RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks.

RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability.

IL-33/ST2 enhances MMP-12 expression by macrophages to mediate inflammatory and immune response in IgG4-Related Ophthalmic Disease.

IgG4-Related Ophthalmic Disease (IgG4-ROD) is a chronic autoimmune-mediated fibrotic disease that predominantly affects the lacrimal glands, often leading to loss of function in the involved tissues or organs. Recent studies have demonstrated that MMP-12 is highly expressed in IgG4-ROD and plays a significant role in regulating immune responses. In this study, we reviewed nine patients diagnosed with IgG4-ROD based on clinical manifestations and histological analysis, and we investigated the expression of IL-33/ST2 and MMP-12 in IgG4-ROD lacrimal gland tissues using IHC. We found that IL-33 interacts with its specific receptor ST2, both of which are significantly overexpressed in IgG4-ROD tissues. Additionally, we successfully constructed a mouse model by introducing the LatY136F mutation into C57BL/6 mice to mimic IgG4-ROD lacrimal gland involvement, which helped elucidate the mechanisms involved in the induction of MMP-12. Furthermore, immunofluorescence staining confirmed that most MMP-12+ cells were derived from M2 macrophages, and an ELISA assay demonstrated that IL-33 upregulates MMP-12 in IgG4-ROD. Collectively, these data suggest that the IL-33/ST2/MMP-12 signaling pathway is activated in IgG4-ROD, with IL-33/ST2 potentially promoting M2 macrophage polarization and activation to produce MMP-12, which may serve as a novel therapeutic target for IgG4-ROD.

Improving photosynthetic efficiency of rice via over-expressing a ferredoxin-like protein gene from Methanothermobacter thermautotrophicus.

Ferredoxins (Fds) are crucial in various essential plant metabolic processes, including photosynthesis, fermentation and aerobic nitrogen fixation, due to their role in electron transport rate (ETR). However, the full scope of ferredoxin's function across prokaryotes and eukaryotic plants remains less understood. This study investigated the effect of MtFd from Methanothermobacter thermoautotrophicus on rice photosynthetic efficiency. We found that MtFd was localized in the chloroplasts of rice protoplasts. Transgenic analysis showed that MtFd significantly enhanced the photosynthetic capacity compared to the wild-type plants. This enhancement was evident through increased ETR, NADPH content and net photosynthetic rates, as well as decreased non-photochemical quenching (NPQ). Despite similar biomass to wild type plants, MtFd transgenic plants exhibited a marked increase in grain size and the 1000-grian weight. The elevated ETR and surplus free electrons in transgenic plants result in a considerable rise in cellular ROS content, which in turn enhances the enzymatic activity of the antioxidant system. In summary, our findings suggest that introducing the Fd protein from M. thermoautotrophicus into transgenic rice improves photosynthetic efficiency by accelerating ETR, which triggers the cellular oxidative stress response.

Choroidal structural changes following vitrectomy performed with phacoemulsification in unilateral idiopathic epiretinal membrane.

BACKGROUND: This study aims to determine the influence of vitrectomy combined with macular epiretinal membrane dissection and internal limiting membrane (ILM) peeling and phacoemulsification on choroidal vasculature in patients with unilateral idiopathic epiretinal membrane (IERM) and concurrent cataract using optical coherence tomography (OCT). METHODS: This retrospective study included 26 eyes of 26 patients (8 males and 18 females) with unilateral IERM without vitreomacular traction (VMT) (group 1) and the patients' fellow eyes (n = 26, group 2). Three-port 25-G pars plana vitrectomy (PPV) combined with macular epiretinal membrane dissection and ILM peeling and phacoemulsification was performed on all patients. The comprehensive ophthalmologic examinations of all patients involved OCT measurements at every visit before and after surgery, and the choroidal thickness (CT), central macular thickness (CMT) and choroidal vascularity index (CVI) were calculated. RESULTS: The mean age of the IERM patients was 66.58 ± 7.06 years. Postoperatively, best corrected visual acuity (BCVA) was significantly greater than baseline (P = 0.023). The CVI of the IERM eyes was significantly lower (P < 0.01) than that of the fellow eyes at baseline. The subfoveal CT in the IERM eyes was lower than that in the fellow eyes (P = 0.023), but there was, no significant difference in the average CT between the two groups at baseline (P = 0.071). In eyes with IERM, the CVI significantly increased at 1 week, 1 month (P < 0.001), and 3 months (P = 0.049) postoperatively, the subfoveal CT was markedly thickened 1 month after surgery (P = 0.001), the temporal 3 mm and nasal CT significantly increased at 1 week and 1 month postoperatively (P = 0.041, P = 0.022 for temporal 3 mm; P < 0.001, P = 0.047 for nasal 1.5 mm; P = 0.01, P = 0.001 for nasal 3 mm), and only the temporal 3 mm CT increased significantly at 3 months postoperatively (P = 0.017). The baseline CMT of the IERM eyes was significantly thicker than that of the fellow eyes (P < 0.001). CMT significantly decreased at 3 months postoperatively in IERM eyes(P = 0.033). CONCLUSIONS: The increase in the CVI in the IERM eyes without VMT after combined PPV with ILM peeling and phacoemulsification persists for at least 3 months.

