Comparison of the Efficacy of Anti-Obesity Medications in Real-World Practice.

Purpose: Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting. Patients and Methods: The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit. Results: A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area. Conclusion: All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.

Exploring the Correlation between Systemic Inflammatory Markers and Carotid Atherosclerosis Indices in Middle-Aged Adults: A Cross-Sectional Study.

BACKGROUND: This study investigated the association between atherosclerosis and systemic inflammation markers, specifically the C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), in healthy middle-aged adults. METHODS: A retrospective cross-sectional study was conducted on a total of 1264 Korean adults aged 40-65. We assessed these inflammatory markers and carotid metrics, such as carotid intima-media thickness (cIMT), plaque number (PN), plaque stenosis score (PSS), and plaque score (PS), using linear regression, logistic regression, and receiver operating characteristic analysis. RESULTS: In males, the ESR and CRP were significantly correlated with the PN (p < 0.001 and p = 0.048, respectively). The ESR was correlated with the PN in females (p = 0.004). The NLR and PLR both correlated with the PS in males (p < 0.001 and p = 0.015, respectively) and females (p = 0.015 and p = 0.023, respectively). The odds ratio for the NLR as a risk factor for increased cIMT was 1.15 (95% confidence interval [CI], 1.03-2.15) for males and 1.05 (95% CI, 1.01-1.29) for females. The AUC for the NLR and PLR as a predictor for the PS showed significance in both men and women. CONCLUSIONS: Inflammatory markers, particularly the NLR and PLR, demonstrate a correlation with carotid atherosclerosis. Both the NLR and PLR hold potential as valuable surrogate markers for carotid atherosclerosis. To further substantiate their predictive efficacy, further prospective studies are needed.

Impact of the Great Recession on Adults With Autism and Their Mothers.

Autistic individuals and their families are at risk for poor outcomes in employment and mental health and may be vulnerable to long-term effects of broader societal conditions. The aim of the current longitudinal study was to understand the impact of the Great Recession of 2007-2009 on autistic individuals and their mothers (N = 392). Hierarchical linear modeling (HLM) results indicated that problem behavior of autistic adults increased in the years following the recession. The rate at which autistic individuals moved away and lived separately from their mothers also slowed during the recession. Mothers experienced significantly higher levels of depressive symptoms postrecession, compared to prerecession. In many other respects, the autistic individuals and their mothers did not experience negative outcomes, suggesting resilience and a strong safety net. These included the physical health and vocational/employment status of the autistic adults and their mothers. Results point to specific areas of vulnerability of autistic individuals and their mothers during the economic downturn, as well as a broad pattern of resilience in these families.

Acoustic correlates of perceived personality from Korean utterances in a formal communicative setting.

The aim of the present study was to find acoustic correlates of perceived personality from the speech produced in a formal communicative setting-that of Korean customer service employees in particular. This work extended previous research on voice personality impressions to a different sociocultural and linguistic context in which speakers are expected to speak politely in a formal register. To use naturally produced speech rather than read speech, we devised a new method that successfully elicited spontaneous speech from speakers who were role-playing as customer service employees, while controlling for the words and sentence structures they used. We then examined a wide range of acoustic properties in the utterances, including voice quality and global acoustic and segmental properties using Principal Component Analysis. Subjects of the personality rating task listened to the utterances and rated perceived personality in terms of the Big-Five personality traits. While replicating some previous findings, we discovered several acoustic variables that exclusively accounted for the personality judgments of female speakers; a more modal voice quality increased perceived conscientiousness and neuroticism, and less dispersed formants reflecting a larger body size increased the perceived levels of extraversion and openness. These biases in personality perception likely reflect gender and occupation-related stereotypes that exist in South Korea. Our findings can also serve as a basis for developing and evaluating synthetic speech for Voice Assistant applications in future studies.

Childhood abuse and opioid prescription use in adulthood: Differences between non-Hispanic Whites and non-Hispanic Blacks in the United States.

Despite the rapid rise in opioid prescription medication usage, little research has examined the role of early life adversity, such as childhood abuse, particularly in the context of race, in opioid prescription usage in adulthood. Guided by the life course perspective, the current study investigates whether experiencing childhood abuse increases the risk of opioid prescription use in adulthood and whether this association varies by race. Data were sourced from the second wave of the Midlife in the United States (MIDUS) study (2004-2005). The analytic sample consisted of two groups: non-Hispanic Whites (n = 714) and non-Hispanic Blacks (n = 151). Opioid prescription use was identified from the participants' medication list using the MULTUM Lexicon Drug Database Classification System. Three types of childhood abuse-emotional, physical, and sexual-were assessed via summary scales derived from the Childhood Trauma Questionnaire. The results indicate a significant interaction between childhood physical abuse and race. Among non-Hispanic Whites, higher exposure to physical abuse during childhood was associated with greater odds of opioid prescription use in adulthood, even after adjusting for chronic pain, physical and mental health, and sociodemographic characteristics. However, the association between childhood physical abuse and opioid prescription use in adulthood was non-significant among non-Hispanic Black individuals. These findings underscore the long-term adverse health effects of physical abuse in childhood, particularly for non-Hispanic Whites, and suggest support for developing and implementing tailored intervention strategies.

The Korean Speech Recognition Sentences: A Large Corpus for Evaluating Semantic Context and Language Experience in Speech Perception.

