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Purpose The individual placement and support (IPS) model of supported employment is a leading evidence-based practice in community mental health services. In Japan, individualized supported employment that is highly informed by the philosophy of the IPS model has been implemented. While there is a body of evidence demonstrating the association between program fidelity and the proportion of participants gaining competitive employment, the association between fidelity and a wider set of vocational and individual outcomes has received limited investigation. This study aimed to assess whether high-fidelity individualized supported employment programs were superior to low-fidelity programs in terms of vocational outcomes, preferred job acquisition, and patient-reported outcome measures (PROMs). Methods A prospective longitudinal study with 24-month follow-up analyzed 16 individualized supported employment programs. The Japanese version of the individualized Supported Employment Fidelity scale (JiSEF) was used to assess the structural quality of supported employment programs (scores: low-fidelity program, ≤ 90; high-fidelity program, ≥ 91). Job acquisition, work tenure, work earnings, job preference matching (e.g., occupation type, salary, and illness disclosure), and PROMs such as the INSPIRE and WHO-Five Well-being index were compared between groups. Results There were 75 and 127 participants in the low-fidelity group (k = 6) and high-fidelity group (k = 10), respectively. The high-fidelity group demonstrated better vocational outcomes than the low-fidelity group, i.e., higher competitive job acquisition (71.7% versus 38.7%, respectively, adjusted odds ratio (aOR) = 3.6, p = 0.002), longer work tenure (adjusted mean difference = 140.8, p Conclusion High-fidelity individualized supported employment programs resulted in good vocational outcomes in a real-world setting. However, enhancing service quality to increase desired job acquisition and improve PROMs will be important in the future. Clinical Trial Registration UMIN000025648

Objective In an effort to reduce mortality from gastric cancer, endoscopic screening was introduced in 2016 as a nationwide screening program in Japan. Recent developments in high-definition endoscopic imaging and diagnostic strategies have enabled the simultaneous detection of other upper gastrointestinal (U-GI) malignancies. Therefore, we conducted a study to evaluate the feasibility of endoscopic screening for U-GI malignancy in a comprehensive health checkup. Methods We retrospectively reviewed the data of 13,120 participants who had received a comprehensive health checkup in a single institution between April 2012 and March 2018. Participants were divided into two groups [gastrointestinal endoscopy (GIE) group (n=9,142) and gastrointestinal X-ray (X-ray) group (n=3,978)] and compared with regards to the screening results, adverse events, and detection rate of U-GI malignancies (gastric cancer or other) using a propensity-score matched analysis. Results The gastric cancer detection rate was significantly higher in the GIE group [34/9,142 (0.48%)] than in the X-ray group [3/3,978 (0.08%)] (p=0.003). Other U-GI malignancies were found only in the GIE group and comprised two hypopharyngeal cancers, five esophageal cancers, two duodenal cancers, and one duodenal gastrointestinal stromal tumor. Adverse events occurred in 6/9,142 (0.07%) participants in the GIE group and 18/3,978 (0.45%) participants in the X-ray group (p

The growing literature on gender inequality in academia attests to the challenge that awaits female researchers during their academic careers. However, research has not yet conclusively resolved whether these biases persist during the peer review process of research grant funding and whether they impact respective funding decisions. Whereas many have argued for the existence of gender inequality in grant peer reviews and outcomes, others have demonstrated that gender equality is upheld during these processes. In the present paper, we illustrate how these opinions have come to such opposing conclusions and consider methodological and contextual factors that render these findings inconclusive. More specifically, we argue that a more comprehensive approach is needed to further the debate, encompassing individual and systemic biases as well as more global social barriers. We also argue that examining gender biases during the peer review process of research grant funding poses critical methodological challenges that deserve special attention. We conclude by providing directions for possible future research and more general considerations that may improve grant funding opportunities and career paths for female researchers.