Dipping Pattern and 1-year stroke functional outcome in ischemic stroke or transient ischemic attack.

AIMS: This study aimed to explore whether a relationship exists between dipping patterns and 1-year functional outcome in patients with acute ischemic stroke (IS) or transient ischemic attack (TIA). METHODS: Data from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke Study (BOSS), a nationwide, hospital-based, longitudinal cohort study, was used for this study. Patients with acute IS or TIA were recruited within 7 days after onset and ambulatory blood pressure monitoring was performed during hospitalization. Patients were defined as dippers if nocturnal systolic blood pressure fell by ≥10%, non-dippers if 0-10%, and reverse dippers if < 0%. Poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-5. Logistic regression analysis was used to test the association between dipping patterns and 1-year functional outcome. RESULTS: Among the 1808 IS/TIA patients, 19.19% were dippers, 53.21% were non-dippers, and 27.60% were reverse dippers. Poor functional outcome occurred in 22.44% of reverse dippers, which was significantly higher than that of dippers (16.14%) and non-dippers (16.53%) (P = .014). A univariate analysis revealed that reverse dipping was a risk factor for poor functional outcome (Odds ratio 1.504, 95% confidence interval 1.055-2.145, P = .024). However, this significance disappeared after adjusting for confounders. CONCLUSIONS: Reverse dipping was prevalent in patients with IS/TIA. The higher incidence of 1-year poor functional outcome in reverse dippers warrants further investigation.

Identification and Validation of a Metabolism-Related Prognostic Signature Associated with M2 Macrophage Infiltration in Gastric Cancer.

High levels of M2 macrophage infiltration invariably contribute to poor cancer prognosis and can be manipulated by metabolic reprogramming in the tumor microenvironment. However, the metabolism-related genes (MRGs) affecting M2 macrophage infiltration and their clinical implications are not fully understood. In this study, we identified 173 MRGs associated with M2 macrophage infiltration in cases of gastric cancer (GC) using the TCGA and GEO databases. Twelve MRGs were eventually adopted as the prognostic signature to develop a risk model. In the high-risk group, the patients showed poorer survival outcomes than patients in the low-risk group. Additionally, the patients in the high-risk group were less sensitive to certain drugs, such as 5-Fluorouracil, Oxaliplatin, and Cisplatin. Risk scores were positively correlated with the infiltration of multiple immune cells, including CD8+ T cells and M2 macrophages. Furthermore, a difference was observed in the expression and distribution between the 12 signature genes in the tumor microenvironment through single-cell sequencing analysis. In vitro experiments proved that the M2 polarization of macrophages was suppressed by Sorcin-knockdown GC cells, thereby hindering the proliferation and migration of GC cells. These findings provide a valuable prognostic signature for evaluating clinical outcomes and corresponding treatment options and identifying potential targets for GC treatment.

Replication fork stability confers chemoresistance in BRCA-deficient cells.

Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance.

