybrid groups. At the end of the follow-up period, the patency rates in the hybrid and endovascular groups were 100% and 89.17% (107/120), respectively. The endovascular group achieved primary patency rates of 94.12%, 92.44%, and 89.08% at 6, 12, and 24 months postoperatively, respectively, whereas the primary patency rate remained at 100% in the hybrid group, with no significant variation between the endovascular and hybrid groups (P = 0.289). The endovascular group was further divided into a stent subgroup (110 patients) and a thrombolysis/stent subgroup (10 patients), and no prominent variation was noted in the primary patency between the two subgroups (P = 0.276). Conclusion: Although open surgery is the gold standard treatment for TASC II D-type AIOD, endovascular and hybrid treatments are feasible and effective. Both methods showed good technical success and early to midterm primary patency rates.

Mitochondria-associated endoplasmic reticulum membranes dysfunction contributes to PARP-1-dependent cell death under oxidative stress in retinal precursor cells.

Persistent poly (ADP-ribose) polymerase 1 (PARP-1) activation has proven detrimental and can lead to PARP-1-dependent cell death. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for many biological pathways, such as autophagy and mitochondria fission and fusion. This study aimed to alleviate the effects of hydrogen peroxide (H2 O2 )-induced persistent PARP-1 activation and MAM dysregulation by the usage of a PARP-1 inhibitor. Results showed that receptor-interacting protein kinase (RIPK) 1 inhibitor (necrostatin-1) and PARP-1 inhibitor (olaparib) protected retinal precursor cells from H2 O2 -induced death, while a pan-caspase inhibitor (Z-VAD-FMK) failed to protect R28 cells. Olaparib also alleviated H2 O2 -induced MAM dysregulation, as evidenced by decreased VDAC1/ITPR3 interactions and reduced mitochondrial membrane potential collapse. Additionally, olaparib also inhibited H2 O2 -induced autophagy. Inhibiting autophagic flux increased MAM signaling under both normal and oxidative conditions. Furthermore, H2 O2 treatment caused a reduction in the protein level of mitofusin-2 (MFN2) in a dose- and time-dependent manner. Mfn2 knockdown was found to further magnify MAM dysregulation and mitochondrial dysfunction under normal and oxidative conditions. Mfn2 overexpression surprisingly enhanced H2 O2 -induced MAM signaling and failed to rescue H2 O2 -induced mitochondrial dysfunction. These results indicate that MAMs probably serve as a membrane source for oxidative stress-associated autophagy. MAM dysregulation also contributed to H2 O2 -induced PARP-1-dependent cell death. However, more studies are required to decipher the link between the modulation of Mfn2 expression, changes in MAM integrity, and alterations in mitochondrial performances.

Structural Insights Uncover the Specific Phosphoinositide Recognition by the PH1 Domain of Arap3.

Arap3, a dual GTPase-activating protein (GAP) for the small GTPases Arf6 and RhoA, plays key roles in regulating a wide range of biological processes, including cancer cell invasion and metastasis. It is known that Arap3 is a PI3K effector that can bind directly to PI(3,4,5)P3, and the PI(3,4,5)P3-mediated plasma membrane recruitment is crucial for its function. However, the molecular mechanism of how the protein recognizes PI(3,4,5)P3 remains unclear. Here, using liposome pull-down and surface plasmon resonance (SPR) analysis, we found that the N-terminal first pleckstrin homology (PH) domain (Arap3-PH1) can interact with PI(3,4,5)P3 and, with lower affinity, with PI(4,5)P2. To understand how Arap3-PH1 and phosphoinositide (PIP) lipids interact, we solved the crystal structure of the Arap3-PH1 in the apo form and complex with diC4-PI(3,4,5)P3. We also characterized the interactions of Arap3-PH1 with diC4-PI(3,4,5)P3 and diC4-PI(4,5)P2 in solution by nuclear magnetic resonance (NMR) spectroscopy. Furthermore, we found overexpression of Arap3 could inhibit breast cancer cell invasion in vitro, and the PIPs-binding ability of the PH1 domain is essential for this function.

