Humeral stem alignment of curved short stem in reverse shoulder arthroplasty: Varus/Valgus alignment is not a determinant for clinical outcomes.

BACKGROUND: This study aimed to investigate the influence of curved short stem alignment within the proximal humerus on the clinical outcomes of reverse shoulder arthroplasty. We hypothesized that the varus/valgus alignment would yield clinical outcomes comparable to those of a neutral alignment. METHODS: We retrospectively reviewed 167 patients who underwent reverse shoulder arthroplasty using the Aequalis Ascend Flex implant between January 2017 and December 2021. The study categorized the patients into three groups based on the angle difference between the humeral axis and the stem axis: neutral group (GN, defined as within ±5 degrees), valgus group (GL), and varus group (GR). Functional outcomes were assessed using the visual analog scale pain score, subjective shoulder value, American Shoulder and Elbow Surgeons score, University of California Los Angeles shoulder score, and active range of motion. Routine radiographic evaluations were also conducted to assess the filling ratio and bone resorption. RESULTS: Among 138 patients, 89 were in the GN group, 37 (27%) in the GL group, and 12 (9%) in the GR group. The average degree of varus alignment was 6 (range from 5 to 7 degrees), while the average degree of valgus alignment was -7 (range from -8 to -5 degrees). According to our findings, the clinical outcomes did not exhibit significant differences between the three groups. Furthermore, the radiological outcomes showed no significant differences among the three groups. CONCLUSIONS: Compared to neutral alignment, varus or valgus alignment of the humeral stem in reverse shoulder arthroplasty using a curved short stem does not significantly affect clinical outcomes.

Surgical Results with Low-Grade Arteriovenous Malformations : A Single Center 14-Year Experience.

OBJECTIVE: Advancements in AVM surgical techniques for cerebral arteriovenous malformation (AVM) underscore its efficacy. Our research aims to showcase the positive outcomes of treating low-grade AVMs surgically, focusing on safety and effectiveness. METHODS: We retrospectively reviewed 55 patients (36 males and 19 females; average age 37.4 years) with Spetzler-Martin (S-M) grade 1 and 2 AVMs who underwent surgical resection between January 2009 and December 2022. RESULTS: In our study, 55 patients with S-M grade 1 and 2 AVMs underwent surgical resection, evenly divided between grades 1 (50.9%) and 2 (49.1%). Intracranial hemorrhage was the primary symptom in 74.5% of cases. Pre-operative Glasgow coma scale (GCS) scores revealed 69.1% of patients scored above 13, with 18% below 8. Successful resection was achieved in 87.3%. Postoperatively, 95.5% of ruptured and 90.9% of unruptured AVM patients showed lower or same modified Rankin scale scores. Poorer outcomes were significantly linked to lower GCS scores and intranidal/flow-related aneurysms through multivariate logistic regression. Postoperative seizures noted in nine patients, were exclusive to the ruptured AVM group. CONCLUSION: Our findings indicate surgical resection as a beneficial treatment for low-grade AVMs, yielding high cure rates and positive functional outcomes in both ruptured and unruptured cases. Preoperative GCS scores and the presence of associated aneurysms are predictive of postoperative functional status. Additionally, managing postoperative seizures effectively is key to enhancing prognosis.

Comparing the Biomechanical Stability of Cerclage Cable with Plate Insert Versus Locking Screw in Periprosthetic Humeral Fracture.

BACKGROUND: In the setting of periprosthetic humeral fractures, the humeral stem of the implant represents a substantial challenge to the optimal method of proximal fixation. This study aimed to compare the initial biomechanical stability provided by cerclage cables with a locking plate insert versus bicortical locking screws (i.e., the gold standard for fixation) in fresh cadaveric humeri. METHODS: After calculating the sample size, we utilized 10 sets of cadaveric specimens and created a 5-mm osteotomy gap 120 mm distal to the tip of the greater tuberosity, simulating a Wright and Cofield type-B periprosthetic humeral fracture on each specimen. Using 3 locking screws for distal fragment fixation, identical in all specimens, the specimens were assigned to Group A (3 cerclage cables with a plate insert) or Group B (3 locking bicortical screws) for proximal fragment fixation. Biomechanical tests included stiffness in varus and valgus bending, torsion, and axial compression, and a single load to failure. RESULTS: No significant differences were observed in the biomechanical metrics between the 2 groups. CONCLUSIONS: Our study revealed that fixation with use of cerclage cables with a plate insert demonstrated biomechanical stability comparable with that of bicortical locking screw fixation when addressing the proximal fragment in Wright and Cofield type-B periprosthetic humeral fractures. CLINICAL RELEVANCE: For proximal fragment fixation of periprosthetic humeral fractures, cerclage cables with a plate insert can be utilized as an effective fixation method that offers initial fixation strength that is comparable to the use of 3 locking bicortical screws.