Purpose: Endoscopic submucosal dissection is a promising method for the resection of superficial gastric neoplasms. To date, several institutions have used proton pump inhibitor injections over the perioperative period. However, there is very little evidence regarding their efficacy. To overcome this limitation, we compared procedural outcomes and the prevention of adverse events of proton pump inhibitor injection with an orally administered active potassium-competitive acid blocker alone. Participants and Methods: We enrolled a total of 150 patients treated for superficial gastric neoplasms at a single institution between April 2015 and December 2018. Patients treated for 2 days with proton pump inhibitor injections following 12 days of oral potassium-competitive acid blocker (proton pump inhibitor group=80) were compared with patients treated for 14 days orally with potassium-competitive acid blocker alone (potassium-competitive acid blocker group=70) using propensity score analysis. We evaluated intragastric pH levels prior to endoscopic submucosal dissection, frequency of intraoperative major bleeding, procedure time, en bloc resection rate, curability, ulcer reduction rate 14 days after endoscopic submucosal dissection, and adverse events (including perforation and postoperative bleeding). Results: Propensity score analysis yielded 43 matched pairs. The comparison demonstrated similar values for the outcomes. For all cases, we observed intragastric pH levels >6.4 prior to endoscopic submucosal dissection. Postoperative bleeding rates were 2.3% (1/43) in the proton pump inhibitor group and 0.0% (0/43) in the potassium-competitive acid blocker group (P=0.315). Conclusions: Oral potassium-competitive acid blocker alone was as effective as proton pump inhibitor injection, with a low incidence of adverse events. Based on these results, proton pump inhibitor injection might be omitted during gastric endoscopic submucosal dissection.

SummaryPlant nucleotide-binding leucine-rich repeat receptors (NLRs) initiate immune responses and the hypersensitive response by recognizing pathogen effectors. Xa1 encodes an NLR with an N-terminal BED domain, and recognizes transcription activator-like (TAL) effectors of Xanthomonas oryzae pv. oryzae (Xoo). The molecular mechanisms controlling the recognition of TAL effectors by Xa1 and the subsequent induction of immunity remain poorly understood.Xa1 interacts in the nucleus with two TAL effectors via the BED domain. We identified the AP2/ERF-type transcription factor OsERF101/OsRAP2.6 as an interactor with Xa1, and found that it also interacts with the TAL effectors.Overexpression of OsERF101 exhibited an enhanced resistance to an incompatible Xoo strain only in the presence of Xa1, indicating that OsERF101 functions as a positive regulator of Xa1-mediated immunity. Unexpectedly, oserf101 mutants also showed enhanced Xa1-dependent resistance, but in a different manner from the overexpressing plants. This result revealed an additional Xa1-mediated immune pathway that is negatively regulated by OsERF101. Furthermore, OsERF101 directly interacted with the TAL effectors.Our results show that OsERF101 regulates the recognition of TAL effectors and the Xa1-mediated activation of the immune response. These data provide new insights into the molecular mechanism of NLR-mediated immunity in plants.

Simple Summary Stimulator of interferon genes (STING) is currently recognized as a driver for anti-tumor immunity against various malignancies and is expected to enhance the anti-tumor effects. In this review, we summarized recent knowledges gained from epigenetics-mediated skin cancer development and discussed the clinical application of STING agonists in the treatment of skin cancer. Abstract Recent developments in immunotherapy against malignancies overcome the disadvantages of traditional systemic treatments; however, this immune checkpoint treatment is not perfect and cannot obtain a satisfactory clinical outcome in all cases. Therefore, an additional therapeutic option for malignancy is needed in oncology. Stimulator of interferon genes (STING) has recently been highlighted as a strong type I interferon driver and shows anti-tumor immunity against various malignancies. STING-targeted anti-tumor immunotherapy is expected to enhance the anti-tumor effects and clinical outcomes of immunotherapy against malignancies. In this review, we focus on recent advancements in the knowledge gained from research on STING signaling in skin cancers. In addition to the limitations of STING-targeted immunotherapy, we also discuss the clinical application of STING agonists in the treatment of skin cancer.