Comparison of the clinical and genetic features of autosomal dominant optic atrophy and normal tension glaucoma in young Chinese adults.

BACKGROUND/OBJECTIVES: To compare the clinical and optical coherence tomography (OCT) characteristics of autosomal dominant optic atrophy (ADOA) and normal tension glaucoma (NTG) in Chinese patients. SUBJECTS/METHODS: Twenty-four unrelated patients with ADOA and 21 unrelated patients with NTG, younger than 30 years, were enrolled in this study. Data regarding the demographic and clinical characteristics of the patients were collected, and their peripapillary retinal nerve fibre layer (RNFL) and macular ganglion cell complex (GCC) thicknesses were evaluated using OCT. Sequencing of genes associated with neuro-ophthalmic disorders was performed for all patients. RESULTS: The average age at onset of the ADOA group (13.92 ± 10.73 years) was significantly younger than that of the NTG group (23.67 ± 4.98 years, P = 0.002). Best-corrected visual acuity was significantly poorer in the ADOA group (0.75 ± 0.32) than in the NTG group (0.16 ± 0.19, P < 0.001). The average peripapillary RNFL thickness and the RNFL thicknesses in the temporal upper, temporal lower, and nasal lower sectors were significantly thinner in the ADOA group than in the NTG group (all P < 0.05). Moreover, the macular GCC thickness of the ADOA group was significantly thinner than that of the NTG group (P < 0.001). Twenty-three OPA1 variants (11 novel OPA1 variants) and one OPA3 variant were detected in 24 patients with ADOA. CONCLUSIONS: Our study revealed a distinct difference between the patterns of RNFL and GCC loss in ADOA and NTG, which will help to differentiate ADOA from NTG in young patients. Additionally, this study expanded the genetic spectrum of ADOA.

TIPARP is involved in the regulation of intraocular pressure.

Elevated intraocular pressure (IOP) is the major risk factor for glaucoma. The molecular mechanism of elevated IOP is unclear, which impedes glaucoma therapy. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible Poly-ADP-ribose Polymerase (TIPARP), a member of the PARP family, catalyses mono-ADP-ribosylation. Here we showed that TIPARP was widely expressed in the cornea, trabecular meshwork, iris, retina, optic nerve, sclera, and choroid of human eyes. The expression of TIPARP was significantly upregulated in the blood and trabecular meshwork of patients with primary open angle glaucoma compared with that of healthy controls. Transcriptome analysis revealed that the expression of genes related to extracellular matrix deposition and cell adhesion was decreased in TIPARP-upregulated human trabecular meshwork (HTM) cells. Moreover, western blot analysis showed that collagen types I and IV, fibronectin, and α-SMA were increased in TIPARP-downregulated or TIPARP-inhibited HTM cells. In addition, cross-linked actin networks were produced, and vinculin was upregulated in these cells. Subconjunctival injection of the TIPARP inhibitor RBN-2397 increased the IOP in Sprague-Dawley rats. Therefore, we identified TIPARP as a regulator of IOP through modulation of extracellular matrix and cell cytoskeleton proteins in HTM cells. These results indicate that TIPARP is a potential therapeutic target for ocular hypertension and glaucoma.

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage.