Triptycene Branched Poly(aryl-co-aryl piperidinium) Electrolytes for Alkaline Anion Exchange Membrane Fuel Cells and Water Electrolyzers.

Alkaline polymer electrolytes (APEs) are essential materials for alkaline energy conversion devices such as anion exchange membrane fuel cells (AEMFCs) and water electrolyzers (AEMWEs). Here, we report a series of branched poly(aryl-co-aryl piperidinium) with different branching agents (triptycene: highly-rigid, three-dimensional structure; triphenylbenzene: planar, two-dimensional structure) for high-performance APEs. Among them, triptycene branched APEs showed excellent hydroxide conductivity (193.5 mS cm-1 @80 °C), alkaline stability, mechanical properties, and dimensional stability due to the formation of branched network structures, and increased free volume. AEMFCs based on triptycene-branched APEs reached promising peak power densities of 2.503 and 1.705 W cm-2 at 75/100 % and 30/30 % (anode/cathode) relative humidity, respectively. In addition, the fuel cells can run stably at a current density of 0.6 A cm-2 for 500 h with a low voltage decay rate of 46 µV h-1 . Importantly, the related AEMWE achieved unprecedented current densities of 16 A cm-2 and 14.17 A cm-2 (@2 V, 80 °C, 1 M NaOH) using precious and non-precious metal catalysts, respectively. Moreover, the AEMWE can be stably operated under 1.5 A cm-2 at 60 °C for 2000 h. The excellent results suggest that the triptycene-branched APEs are promising candidates for future AEMFC and AEMWE applications.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Emulation Evaluation of Interior Beam-Column Connections in PC and RC Moment-Resisting Frames.

Precast concrete (PC) structures have many advantages, but their use in the construction of middle- to high-rise buildings is limited. The construction of PC structures requires skills in various operations such as transportation, assembly, lifting, and structural soundness. In particular, regarding the seismic design of PC structures, it is necessary to clearly evaluate whether they have the same structural performance and usability as integral RC (cast-in-place) structures. In this paper, an experimental study was conducted to investigate whether PC members can achieve a seismic performance equivalent to that of RC members in beam-column joints, which are representative moment-resisting frames. The main variables are the two types of structural systems (intermediate and special moment-resisting frames) and the design flexural strength ratio of the columns and beams. The experimental and analytical results showed that the seismic performance of the PC specimens was equivalent to that of the RC specimens in terms of strength, stiffness, energy dissipation, and strain distribution, except for the specimen with splice sleeve bond failure of the column reinforcement (poor filling of the internal mortar). In addition, the I series satisfied the present emulation evaluation criteria for special moment-resisting frames of PC structures, confirming the possibility of applying intermediate moment-resisting frames.

Meningioma Originating From Choroid Plexus of Foramen of Luschka: A Rare Case Report and Tip of Differential Diagnosis.

Meningiomas are the most common benign brain tumors, and most of them originate from the dura mater. However, in some cases, they can originate from the choroid plexus, and they are rarely found in the posterior cranial fossa. A 63-year-old female patient presented with dizziness and swallowing difficulty and was found to have a homogeneously enhancing mass in the right posterior cranial fossa. Mass removal was performed through retrosigmoid suboccipital craniotomy, and the mass was confirmed to originate from the choroid plexus. The pathological diagnosis was meningothelial meningioma. The patient had temporary swallowing difficulty but recovered without any neurological sequelae. We report a rare case of a lower cerebellopontine angle meningioma without dural attachment originating from the choroid plexus of the foramen of Luschka.

Effect of Ground Granulated Blast Furnace Slag Replacement Ratio on Structural Performance of Precast Concrete Beams.