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulated complement activation. Clinically, aHUS is effectively treated by an anti-C5 monoclonal antibody (mAb) but whether the disease is mediated by the C5a receptor (C5aR) or C5b-9 pathway, or both, is unknown. Here we address this in a factor H mutant mouse (FHR/R) which developed complement-mediated TMA as well as macrovascular thrombosis caused by an aHUS-related factor H point mutation (mouse W1206R, corresponding to human W1183R). C5 deficiency and anti-C5 mAb treatment blocked all disease manifestations in FHR/R mice. C5aR1 gene deficiency prevented macrovascular thrombosis in various organs but did not improve survival or reduce renal TMA. Conversely, C6 or C9 deficiency significantly improved survival and markedly diminished renal TMA but did not prevent macrovascular thrombosis. Interestingly, as they aged both FHR/R C6−/− and FHR/R C9−/− mice developed glomerular disease reminiscent of C3 glomerulonephritis. Thus, C5aR and C5b-9 pathways drove different aspects of disease in FHR/R mice with the C5aR pathway being responsible for macrovascular thrombosis and chronic inflammatory injury while the C5b-9 pathway caused renal TMA. Our data provide new understanding of the pathogenesis of complement-mediated TMA and macrovascular thrombosis in FHR/R mice and suggest that C5 blockade is more effective for the treatment of aHUS than selectively targeting the C5aR or C5b-9 pathway alone.

Plant nucleotide-binding leucine-rich repeat receptors (NLRs) initiate immune responses by recognizing pathogen effectors. The rice gene Xa1 encodes an NLR with an N-terminal BED domain, and recognizes transcription activator-like (TAL) effectors of Xanthomonas oryzae pv. oryzae (Xoo). Our goal is to elucidate the molecular mechanisms controlling the induction of immunity by Xa1. We used yeast two-hybrid assays to screen for host factors that interact with Xa1 and identified the AP2/ERF-type transcription factor OsERF101/OsRAP2.6. Molecular complementation assays were used to confirm the interactions among Xa1, OsERF101, and two TAL effectors. We created OsERF101-overexpressing and knockout mutant lines in rice and identified genes differentially regulated in these lines, many of which are predicted to be involved in regulation of response to stimulus. Xa1 interacts in the nucleus with the TAL effectors and OsERF101 via the BED domain. Unexpectedly, both the overexpression and knockout lines of OsERF101 displayed Xa1-dependent, enhanced resistance to an incompatible Xoo strain. Different sets of genes were up- or down-regulated in the overexpression and knockout lines. Our results indicate that OsERF101 regulates the recognition of TAL effectors by Xa1, and functions as a positive regulator of Xa1-mediated immunity. Further, an additional Xa1-mediated immune pathway is negatively regulated by OsERF101., イネが病原菌の感染力の源を検出して免疫を誘導する仕組みを解明 --病気に強い植物の開発に期待--. 京都大学プレスリリース. 2022-09-07.

We present a preliminary validation of a newly built questionnaire aimed at evaluating people’s openness towards the notion of non-binary gender. To explore the validity of our questionnaire, we ran a principal component analysis to evaluate the existence of three overarching dimensions (Gender Categories, Gender Fluidity, and Gender Definitions) that were at the very foundation of our questionnaire. We also explored the link between our questionnaire and measures of one’s political orientation and feminist identification. In all, our questionnaire was found to have an acceptable level of reliability, and as such, constitutes an important tool for better understanding people’s attitudes towards non-binary gender.