Glaucoma is the most common cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) and relative hypoxia in the retina stimulate the production of reactive oxygen species (ROS), which, in turn, puts the retina and optic nerve under chronic oxidative stress. Emerging evidence has shown that oxidative stress can trigger PARP-1 overactivation, mitochondrial-associated endoplasmic reticulum membrane (MAM) dysregulation, and NLRP3 activation. Oxidative damage can trigger inflammasome activation, and NLRP3 is the only inflammasome associated with MAM dysregulation. In addition, multiple transcription factors are located on the MAM. This study aimed to investigate the protective effects and underlying mechanisms of a PARP-1 inhibitor (olaparib) against chronic ocular hypertension-associated retinal cell damage. We also mimicked hypoxic stimulation of a retinal precursor cell line by exposing the cells to 0.2% O2 in vitro. We discovered that chronic ocular hypertension (COH) induces oxidative damage and MAM dysregulation in the retinal ganglion cells (RGCs). The protein levels of cleaved-PARP and NLRP3 were upregulated in the retinas of the COH rats. Olaparib, a PARP-1 inhibitor, alleviated COH-induced RGC loss, retinal morphological alterations, and photopic negative response amplitude reduction. Olaparib also relieved hypoxic stimulation-induced loss of cell viability and MAM dysregulation. Additionally, some indicators of mitochondrial performance, such as reactive oxygen species accumulation, mitochondrial Ca2+ influx, and mitochondrial membrane potential collapse, decreased after olaparib treatment. Olaparib attenuated the hypoxia-induced upregulation of NLRP3 protein levels as well as the phosphorylation of ERK1/2 and histone H2A.X. These results suggest that olaparib protects RGCs from chronic intraocular pressure elevation in vivo and alleviates the abnormal MAM dysregulation and mitochondrial dysfunction caused by hypoxia in vitro. This protection may be achieved by inhibiting PARP-1 overactivation, NLRP3 upregulation, and phosphorylation of ERK1/2.

Vav2 is a novel APP-interacting protein that regulates APP protein level.

Amyloid precursor protein (APP) is a transmembrane protein that plays critical role in the pathogenesis of Alzheimer's disease (AD). It is also involved in many types of cancers. Increasing evidence has shown that the tyrosine phosphorylation site Y682 in the intracellular tail of APP is crucial for APP function. Here, we report that Vav2, a guanine nucleotide exchange factor (GEF) for Rho family GTPase, is a novel interaction partner of APP. We found that Vav2-SH2 domain was able to bind directly to the Y682-phosphorylated intracellular tail of APP through isothermal titration calorimetry and NMR titrating experiments. The crystal structure of Vav2-SH2 in complex with an APP-derived phosphopeptide was determined to understand the structural basis of this recognition specificity. The interaction of APP and Vav2 in a full-length manner was further confirmed in cells by GST pull-down, co-immunoprecipitation and immunofluorescence staining experiments. In addition, we found overexpression of Vav2 could inhibit APP degradation and markedly increase the protein levels of APP and its cleavage productions in 20E2 cells, and this function of Vav2 required a functional SH2 domain.

Site-Specific 19F NMR Method for Detecting Arf6 GEF Activity.

Guanine nucleotide exchange factors (GEFs) of small GTPase (sGTPase) coordinate signal networks in normal cells and dysfunction in cancer. Therefore, effective monitoring of GEF activity is very important for studying the regulation of sGTPase signal transduction. In this study, we developed a 1D 19F NMR-based method for rapid detection of the GEF activity of sGTPases. The activity of Arf6GEF in vitro and cell lysate environment can be conveniently detected by tracking the conformational changes of the Arf6 switch region where a tfmF site-specific 19F labeling at Phe47 was introduced. This strategy could potentially be applied to monitor the conformational change of Arf6 or other sGTPase and detect the activities of sGTPase regulatory proteins in physiology and pathology environments.

Biochemical and NMR studies reveal specific interaction between STIMATE C-tail and PI(4,5)P2 or PI(3,4,5)P3-containing membrane.

STIMATE is an endoplasmic reticulum (ER) resident membrane protein that plays key roles in regulating calcium signaling occurring at ER-plasma membrane (PM) junctions. It is also involved in the regulation of ER-PM junction maintenance. STIMATE contains multiple putative transmembrane domains with a polybasic C tail (STIMATE-CT) that directly interacts with stromal interaction molecule 1 (STIM1) to promote STIM1 conformational switch. Here using liposome pulldown assay, we show that STIMATE-CT can specifically interact with PI(4,5)P2 or PI(3,4,5)P3-containing membrane. NMR analysis indicates that STIMATE-CT is intrinsically disordered. Furthermore, NMR titration with bicelles and mutation analysis reveal that the regions of 242VRYR245 and 284KKKK287 in STIMATE-CT are both essential for its membrane binding.

Heterogeneity of Axenfeld-Rieger Syndrome: Molecular and Clinical Findings in Chinese Patients.