This study was conducted to investigate the effect of ground granulated blast furnace slag on the structural performance of precast concrete beams, evaluating the flexural, shear and bonding performance by using the replacement ratio of the ground granulated blast furnace slag as a variable. The design strength of the concrete was set at 45 MPa in consideration of the characteristics of precast concrete products, and the replacement ratio of the ground granulated blast furnace slag to replace cement was 30 to 70%. The experimental results showed that all specimens had similar behavioral characteristics regardless of the replacement ratio of the ground granulated blast furnace slag. Comparison of the prediction results obtained by ACI 318-19 and EC 2 showed that the mean flexural strength and shear strength were higher than 1.19 and 1.43, respectively, and the mean bond strength was 1.57, satisfying the required performance. Therefore, the experimental results showed that in using the ground granulated blast furnace slag as an admixture for precast concrete, the cement replacement ratio may be increased up to 70% without causing any problems in securing the structural performance. Summarizing the results of the present study, a ground granulated blast furnace slag replacement ratio of 50% or lower may be reasonably applied.

Effect of Surface Roughness Characteristics on Structural Performance of Hollow Core Slabs.

This study was conducted to evaluate the flexural performance of hollow core slabs (HCS) incorporating the effect of surface roughness. The HCSs are suitable for long span structures due to reduced self-weight. The specimens were HCS with topping concrete and the variables were cross sectional height and surface roughness. The tests were conducted on simply supported beams under four-point loads. The results showed that specimens with interface roughness applied in the lengthwise direction of members exhibited ductile flexural behavior up to peak load than those with interface roughness applied in the member width direction. Their flexural strength was also higher by 1-7% on average, indicating that they are advantageous in improving structural performance.

Clinical Perspectives to Overcome Acquired Resistance to Anti-Programmed Death-1 and Anti-Programmed Death Ligand-1 Therapy in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors have changed the paradigm of treatment options for non-small cell lung cancer (NSCLC). Monoclonal antibodies targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have gained wide attention for their application, which has been shown to result in prolonged survival. Nevertheless, only a limited subset of patients show partial or complete response to PD-1 therapy, and patients who show a response eventually develop resistance to immunotherapy. This article aims to provide an overview of the mechanisms of acquired resistance to anti-PD-1/PD-L1 therapy from the perspective of tumor cells and the surrounding microenvironment. In addition, we address the potential therapeutic targets and ongoing clinical trials, focusing mainly on NSCLC.

Modified Suturing Techniques in Carotid Endarterectomy for Reducing the Cerebral Ischemic Time.

OBJECTIVE: Carotid endarterectomy (CEA) is an effective surgical procedure for treating symptomatic or asymptomatic patients with carotid stenosis. Many neurosurgeons use a shunt to reduce perioperative ischemic complications. However, the use of shunting is still controversial, and the shunt procedure can cause several complications. In our institution, we used two types of modified arteriotomy suture techniques instead of using a shunt. METHODS: In technique 1, to prevent ischemic complications, we sutured a third of the arteriotomy site from both ends after removing the plaque. Afterward, the unsutured middle third was isolated from the arterial lumen by placing a curved Satinsky clamp. And then, we opened all the clamped carotid arteries before finishing the suture. In technique 2, we sutured the arteriotomy site at the common carotid artery (CCA). We then placed a curved Satinsky clamp crossing from the sutured site to the carotid bifurcation, isolating the unsutured site at the internal carotid artery (ICA). After placing the Satinsky clamp, the CCA and external carotid artery (ECA) were opened to allow blood flow from CCA to ECA. By opening the ECA, ECA collateral flow via ECA-ICA anastomoses could help to reduce cerebral ischemia. RESULTS: The modified suture methods can reduce the cerebral ischemia directly (technique 1) or via using collaterals (technique 2). The modified arteriotomy suture techniques are simple, safe, and applicable to almost all cases of CEA. CONCLUSION: Two modified arteriotomy suture techniques could reduce perioperative ischemic complications by reducing the cerebral ischemic time.

Factors associated with degeneration of rotator cuff tendon : a histological study in patients with rotator cuff tear.