A growing body of recent research suggests that verbal categories, particularly labels, impact categorization and perception. These findings are commonly interpreted as demonstrating the involvement of language on cognition; however, whether these assumptions hold true for grammatical structures has yet to be investigated. In the present study, we investigated the extent to which linguistic information, namely, grammatical gender categories, structures cognition to subsequently influence categorical judgments and perception. In a nonverbal categorization task, French-English bilinguals and monolingual English speakers made gender-associated judgments about a set of image pairs while event-related potentials were recorded. The image sets were composed of an object paired with either a female or male face, wherein the object was manipulated for their conceptual gender relatedness and grammatical gender congruency to the sex of the following target face. The results showed that grammatical gender modulated the N1 and P2/VPP, as well as the N300 exclusively for the French-English bilinguals, indicating the inclusion of language in the mechanisms associated with attentional bias and categorization. In contrast, conceptual gender information impacted the monolingual English speakers in the later N300 time window given the absence of a comparable grammatical feature. Such effects of grammatical categories in the early perceptual stream have not been found before, and further provide grounds to suggest that language shapes perception.

In the field of organic syntheses, the development of environmentally friendly methods based on the concept of green chemistry has been always required. In response to this requirement, we reported solvent- and catalyst-free syntheses of imines using the pressure reduction technique as a key technology. We found that this reaction proceeded very rapidly in the initial stage, but its rate decreased with the passage of time. It was also found that the reaction of benzaldehyde with aniline had a specificity that the phase transition occurred. In this method, the desired imines could be obtained in good to excellent yields, but target compounds had to be given by purifications using organic solvents. Therefore, we tried to develop the perfect synthetic method of imine derivatives without organic or inorganic solvents. We selected two methods and took them into this investigation. One was exactly mixing (1:1, substance ratio) aldehydes and amines and the other was employing lower pressure (>0.1 mmHg, previous method: 1.0 mmHg) at the pressure reducing technique. When this improved synthetic method was performed, it was revealed that pure target imines were obtained in excellent yields without any purification.

Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of complement-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain.Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality.Results P deficiency completely rescued FHR/R mice from premature death and prevented thrombocytopenia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice.Conclusions These results contrast with the detrimental effect of P inhibition observed in a murine model of C3 glomerulopathy and suggest that P contributes critically to aHUS pathogenesis. Inhibition of P in aHUS may be of therapeutic benefit.

Complement plays a key role in host defense, but its dysregulation can cause autologous tissue injury. Complement activation is normally controlled by regulatory proteins, including factor H (FH) in plasma and membrane cofactor protein (MCP) on the cell surface. Mutations in FH and MCP are linked to atypical hemolytic uremic syndrome, a type of thrombotic microangiopathy (TMA) that causes renal failure. We describe here that disruption of FH function on the cell surface can also lead to disseminated complement-dependent macrovascular thrombosis. By gene targeting, we introduced a point mutation (W1206R) into murine FH that impaired its interaction with host cells but did not affect its plasma complement-regulating activity. Homozygous mutant mice carrying this mutation developed renal TMA as well as systemic thrombophilia involving large blood vessels in multiple organs, including liver, lung, spleen, and kidney. Approximately 30% of mutant mice displayed symptoms of stroke and ischemic retinopathy, and 48% died prematurely. Genetic deficiency of complement C3 and factor D prevented both the systemic thrombophilia and renal TMA phenotypes. These results demonstrate a causal relationship between complement dysregulation and systemic angiopathy and suggest that complement activation may contribute to various human thrombotic disorders involving both the micro- and macrovasculature.

Little is known about the association between service intensity and fidelity scale score in supported employment programs. This study compares service contents and intensity in low- and high-fidelity programs and examines the validity of the Japanese version of the individualized Supported Employment Fidelity Scale.The vocational outcomes and service provision data for 51 individuals with schizophrenia in 13 supported employment programs were collected over a 12-month study period. Outcomes, service contents, and service intensity were compared between the low-fidelity group (seven programs; N=29) and the high-fidelity group (six programs; N=22).In both groups, 70% of the total services (hours) were provided in the first 6 months. The high-fidelity group, which was associated with better vocational outcomes than the low-fidelity group (employment rate, 68% versus 38%, respectively), made the greatest effort in job development outside of the agency, whereas the low-fidelity group spent more time on group services. In addition, before the client obtained a job, high-fidelity programs provided outreach services (B=7.2, p=0.043) and agency-based individual services (B=5.7, p0.001) at greater intensity than did low-fidelity programs. However, no significant between-group difference was found in service intensity once clients were employed.Supported employment programs with a high fidelity score focus more intensely on providing individual services in and outside of the agency, particularly before clients obtain a job. However, clarification of the relationships among service quality at the structure level, amount of follow-up services, and individual needs in supported employment programs is a future issue.