Axenfeld-Rieger Syndrome (ARS) is a rare disease with a wide spectrum of ocular and systemic manifestations. The genetic spectrum of Chinese patients with ARS and genotype-phenotype correlations have yet to be described. To explore the molecular and clinical features in Chinese patients, fifty-five patients clinically diagnosed with ARS from independent families were recruited. Complete ophthalmic examinations and next generation sequencing of anterior segment dysgenesis associated genes were performed in all patients, and segregation in available relatives was verified using Sanger sequencing. 18 FOXC1 variants, 13 PITX2 variants, and two gross deletions spanning FOXC1 were detected in 35 out of 55 (63.6%) patients. 12 FOXC1 variants, 9 PITX2 variants, and two gross deletions were novel. There was a wide range of variability and severity in ocular and systemic manifestations displayed in our patients. Patients with FOXC1 variants were diagnosed at a younger age and had a lower prevalence of systemic manifestations than patients harboring PITX2 variants and those without variants. To our best knowledge, this is the largest study of Chinese patients with ARS to date. Our findings expand the genetic spectrum of ARS and reveal genotype-phenotype correlations in Chinese patients with ARS. Genetic and clinical heterogeneity were present in our patients. Awareness of the extensive characterization may aid in the clinical management and genetic counseling of patients with this rare disease.

The NAM/ATAF1/2/CUC2 transcription factor PpNAC.A59 enhances PpERF.A16 expression to promote ethylene biosynthesis during peach fruit ripening.

Peach is a typical climacteric fruit that releases ethylene during fruit ripening. Several studies have been conducted on the transcriptional regulation of ethylene biosynthesis in peach fruit. Herein, an ethylene response factor, PpERF.A16, which was induced by exogenous ethylene, could enhance ethylene biosynthesis by directly inducing the expression of 1-aminocyclopropane-1-carboxylic acid synthase (PpACS1) and 1-aminocyclopropane-1-carboxylic acid oxidase (PpACO1) genes. Moreover, the NAM/ATAF1/2/CUC2 (NAC) transcription factor (TF) PpNAC.A59 was coexpressed with PpERF.A16 in all tested peach cultivars. Interestingly, PpNAC.A59 can directly interact with the promoter of PpERF.A16 to induce its expression but not enhance LUC activity driven by any promoter of PpACS1 or PpACO1. Thus, PpNAC.A59 can indirectly mediate ethylene biosynthesis via the NAC-ERF signaling cascade to induce the expression of both PpACS1 and PpACO1. These results enrich the genetic network of fruit ripening in peach and provide new insight into the ripening mechanism of other perennial fruits.

Fixation options for reconstruction of the greater trochanter in unstable intertrochanteric fracture with arthroplasty.

INTRODUCTION: With the aggravation of population aging, the incidence of intertrochanteric fracture also increases dramatically. Patients are often elderly accompany with severe osteoporosis and various complications. Therefore, we should select an individualized treatment based on the each patient's state. Arthroplasty is recommended for unstable fractures with obvious osteoporosis, ipsilateral femoral head necrosis or arthritis. Rigid fixation of the greater trochanter with arthroplasty is challenging because of the powerful pulling forces created by multiple muscles being transmitted to the greater trochanter. Currently, there are few contemporary literatures on the evaluation of unstable intertrochanteric fracture with efficient fixation of the greater trochanter. Moreover, there is no consensus to choose which implant to immobilize the greater trochanter. The purpose of this study was to review previous literatures and provide a valuable guidance. CONCLUSIONS: The locking plate, which not only provides rigid fixation but also results in lower rate of postoperative complications. However, further prospective randomized and cohort studies are needed.

Hoffa fracture combined with rotational dislocation of the knee joint: A novel case report.