Factors associated with tendon degeneration have not been fully investigated. The purpose of this study was to identify factors associated with tendon degeneration in patients with rotator cuff tear. A total of 93 patients with a full-thickness rotator cuff tear (fRCT) were included in the study. A full-thickness supraspinatus tendon sample was harvested from the middle portion between the lateral edge and the musculotendinous junction, and assessed histologically. Association between the degree of tendon degeneration and factors in demographic, clinical, radiologic, and arthroscopic categories were investigated. The mean of the total degeneration score was significantly lower in patients with symptom duration of 6 months or less than longer than 6 months (13.1 ± 2.6 vs 14.4 ± 2.3, p = 0.010). This study showed that tendon degeneration significantly progressed 6 months after the onset of symptoms, and suggested early intervention to avoid further deterioration of tendon degeneration.

Retrospective Comparative Outcomes Analysis of Arthroscopic Versus Open Bone Graft and Fixation for Unstable Scaphoid Nonunions.

PURPOSE: To compare union rates and clinical and radiologic outcomes after arthroscopic and open bone grafting and internal fixation for unstable scaphoid nonunions. METHODS: Between March 2009 and November 2014, patients with unstable scaphoid nonunion underwent arthroscopic (group A) or open (group O) bone grafting and internal fixation. One senior surgeon alternatively performed either arthroscopic or open osteosynthesis for the same surgical indications. Visual analog scale score, grip strength, active range of motion, Mayo wrist score (MWS), and Disabilities of Arm, Shoulder, and Hand score were assessed preoperatively and postoperatively. Union was determined by computed tomography 8 to 10 weeks postoperatively with bridging trabecula at the nonunion site. Scapholunate angle (SLA), radiolunate angle (RLA), and lateral intrascaphoid angle (LISA), plus height/length ratio (HLR) served to gauge carpal bone alignment in preoperative and postoperative radiographs. Those outcomes of patients with carpal collapse deformities, who met following conditions; (1) LISA of >45° or HLR of >0.65 on computed tomography images or (2) SLA of >60° or RLA of >10° on plain radiographs, were also compared. RESULTS: Overall, 62 patients qualified for study (group A, 28; group O, 34). Union rates did not differ by patient subset (group A, 96.4%; group O, 97.1%; P â‰’ 1); and visual analog scale score, grip strength, range of motion, Mayo Wrist Score, and Disabilities of Arm, Shoulder, and Hand scores were similar at last follow-up. In radiographic assessments, SLA, RLA, and LISA were similar, whereas scaphoid HLR excelled through open technique (group A, 0.59 ± 0.07; group O, 0.55 ± 0.05; P = .002). Subgroup analysis of patients with carpal collapse deformities (group A, 9; group O, 14) showed that all radiographic measures in group A (vs group O) reflected lesser correction (SLA, 56.7° ± 7.3° vs 49.2°±9.1° [P = .049]; RLA, 9.2° ± 2.0° vs 5.7° ± 3.0° [P = .005]; LISA, 34.8° ± 4.8° vs 25.6° ± 13.0° [P = .028]; HLR, 0.66 ± 0.04 vs 0.54 ± 0.07 [P < .001]). CONCLUSIONS: Arthroscopic and open bone grafting and internal fixation in treating unstable scaphoid nonunions, did not show any significant differences in clinical and radiologic outcomes at the minimum of 2 years after operation. In scaphoid nonunions with carpal collapse deformities, open bone grafting restored better carpal alignment than arthroscopic bone grafting, although there were no differences in clinical outcomes between the 2 techniques. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Effect of femoral component position on biomechanical outcomes of unicompartmental knee arthroplasty.

BACKGROUND: The positions of unicompartmental femoral components do not always follow the neutral center of the medial distal femoral condyle. The biomechanical effect of the center of the distal femoral condyle has not yet been evaluated, and the optimal femoral position in unicompartmental knee arthroplasty (UKA) is yet to be biomechanically justified. The purpose of this study was to evaluate, using finite element analysis, the effect of the center of the distal femoral component on the biomechanical outcomes of UKA with respect to the contact stresses in the polyethylene (PE) insert and articular cartilage. METHODS: Five models in which the centers of the distal femoral components were translated by three millimeters and five millimeters to the medial and lateral sides, respectively, from the neutral position were modeled and analyzed in a gait loading condition. RESULTS: The contact stresses on the PE insert increased as the center of the femoral component translated to the lateral side and, in contrast, the contact stresses decreased as it translated to the medial side. For the articular cartilage the contact stresses increased and decreased as the center of the femoral component translated to the medial and lateral sides. CONCLUSION: This study implied that the best position for the femoral component in UKA could be the center of the distal femoral condyle. Femoral component position could be one of the sensitive factors that influenced the contact stresses on the PE insert and articular cartilage, and the postoperative significance of the femoral component position in UKA.