Aim The aim of this study was to clarify whether improvement of cognitive functioning by cognitive remediation therapy can improve work outcome in schizophrenia and other severe mental illnesses when combined with supported employment. Methods The subjects of this study were persons with severe mental illness diagnosed with schizophrenia, major depression, or bipolar disorder (ICD-10) and cognitive dysfunction who participated in both cognitive remediation using the Thinking Skills for Work program and a supported employment program in a multisite, randomized controlled study. Logistic and multiple linear regression analyses were performed to clarify the influence of cognitive functioning on vocational outcomes, adjusting for demographic and clinical variables. Results Improvement of cognitive functioning with cognitive remediation significantly contributed to the total days employed and total earnings of competitive employment in supported employment service during the study period. Any baseline demographic and clinical variables did not significantly contribute to the work-related outcomes. Conclusion A cognitive remediation program transferring learning skills into the real world is useful to increase the quality of working life in supported employment services for persons with severe mental illness and cognitive dysfunction who want to work competitively.

The generic use of masculine plural forms in grammatical gender languages has been criticized for activating unequal gender representations that are male dominant. The present study examined whether the recently introduced gender-neutral forms of nominalized adjectives and participles in German provide references that induce more balanced representations. We used cross-linguistic differences as a means to illustrate the flexibility of the gender representation system and investigated both native and nonnative (French–German bilinguals) speakers of German. Although a masculine bias persisted when participants read role nouns in the masculine plural form, the study suggests that the usage of nominalized forms can attenuate this male bias, even for nonnative speakers. The results of the study provide further support for the use of gender-neutral language.

Purpose Dense deposit disease (DDD) is caused by dysregulation of the alternative pathway of the complement cascade and characterized by electron-dense deposits in the kidney glomerular basement membrane (GBM) and drusen in Bruch's membrane (BrM). Complement factor H (fH) and factor properdin (fP) regulate complement activation; fH inhibits alternative pathway (AP) activation, whereas fP promotes it. We report pathologic changes in eyes of an fH and fP double-mutant mouse, which we previously showed have dense deposits in the GBM and early mortality from nephropathy. Methods fHm/m, fP-/-, and fHm/m/fP-/- mice were generated on a C57BL/6-129J background. Fundus imaging at 8 weeks of age was followed by analysis via light and electron microscopy. Retinal function was assessed by electroretinography (ERG). Complement levels and localization were tested by immunohistochemistry and ELISA. Retinas of fHm/m/fP-/- mice treated with intraperitoneal injections of an anti-C5 antibody were compared to those of age- and genotype-matched mice injected with an isotype control antibody. Results fHm/m/fP-/- mice suffered early-onset retinal hypopigmented spots detected using in vivo retinal photography, and histologic examination showed basal laminar deposits (BLamD), degeneration of the photoreceptors, and RPE vacuolization. ERG showed diminished retinal function. The anti-C5 antibody was retina-protective. Conclusions This unique mouse represents a new model of complement-mediated rapid-onset DDD, and could be useful in exploring the pathologic changes associated with BLamD in age-related macular degeneration.

Two experiments assessed the extent to which grammatical gender provides a predictive basis for bilinguals' judgments about perceptual gender. In both experiments, French-English bilinguals and native English monolinguals were consecutively presented with images of objects manipulated for their (i) conceptual gender association and (ii) grammatical gender category and were instructed to make a decision on a subsequent target face. The experiments differed in the implicitness of the association between the object primes and target faces. Results revealed that when prior knowledge sources such as conceptual gender can be strategically used to resolve the immediate task (Experiment 1), this information was readily extracted and employed. However, grammatical gender demonstrated a more robust and persisting effect on the bilinguals' judgments, indicating that the retrieval of obligatory grammatical information is automatic and modulates perceptual judgments (Experiment 2). These results suggest that grammar enables an effective and robust means to access prior knowledge which may be independent of task requirements.