A prospective study on tryptophan immunoadsorption in AQP4 antibody-positive neuromyelitis optica spectrum disorders.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) is a rare inflammatory demyelinating disease of the central nervous system. NMOSD pathogenesis is mainly mediated by antibodies directed against aquaporin4 (AQP4 antibody). Immunoadsorption (IA) could specifically remove pathogenic antibody to alleviate the disease. Until now, prospective studies concerning the efficacy of IA on NMOSD are scarce. This study aims to prospectively evaluate the efficacy and safety of IA in the treatment of NMOSD. PATIENTS AND METHODS: We included patients with AQP4 antibody-positive NMOSD who were hospitalized from September 2019 to September 2020, with no significant improvement in symptoms after 1 week of high-dose intravenous steroid therapy. Tryptophan IA therapy was initiated with five sessions on alternate days. Expanded Disability Status Scale (EDSS), visual acuity, and laboratory values were measured before and after IA, with a follow-up of 6 months. Spinal magnetic resonance imaging (MRI) characteristics were collected. Related side effects were recorded. RESULTS: Seven patients were enrolled in the present study. After five IA, the patients' EDSS decreased from 5.71 ± 2.04 to 4.64 ± 2.29, P = .006. The visual acuity of the three visually impaired patients was improved. AQP4-IgG decreased significantly from 80.00 (interquartile range [IQR], 21.00-80.00) (U/mL) to 9.72 (IQR, 5.21-55.57) (U/mL) (P = .018). MRI of the spinal cord showed the scope of the myelopathy was narrowed and no significant enhancement was observed on postcontrast T1-weighted image at 90 days after treatment. Only one patient had transient hypotension. CONCLUSIONS: Tryptophan IA therapy effectively and safely improved neurological function and visual acuity, and reduced the AQP4 antibody concentration in patients with NMOSD.

Modified levator muscle complex suspension on treating pediatric blepharoptosis with poor Bell's phenomenon.

PURPOSE: To evaluate the surgical outcomes of pediatric congenital blepharoptosis with poor Bell's phenomenon (BP) treated with modified levator muscle complex suspension. METHODS: Forty-two pediatric congenital blepharoptosis patients with poor BP were treated with modified levator muscle complex suspension, and their major surgical outcomes such as marginal reflex distance1 (MRD1), palpebral fissure height (PFH), and postoperative lagophthalmos were retrospectively reviewed. RESULTS: The mean follow-up was 10.28 ± 9.89 months (range 3-32 Months). Surgical success was achieved in 54 (87.1%) of 62 eyelids at the final visit, including excellent results in 46 (74.2%) eyelids, good results in 8 (12.9%) eyelids, and poor results in 8 (12.9%) eyelids, respectively. The postoperative PFH of affected eyes (7.97 ± 1.47 mm) was significantly improved compared with that before surgery (3.58 ± 1.31 mm). The mean MRD1 was improved from - 1.48 ± 1.36 mm before surgery to 2.94 ± 1.46 mm after surgery. The postoperative MRD1 was ≥ 3 mm in 46 eyelids and < 3 mm in 16 eyelids. The mean lagophthalmos was 1.42 ± 1.20 mm 3 months after surgery. All of the patients presented complete blink postoperatively. Postoperative complications were rarely observed during follow-up. No patient had exposure keratitis, but blepharoptosis recurred in 6 patients (8 eyelids). All patients had satisfactory eyelid symmetry and contour. No complications were observed until the last visit. CONCLUSIONS: The modified method results complete blink, mild, and quick recovery of lagophthalmos, flexible eyelid motility, stable ocular surface, and it is simple to perform with few complications and a low recurrence rate at 12.9%, which is worth to wide application on poor Bell's phenomenon blepharoptosis.

Hepatitis B surface antigen kinetics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B.

The outcome of nucleos(t)ide analogues (NAs) discontinuation and retreatment is still uncertain. We evaluated hepatitis B surface antigen (HBsAg) kinetics after NAs discontinuation and during retreatment due to off-treatment clinical relapse among non-cirrhotic HBeAg-positive CHB patients. Four groups were studied: 129 HBeAg-positive patients from a prospective cohort who stopped NAs therapy after achieving sustained response (Group A), 39 patients who received retreatment after off-treatment clinical relapse in the discontinuation group (Group B), 214 patients who maintained treatment after achieving sustained response (Group C) and 291 patients who firstly initiated antiviral treatment (Group D). During a 5-year follow-up, the cumulative incidence of HBsAg loss was significantly higher in Group A than Group C (22.3% vs. 1.6%, p < .001). The quantitative HBsAg (qHBsAg) level at enrolment and NAs discontinuation were independently associated with HBsAg loss. Additionally, patients in Group B showed significantly greater HBsAg loss than those in the Groups C and D, with 5-year cumulative incidences of 9.0%, 1.6% (p = .040) and 0.6% (p < .001), respectively. Moreover, patients in the Group B exhibited better virologic response (100% vs. 98.8%, p < .001) and HBeAg seroconversion (92.6% vs. 69.8%, p < .001) than those in Group D at year 5. Propensity score-matched analysis also showed the similar trend of HBsAg decline. NAs discontinuation with or without subsequent retreatment resulted in a more profound reduction of HBsAg in non-cirrhotic HBeAg-positive patients, suggesting that discontinuation may be a potential cure strategy for those with sustained virological suppression.