Current Status of Atopic Dermatitis-Related Information Available on the Internet in South Korea.

BACKGROUND: Patients with atopic dermatitis (AD) often resort to the internet for disease-related information. We believe that dermatologists be informed about the current accessibility of information to patients and the potential for misleading patients into making poor treatment decisions. OBJECTIVE: The study was carried out in order to determine the nature of AD-related information available on the internet in Korea, and to identify any changes since our last survey in 2005. The quality of information offered and the involvement of medical doctors in certain websites were also investigated. METHODS: Taking into account the current search engine market share in Korea, we gathered all search results obtained from the three major search engines using the keyword 'atopy', and investigated the nature of the information retrieved. RESULTS: The search results showed less commercial sites than our previous study in 2005. There is a dramatic increase in the number of public bodies offering information about AD. In addition, the quality of information available online has improved since our last survey. CONCLUSION: The phenomenon of 'commercial overcrowding' seems to have stabilized. As AD becomes a more social phenomenon, patients are better informed than ever before. However, the information available on the internet still requires to be accompanied by consultation by dermatologists. We believe that self-regulation using a format such as the Health on the Net Foundation's code of conduct (HONcode) may improve the quality of online information accessible to patients with AD in Korea.

Comparison between intracytoplasmic sperm injection and intracytoplasmic morphologically selected sperm injection in oligo-astheno-teratozoospermia patients.

OBJECTIVE: The aim of this study was to evaluate the efficiency of the intracytoplasmic morphologically selected sperm injection (IMSI) technique compared with conventional ICSI and previous ICSI attempts in oligo-astheno-teratozoospermia (OAT) patients. METHODS: The sperms were selected under high magnification (6,600×) and used to induce fertilization in previous ICSI patients by IMSI. These results were compared with previous conventional ICSI cycles in patients with OAT infertility. RESULTS: These results demonstrated no significant difference in the fertilization rate between IMSI and previous ICSI cycles (67.7% vs. 65.0%). However, the pregnancy and implantation rates with IMSI were significantly higher than those of the ICSI cycles (33.3% vs. 12.5% and 14.6% vs. 5.4%, respectively; p<0.05). The miscarriage rate among pregnant patients (18.2% vs. 37.5%) showed no statistically significant difference between groups. CONCLUSION: Compared to conventional ICSI, this study found that IMSI increased the IVF-ET success rates in patients with OAT.

STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis.

STAT3 regulates CD4+ T cell survival and differentiation. However, its effects on CD8+ T cells are not well understood. Here, we show that in comparison to WT CD8+ T cells, STAT3-deficient CD8+ T cells exhibit a preactivated memory-like phenotype, produce more IL-2, proliferate faster, and are more sensitive to activation-induced cell death (AICD). The enhanced proliferation and sensitivity to AICD correlated with downregulation of class-O forkhead transcription factors (FoxO1, FoxO3A), p21(waf1), p27(KIP1), Bcl-2, OX-40, and upregulation of FasL, Bax, and Bad. We examined whether STAT3-deficient CD8+ T cells can mount effective response during herpes simplex virus (HSV-1) infection and experimental autoimmune uveitis (EAU). Compared to WT mice, HSV-1-infected STAT3-deficient mice (STAT3KO) produced less IFN-γ and virus-specific KLRG-1+ CD8+ T cells. STAT3KO mice are also resistant to EAU and produced less IL-17-producing Tc17 cells. Resistance of STAT3KO to EAU correlated with marked expansion of IL-10-producing regulatory CD8+ T cells (CD8-Treg) implicated in recovery from autoimmune encephalomyelitis. Thus, increases of IL-6-induced STAT3 activation observed during inflammation may inhibit expansion of CD8-Tregs, thereby impeding recovery from uveitis. These results suggest that STAT3 is a potential therapeutic target for upregulating CD8+ T cell-mediated responses to viruses and suggest the successful therapeutic targeting of STAT3 as treatment for uveitis, derived, in part, from promoting CD8-Treg expansion.

Molecular characteristics of cancer stem-like cells derived from human breast cancer cells.