Purpose: To investigate image-registration errors when using fiducial markers with a manual method and the point-based rigid-body registration (PRBR) algorithm in accelerated partial breast irradiation (APBI) patients, with accompanying fiducial deviations. Methods: Twenty-two consecutive patients were enrolled in a prospective trial examining 10-fraction APBI. Titanium clips were implanted intraoperatively around the seroma in all patients. For image-registration, the positions of the clips in daily kV x-ray images were matched to those in the planning digitally reconstructed radiographs. Fiducial and gravity registration errors (FREs and GREs, respectively), representing resulting misalignments of the edge and center of the target, respectively, were compared between the manual and algorithm-based methods. Results: In total, 218 fractions were evaluated. Although the mean FRE/GRE values for the manual and algorithm-based methods were within 3 mm (2.3/1.7 and 1.3/0.4 mm, respectively), the percentages of fractions where FRE/GRE exceeded 3 mm using the manual and algorithm-based methods were 18.8%/7.3% and 0%/0%, respectively. Manual registration resulted in 18.6% of patients with fractions of FRE/GRE exceeding 5 mm. The patients with larger clip deviation had significantly more fractions showing large FRE/GRE using manual registration. Conclusions: For image-registration using fiducial markers in APBI, the manual registration results in more fractions with considerable registration error due to loss of fiducial objectivity resulting from their deviation. The authors recommend the PRBR algorithm as a safe and effective strategy for accurate, image-guided registration and PTV margin reduction.

RÉSUMÉDans cet article, nous présentons les recherches, relativement récentes, sur l'intégration du genre dans la représentation mentale d'une lectrice ou d'un lecteur, en mettant l'accent sur leurs controverses ainsi que sur les pistes encore peu (ou pas) explorées. Nous espérons ainsi susciter l'intérêt de la communauté francophone sur ce sujet, jusqu'ici relativement discrète. Au travers de cette présentation, nous souhaitons également souligner les retombées sociétales des recherches sur ce sujet, principalement au travers de l'identification de processus langagiers discriminants.Si la recherche a jusqu'ici principalement ciblé des adultes dits monolingues entre 19 et 25 ans, nous présenterons également les quelques études qui ont été menées sur les enfants entre 6 et 15 ans, un projet en cours sur des enfants entre 2 et 3 ans et quelques résultats d'une étude récente examinant l'influence du bilinguisme sur la représentation du genre.

Background: In Japan, Job assistance for SMI have been not active. Compared with mental retardation, employment rate of SMI was low. The needs of the effective job assistance for SMI are growing. The purpose of this study was to determine the effectiveness of the combination approach of Cognitive Remediation (CR) and Supported Employment (SE) in clinical outcomes, including cognitive functioning and psychiatric symptoms besides vocational outcomes. Methods: The participants diagnosed with schizophrenia or schizoaffective disorder were assigned to CR+SE group (n=52) and SE group (n=57). CR comprised computer based trainings using COGPACK and group works. SE was individualized vocational support provided by employment specialists. Outcome measures included cognitive functioning, psychiatric symptoms, social functioning, performance of tasks as clinical outcomes, employment rate, duration of employment, and earned wage as vocational outcome. Results: CR+SE group displayed significantly better psychiatric symptoms (F=3.490, pDiscussions: This is the first controlled study to determine the effectiveness of CR on vocational outcomes in Japan. The results showed that CR and SE programs were feasible in Japan and that CR using COGPACK had favorable effects on cognitive functioning, psychiatric symptoms, and social functioning, which is consistent with previous researches.