A Local D4h Symmetric Dysprosium(III) Single-Molecule Magnet with an Energy Barrier Exceeding 2000†K*.

Three six-coordinate DyIII single-molecule magnets (SMMs) [Dy(Ot Bu)2 (L)4 ]+ with local D4h symmetry are obtained by optimizing the equatorial ligands. One of the compounds with L=4-phenylpyridine shows an energy barrier (Ueff ) of 2075(11) K, which is the third largest Ueff , and the first Ueff >2000 K for SMMs with axial-type symmetry so far. Ab initio analysis indicates that the exceptional uniaxial magnetic anisotropy is deeply related to the axially compressed octahedral geometry. This work provides a new insight into the local D4h symmetry for high-performance SMMs.

Amblyopia and Refractive Status in Congenital Ptosis: The Effect and Timing of Surgical Correction.

PURPOSE: The aim of this study was to explore the effect of congenital ptosis on the visual function of patients and observe the improvement in visual function after the correction of ptosis at different surgical times. METHODS: We performed a retrospective study of 265 patients (346 eyes) with congenital ptosis at the same hospital. Each patient underwent an ophthalmic examination, including optometry and measurement of the affected palpebral fissure height and upper eyelid margin reflex distance. Preoperative clinical and morphologic data were compared with postoperative data. RESULTS: The refractive error of the patient population was significantly different from that of the general population (P < 0.01). The rates of strabismus and amblyopia were 12.45% and 36.98%, respectively, in the ptosis patients, both of which are higher than the rates in the general population (P < 0.01), especially for unilaterally affected patients and patients with the optical axis covered. The refractive error of patients younger than 5 years was improved postoperatively (P < 0.05). The number of cases of amblyopia and strabismus was reduced, as was the percentage of cases of with-the-rule astigmatism (P < 0.05). CONCLUSION: Congenital ptosis can result in refractive error, strabismus, and amblyopia, which could seriously impair the visual function of patients. The impairment is more pronounced in unilaterally affected patients. Surgery is conducive to the recovery of visual function, especially in patients younger than 5 years. Satisfactory curative effects can be obtained before the age of 3 years; thus, unilaterally affected patients, severely affected patients, and patients with impaired visual function should undergo surgery as soon as possible.

Holliday junction recognition protein interacts with and specifies the centromeric assembly of CENP-T.

The centromere is an evolutionarily conserved eukaryotic protein machinery essential for precision segregation of the parental genome into two daughter cells during mitosis. Centromere protein A (CENP-A) organizes the functional centromere via a constitutive centromere-associated network composing the CENP-T complex. However, how CENP-T assembles onto the centromere remains elusive. Here we show that CENP-T binds directly to Holliday junction recognition protein (HJURP), an evolutionarily conserved chaperone involved in loading CENP-A. The binding interface of HJURP was mapped to the C terminus of CENP-T. Depletion of HJURP by CRISPR-elicited knockout minimized recruitment of CENP-T to the centromere, indicating the importance of HJURP in CEPN-T loading. Our immunofluorescence analyses indicate that HJURP recruits CENP-T to the centromere in S/G2 phase during the cell division cycle. Significantly, the HJURP binding-deficient mutant CENP-T6L failed to locate to the centromere. Importantly, CENP-T insufficiency resulted in chromosome misalignment, in particular chromosomes 15 and 18. Taken together, these data define a novel molecular mechanism underlying the assembly of CENP-T onto the centromere by a temporally regulated HJURP-CENP-T interaction.

Clinical and microbiological characteristics of Cryptococcus gattii isolated from 7 hospitals in China.

BACKGROUND: Infection, even outbreak, caused by Cryptococcus gattii (C. gattii) has been reported in Canada and the United States, but there were sparsely-reported cases of C. gattii in China. Our interest in occurrence, clinical manifestation, laboratory identification and molecular characterization of Chinese C. gattii strains leads us to this research. RESULTS: Out of 254 clinical isolates, initially identified as Cryptococcus neoformans (C. neoformans), eight strains were re-identified as C. gattii. Multi-locus sequence typing (MLST) showed genotype VGI accounted for the most (6 / 8), the other two strains were genotype VGII (VGIIa and VGIIb respectively) with 3 specific spectra of molecular weight about 4342, 8686, 9611 Da by MALDI-TOF MS. The minimal inhibitory concentrations (MICs) of Fluconazole with Yeast one was 2~4 times higher than that with ATB fungus 3 and MICs of antifungal agents against VGII strains were higher than against VGI strains. Comparative proteome analysis showed that 329 and 180 proteins were highly expressed by C. gattii VGI and VGII respectively. The enrichment of differentially expressed proteins was directed to Golgi complex. CONCLUSIONS: Infection by C. gattii in China occurred sparsely. Genotype VGI was predominant but VGII was more resistant to antifungal agents. There was significant difference in protein expression profile between isolates of VGI and VGII C. gattii.