We characterized the cellular properties of cancer stem-like cells (CSLCs) isolated from immortalized MDA-MB453 human breast cancer cells in culture. We showed that although the expression of Octamer-binding transcription factor-4 (OCT4) correlates to stemness in these CSLCs, OCT4 knockdown does not induce their differentiation. Our results suggest that the differentiation program in MDA-MB453 CSLCs is blocked at a step upstream of the transcription of the OCT4 promoter, allowing CSLCs to maintain their population through asymmetric cell division during many repeated passages. Comparative expression analysis indicates that only a subset of genes and signaling pathways known to be associated with survival and maintenance of CSCs are selectively expressed in CSLCs, as compared with non-CSLCs fractionated from the same parental MDA-MB453 cells. These results suggest that selective expression of a limited number of genes may be sufficient for establishment and maintenance of CSLCs with high tumorigenicity.

UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells.

The N-end rule pathway is a proteolytic system in which its recognition components (N-recognins) recognize destabilizing N-terminal residues of short-lived proteins as an essential element of specific degrons, called N-degrons. The RING E3 ligases UBR2 and UBR1 are major N-recognins that share size (200 kDa), conserved domains and substrate specificities to N-degrons. Despite the known function of the N-end rule pathway in degradation of cytosolic proteins, the major phenotype of UBR2-deficient male mice is infertility caused by arrest of spermatocytes at meiotic prophase I. UBR2-deficient spermatocytes are impaired in transcriptional silencing of sex chromosome-linked genes and ubiquitylation of histone H2A. In this study we show that the recruitment of UBR2 to meiotic chromosomes spatiotemporally correlates to the induction of chromatin-associated ubiquitylation, which is significantly impaired in UBR2-deficient spermatocytes. UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent ubiquitylation of H2A and H2B but not H3 and H4, through a mechanism distinct from typical polyubiquitylation. The E3 activity of UBR2 in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. Insufficient monoubiquitylation and polyubiquitylation on UBR2-deficient meiotic chromosomes correlate to defects in double strand break (DSB) repair and other meiotic processes, resulting in pachytene arrest at stage IV and apoptosis. Some of these functions of UBR2 are observed in somatic cells, in which UBR2 is a chromatin-binding protein involved in chromatin-associated ubiquitylation upon DNA damage. UBR2-deficient somatic cells show an array of chromosomal abnormalities, including hyperproliferation, chromosome instability, and hypersensitivity to DNA damage-inducing reagents. UBR2-deficient mice enriched in C57 background die upon birth with defects in lung expansion and neural development. Thus, UBR2, known as the recognition component of a major cellular proteolytic system, is associated with chromatin and controls chromatin dynamics and gene expression in both germ cells and somatic cells.

Higher-order aberration changes after Implantable Collamer Lens implantation for myopia.

PURPOSE: To investigate the changes in higher-order aberrations (HOAs) induced by implantation of Implantable Collamer Lenses (STAAR Surgical) and to explain them in relation to the surgical incision and optical properties. DESIGN: Prospective, observational case study. METHODS: This study included 56 eyes undergoing Implantable Collamer Lens insertion for myopic correction. The corneal incision size was determined according to the amount of astigmatism. HOAs were measured before surgery and 3 months after surgery in 25 eyes having small superior incision (<3.2 mm) surgery and in 31 eyes with large superior incision (3.2 to 4.5 mm) surgery. Changes in spherical aberration, coma, trefoil, and total HOAs (third to sixth order) were analyzed. Laboratory measurements of aberration profiles of Implantable Collamer Lenses with different optical powers were performed to validate clinical measurements. RESULTS: In the small-incision group, trefoil (Z(3)(-3)) and spherical aberration changed significantly (P=.004). In the large-incision group, in addition to trefoil and spherical aberration, total HOA changed significantly (mean change, 0.13 ± 0.17; P=.001). Significant correlations were observed among the incision size, the astigmatism induced, and the trefoil induced. Induced trefoil showed a predominant pattern at the orientation of the incision meridian. Optical measurement of aberrations of the Implantable Collamer Lenses confirmed the postoperative negative spherical aberration. CONCLUSIONS: HOA changes after Implantable Collamer Lens insertion were increased trefoil and induced negative spherical aberration. These changes may be explained by the effect of the corneal incision and the negative spherical aberration in the Implantable Collamer Lens, respectively.