RATIONALE: Hoffa fracture is a rare fracture confined to the coronal-plane involving femoral condyles. This occurs simultaneously with rotational dislocation of the knee joint is extremely rare. Up to now, there is no valid recommendation for the treatment of the Hoffa fracture. PATIENT CONCERNS: A 50-year-old female patient broke her knee joint while skiing, experiencing severe pain in the right knee, which was swollen. She presented limited function of the knee and movement upon arrival in the emergency room. DIAGNOSIS: Comminuted Hoffa fracture in the right knee associated with rotational dislocation in the knee joint. INTERVENTIONS: We treated the dislocated knee joint through manual reduction initially. During the operation, we used posterolateral approach to expose the fracture fragments, thereafter using headless compression screws and a buttress plate to provide sufficient stability for the fracture. Early postoperative rehabilitation was encouraged. OUTCOMES: The patient finally achieved fracture healing three months after operation. In addition, she achieved 0-130° range of function of the knee after four months post-operation, and the patient obtained a satisfactory prognosis after our treatment. LESSONS: By using appropriate surgical approach to obtain enough exposure, headless compression screws and the buttress plate provided adequate stability during early active rehabilitation, which resulted in satisfactory results in the treatment of the injury. We reviewed literatures regarding the treatment of Hoffa fracture to demonstrate that our treatment was effective.

Biochemical and NMR characterization of the interactions of Vav2-SH2 domain with lipids and the EphA2 juxtamembrane region on membrane.

Vav2 is a ubiquitous guanine nucleotide exchange factor (GEF) for Rho family GTPases that is involved in regulating a wide range of biological processes. It interacts with several tyrosine-phosphorylated cell surface receptors, including the Eph family receptors, through its SH2 domain. The interaction of Vav2 with EphA2 is crucial for EphA2-mediated tumor angiogenesis. Here we show that Vav2-SH2 domain is a lipid-binding module that can recognize PI(4,5)P2 and PI(3,4,5)P3 lipids weakly but specifically. The specific lipid-binding site in Vav2-SH2 domain was identified by NMR chemical shift perturbation experiments using the head groups of PI(4,5)P2 and PI(3,4,5)P3, both of which bind to Vav2-SH2 with millimolar binding affinities. In addition, the interaction between Vav2-SH2 and the phosphorylated juxtamembrane region (JM) of EphA2 (Y594 phosphorylated) was investigated using NMR techniques. Furthermore, by using a nickel-lipid containing peptide-based nanodiscs system, we studied the binding of Vav2-SH2 to the phosphorylated JM region of EphA2 on lipid membrane and uncovered a role of membrane environment in modulating this protein-protein recognition.

ABCA1 Regulates IOP by Modulating Cav1/eNOS/NO Signaling Pathway.

Purpose: This study aimed to investigate the role and pathophysiological mechanism of ATP binding cassette transporter A1 (ABCA1) in regulating the IOP and aqueous humor outflow. Methods: ABCA1 expression was measured in trabecular meshwork samples obtained from patients with POAG and human donor eyes by Western blot. To further evaluate the functional significance of ABCA1, porcine angular aqueous plexus (AAP) cells, which are equivalent to human Schlemm's canal endothelial cells, were either treated with ABCA1 agonist GW3965 or transduced with lentivirus expressing ABCA1-shRNA. Transendothelial electrical resistance, protein expression, and nitric oxide (NO) concentration were measured. GW3965 was administered by intracameral injection. IOP and aqueous humor outflow facility were also measured. Results: ABCA1 expression was significantly higher in the trabecular meshwork tissue of patients with POAG compared with controls. ABCA1 upregulation in angular aqueous plexus cells decreased the transendothelial electrical resistance in the angular aqueous plexus monolayers accompanied by a 0.56-fold decrease in caveolin-1 expression and a 2.85-fold and 1.17-fold increase in endothelial NO synthase expression and NO concentration, respectively (n = 3, P < 0.05). Conversely, ABCA1 downregulation increased transendothelial electrical resistance and caveolin-1 expression and decreased endothelial NO synthase expression and NO production (n = 3, P < 0.05). GW3965 decreased IOP and significantly increased conventional outflow facility (P < 0.05). Conclusions: Regulation of aqueous humor outflow via the caveolin-1/endothelial NO synthase/NO pathway is a newly defined function of ABCA1 that is different from its traditional role in mediating cholesterol efflux. ABCA1 is a compelling, novel therapeutic candidate for the treatment of glaucoma and ocular hypertension.