SMAP2 is an Arf GAP and modulates clathrin-coated vesicle formation. SMAP2-deficient male mice exhibited globozoospermia due to acrosome deformation. In SMAP2(−/−) spermatids, budding of proacrosomal vesicles from the TGN was distorted and clathrin traffic–related molecules such as CALM and syntaxin2 were mislocated., The trans-Golgi network (TGN) functions as a hub organelle in the exocytosis of clathrin-coated membrane vesicles, and SMAP2 is an Arf GTPase-activating protein that binds to both clathrin and the clathrin assembly protein (CALM). In the present study, SMAP2 is detected on the TGN in the pachytene spermatocyte to the round spermatid stages of spermatogenesis. Gene targeting reveals that SMAP2-deficient male mice are healthy and survive to adulthood but are infertile and exhibit globozoospermia. In SMAP2-deficient spermatids, the diameter of proacrosomal vesicles budding from TGN increases, TGN structures are distorted, acrosome formation is severely impaired, and reorganization of the nucleus does not proceed properly. CALM functions to regulate vesicle sizes, and this study shows that CALM is not recruited to the TGN in the absence of SMAP2. Furthermore, syntaxin2, a component of the soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complex, is not properly concentrated at the site of acrosome formation. Thus this study reveals a link between SMAP2 and CALM/syntaxin2 in clathrin-coated vesicle formation from the TGN and subsequent acrosome formation. SMAP2-deficient mice provide a model for globozoospermia in humans.

Complement receptor 1–related gene/protein y (Crry) and decay-accelerating factor (DAF) are two murine membrane C3 complement regulators with overlapping functions. Crry deletion is embryonically lethal whereas DAF-deficient mice are generally healthy. Crry−/−DAF−/− mice were viable on a C3−/− background, but platelets from such mice were rapidly destroyed when transfused into C3-sufficient mice. In this study, we used the cre-lox system to delete platelet Crry in DAF−/− mice and studied Crry/DAF-deficient platelet development in vivo. Rather than displaying thrombocytopenia, Pf4-Cre+-Crryflox/flox mice had normal platelet counts and their peripheral platelets were resistant to complement attack. However, chimera mice generated with Pf4-Cre+-Crryflox/flox bone marrows showed platelets from C3−/− but not C3+/+ recipients to be sensitive to complement activation, suggesting that circulating platelets in Pf4-Cre+-Crryflox/flox mice were naturally selected in a complement-sufficient environment. Notably, Pf4-Cre+-Crryflox/flox mouse platelets became complement susceptible when factor H function was blocked. Examination of Pf4-Cre+-Crryflox/flox mouse bone marrows revealed exceedingly active thrombopoiesis. Thus, under in vivo conditions, Crry/DAF deficiency on platelets led to abnormal platelet turnover, but peripheral platelet count was compensated for by increased thrombopoiesis. Selective survival of Crry/DAF-deficient platelets aided by factor H protection and compensatory thrombopoiesis demonstrates the cooperation between membrane and fluid phase complement inhibitors and the body’s ability to adaptively respond to complement regulator deficiencies.

C3 glomerulopathy is a potentially life-threatening disease of the kidney caused by dysregulated alternative pathway complement activation. The specific complement mediator(s) responsible for kidney injury in C3 glomerulopathy are yet to be defined and no specific therapy is currently available. We previously developed a mouse model of lethal C3 glomerulopathy with factor H and properdin gene double mutations. Therefore, we used this model to examine the role of C5 and C5a receptor (C5aR) in the pathogenesis of the disease. Disease severity in these factor H/properdin double-mutant mice was found to be correlated with plasma C5 levels, and prophylactic anti-C5 mAb therapy was effective in preventing lethal C3 glomerulopathy. When given to these double-mutant mice that had already developed active disease with severe proteinuria, anti-C5 mAb treatment also prevented death in half of the mice. Deficiency of C5aR significantly reduced disease severity, suggesting that C5aR-mediated inflammation contributed to C3 glomerulopathy. Thus, C5 and C5aR have a critical role in C3 glomerulopathy. Hence, early intervention targeting these pathways may be an effective therapeutic strategy for patients with C3 glomerulopathy.

Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fH-mutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous disease-specific target validation.