Index-based dietary patterns in relation to gastric cancer risk: a systematic review and meta-analysis.

Dietary indices are widely used in diet quality measurement, and the index-based dietary patterns are related to gastric cancer risk. To evaluate the relationship between different kinds of index-based dietary patterns and gastric cancer risk, we systematically searched four English-language databases and four Chinese-language databases. The quality of studies was assessed by the Newcastle­Ottawa Scale. Meta-analyses were performed to estimate the association between gastric cancer incidence and different types of index-based dietary patterns. The OR and hazard ratios (HR) of gastric cancer incidence were calculated by regression models in case­control studies and prospective cohort studies, respectively. The studies were pooled in the random effects model to calculate the summarised risk estimate of the highest quantile interval of dietary indices, taking the lowest as the referent. The dietary indices included different versions of Mediterranean diet score (MDS) and dietary inflammatory index (DII), healthy eating index, Chinese Food Pagoda score and food index score. The meta-analysis was carried out for studies on MDS and DII. The combined OR of gastric cancer for the highest MDS v. the referent was 0·42 (95 % CI 0·2, 0·86), and the combined HR was 0·89 (95 % CI 0·68, 1·17). The combined OR for DII was 2·11 (95 % CI 1·41, 3·15). Higher Mediterranean dietary pattern consumption might reduce gastric cancer risk, while higher inflammatory diet pattern consumption might increase gastric cancer risk.

Prevalence and characteristics of surgical site hypervirulent Klebsiella pneumoniae isolates.

BACKGROUND: We aim to determine the prevalence of hypervirulent Klebsiella pneumoniae (hvKp), which causes surgical site infections (SSIs), and describe the microbiological and molecular characteristics of hvKp isolates. METHODS: Non-duplicate K. pneumoniae strains were isolated from wound drainage specimens of postoperative patients at the Chinese PLA General Hospital between September 2008 and July 2017. Antimicrobial susceptibility, string test, pulsed-field gel electrophoresis (PFGE), and genome sequencing analyses were performed. RESULTS: Fifty-one K. pneumoniae strains were isolated from wound drainage specimens collected from postoperative patients. Twenty-six hvKp strains, including 17 (17/37, 46.0%) and 9 (9/14, 64.3%) hvKp strains, were isolated from 37 and 14 patients with SSIs and community-acquired infections (CAIs), respectively. Notably, 4 extended-spectrum beta-lactamase (ESBL)-producing hvKp strains (4/26, 15.4%) and 2 carbapenem-resistant hvKp strains (2/26, 7.7%) were found. Thirteen K1 serotype (13/26, 50.0%) and 7 K2 serotype (7/26, 26.9%) strains were identified. Phylogenetic analysis results showed that 13 K1 serotype isolates exhibited a high degree of clonality, while 7 K2 serotype strains were genetically unrelated. MLST analysis indicated that there was a strong correlation between ST23 and the K1 serotype. ST65, ST86, and ST375 were prevalent in K2 serotype strains. Almost all hvKp strains (24/26, 92.3%) harbored large virulence plasmids with a high degree of homology to pNTUH-K2044 and sizes ranging from 140 to 220 kbp. CONCLUSIONS: HvKp strains were prevalent in SSIs. Effective surveillance and control measures should be implemented to prevent the dissemination of such organisms, including the ESBL-producing and carbapenem-resistant hvKp strains.

The chimeric mitochondrial gene orf182 causes non-pollen-type abortion in Dongxiang cytoplasmic male-sterile rice.

D1-cytoplasmic male sterility (CMS) rice is a sporophytic cytoplasmic male-sterile rice developed from Dongxiang wild rice that exhibits a no-pollen-grain phenotype. A mitochondrial chimeric gene (orf182) was detected by mitochondrial genome sequencing and a comparative analysis. Orf182 is composed of three recombinant fragments, the largest of which is homologous to Sorghum bicolor mitochondrial sequences. In addition, orf182 was found only in wild rice species collected from China. Northern blot analysis showed that orf182 transcripts were affected by Rf genes in the isocytoplasmic restorer line DR7. Western blot analysis showed that the ORF182 product was localized in the mitochondria of the CMS line. An expression cassette containing orf182 fused to a mitochondrial transit peptide induced the maintainer line of male sterility, which lacked pollen grains in the anthers. Furthermore, the in vivo expression of orf182 also inhibited the growth of Escherichia coli, with lower respiration rate, excess accumulation of reactive oxygen species and decreased ATP levels. We conclude that the mitochondrial chimeric gene orf182 possesses a unique structure and origin differing from other identified mitochondrial CMS genes, and this gene is connected to non-pollen type of sporophytic male sterility in D1-CMS rice.

Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2.

Human breast cancer susceptibility gene, BRCA2, encodes a 3418-amino acid protein that is essential for maintaining genomic integrity. Among the proteins that physically interact with BRCA2, Partner and Localizer of BRCA2 (PALB2), which binds to the N-terminal region of BRCA2, is vital for its function by facilitating its subnuclear localization. A functional redundancy has been reported between this N-terminal PALB2-binding domain and the C-terminal DNA-binding domain of BRCA2, which undermines the relevance of the interaction between these two proteins. Here, we describe a genetic approach to examine the functional significance of the interaction between BRCA2 and PALB2 by generating a knock-in mouse model of Brca2 carrying a single amino acid change (Gly25Arg, Brca2G25R) that disrupts this interaction. In addition, we have combined Brca2G25R homozygosity as well as hemizygosity with Palb2 and Trp53 heterozygosity to generate an array of genotypically and phenotypically distinct mouse models. Our findings reveal defects in body size, fertility, meiotic progression, and genome stability, as well as increased tumor susceptibility in these mice. The severity of the phenotype increased with a decrease in the interaction between BRCA2 and PALB2, highlighting the significance of this interaction. In addition, our findings also demonstrate that hypomorphic mutations such as Brca2G25R have the potential to be more detrimental than the functionally null alleles by increasing genomic instability to a level that induces tumorigenesis, rather than apoptosis.

Modified Combined Fascia Sheath and Levator Muscle Complex Suspension With Müller Muscle Preservation on Treating Severe Congenital Ptosis.

BACKGROUND: This study aims to evaluate the effect of a modified approach on severe congenital ptosis treatment. METHODS: Through anterior approach, Müller muscle was preserved, meanwhile the upper tarsus was suspended to combined fascia sheath (CFS) and levator muscle (LM) complex. The main outcome measures included marginal reflex distance1 (MRD1), palpebral fissure height (PFH), MRD1 regression, MRD1 improvement, and patient self-satisfaction. RESULTS: There were 70 patients (90 eyelids) with severe congenital ptosis received treatment of modified operation, including 20 bilateral and 50 unilateral ptosis. The average LF was 2.53 ± 1.06 mm. The preoperative MRD1 and PFH was -0.06 ± 0.76 mm and 4.25 ± 0.85 mm, respectively. The follow-up was at least 6 months with average of 12.67 ± 4.92 months. The immediate postoperative MRD1 and PFH average was 4.52 ± 0.39 mm and 9.24 ± 0.26, respectively. The last follow-up MRD1 and PFH average was 2.43 ± 0.57 mm and 7.16 ± 0.69 mm, respectively, which was improved significantly (P < 0.01). There were variety degrees of MRD1 regression especially in the first month after operation, and the last follow-up MRD1 regression was 2.09 ± 0.67 mm. The lagophthalmos was obvious immediately after operation and regularly released after 6 months. Objective curative effect assessment showed 78 (86.7%) satisfactory eyes, 4 (4.4%) improved eyes, and 8 (8.9%) noneffective eyes. Two noneffective eyes required reoperation of frontalis suspension. Self-satisfaction rate was 93.3%. Parameters analysis showed that LF had positive correlation with last follow-up MRD1 and negative correlation with MRD1 improvement (P < 0.01). Five eyes had levator shorten history, which was associated remarkably with CFS + LM curative effect (P < 0.01). Mean swelling time was 0.53 ± 0.41 months, and no complications were observed until the last visit. CONCLUSIONS: This modified method gives powerful correction and vivid eyelid contour, featured with simple surgical procedures, few complications, and satisfactory effect, which is worth to wide application.