PURPOSE: The aim of this study was to develop and validate a large Korean sentence set with varying degrees of semantic predictability that can be used for testing speech recognition and lexical processing. METHOD: Sentences differing in the degree of final-word predictability (predictable, neutral, and anomalous) were created with words selected to be suitable for both native and nonnative speakers of Korean. Semantic predictability was evaluated through a series of cloze tests in which native (n = 56) and nonnative (n = 19) speakers of Korean participated. This study also used a computer language model to evaluate final-word predictabilities; this is a novel approach that the current study adopted to reduce human effort in validating a large number of sentences, which produced results comparable to those of the cloze tests. In a speech recognition task, the sentences were presented to native (n = 23) and nonnative (n = 21) speakers of Korean in speech-shaped noise at two levels of noise. RESULTS: The results of the speech-in-noise experiment demonstrated that the intelligibility of the sentences was similar to that of related English corpora. That is, intelligibility was significantly different depending on the semantic condition, and the sentences had the right degree of difficulty for assessing intelligibility differences depending on noise levels and language experience. CONCLUSIONS: This corpus (1,021 sentences in total) adds to the target languages available in speech research and will allow researchers to investigate a range of issues in speech perception in Korean. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24045582.

Postoperative cervical length to predict success of repeat cerclage in singleton pregnancies with prolapsed membranes after prior cerclage.

Background: This study aimed to evaluate the outcome of repeat cerclage (RC) in singleton pregnancies with prolapsed membranes following a prior cerclage and analyze predictive factors for delivery at ≥26 weeks of gestation following RC. Materials and methods: Patients who underwent RC between 2010 and 2020 at the Hallym University Medical Center were reviewed. Women with singleton pregnancies with prolapsed membranes following prior cerclage were candidates for RC. We analyzed the characteristics, pregnancy outcomes, perioperative clinical and laboratory findings, and postoperative cervical length (CL) to identify the factors for predicting delivery at ≥26 weeks following RC. Results: Thirty-five women with RC were identified; the median gestational age (GA) at a prior cerclage was 14 weeks, the average GA at RC was 21 + 3 weeks, and the median GA at delivery following RC was 26 + 2 weeks. Patients were divided into two groups based on their delivery status at 26 weeks: 17 women delivered at <26 weeks (range, 18 + 4-25 + 6 weeks) (Group A) and 18 women delivered at ≥26 weeks (range, 26 + 2-40 + 3 weeks) (Group B). The median GA at delivery in group A was 22 + 4 weeks, whereas that in group B was 33 + 4 weeks (p < 0.001). No differences in preoperative clinical and laboratory findings were observed between the two groups. However, the postoperative CL in group A was significantly shorter than that in group B (12 mm vs. 21.5 mm, p < 0.001). The ROC curve of postoperative CL predicting delivery at ≥26 weeks showed an AUC of 0.843; a CL of 20 mm showed a sensitivity of 61.1% and a specificity of 100%. Conclusion: RC may prolong singleton pregnancies with prolapsed membranes following prior cerclage. A postoperative CL ≥20 mm may predict the success of RC.

Local CpG- Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors.

Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have durable clinical response. It has been demonstrated that rescuing exhausted CD8 + T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T-cell mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG- Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG- Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG- Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.

Unpacking Psychological Vulnerabilities in Deaths of Despair.

Recent demographic findings show increased rates of death due to suicide, drug addictions, and alcoholism among midlife white adults of lower socioeconomic status (SES). These have been described as "deaths of despair" though little research has directly assessed psychological vulnerabilities. This study used longitudinal data from the Midlife in the U.S. (MIDUS) study to investigate whether low levels of eudaimonic and hedonic well-being predict increased risk of deaths of despair compared to other leading causes of death (cancer, heart disease). The investigation focused on 695 reported deaths with cause of death information obtained from 2004 to 2022 via NDI Plus. Key questions were whether risk for deaths due to despair (suicide, drug addiction, alcoholism) compared to deaths due to cancer or heart disease were differentially predicted by deficiencies in well-being, after adjusting for sociodemographic variables. Low levels of purpose in life, positive relations with others, personal growth and positive affect predicted significantly greater likelihood of deaths of despair compared to deaths due to heart disease, with such patterns prominent among better-educated adults. The findings bring attention to ongoing intervention efforts to improve psychological well-being.

Fabrication of liraglutide-encapsulated triple layer hyaluronic acid microneedles (TLMs) for the treatment of obesity.

Obesity is a chronic metabolic disease that is prevalent worldwide, causing complications that affect the quality of life and longevity of humans. Currently, the low bioavailability upon subcutaneous injection of an appetite suppressant, liraglutide, and health problems in the locally injected region remain to be overcome. In this study, we developed a novel hyaluronic acid-based liraglutide-encapsulated triple-layer microneedle (TLM) as a painless and patient-friendly long-term drug delivery system. In contrast to previous anti-obesity microneedle approaches, this TLM is composed of three layers for complete skin insertion, protecting the encapsulated liraglutide from environmental stresses. Daily topical application of the liraglutide-loaded TLM significantly reduced body weight and improved body composition in a mouse model of high-fat diet-induced obesity. Additionally, it ameliorated diet-induced hepatic steatosis in obese mice. This novel TLM could promote a glucagon-like peptide-1 drug release system for long-term daily administration with relatively higher patient compliance compared to subcutaneous injection.

Risk factors based on myoma characteristics for predicting postoperative complications following cesarean myomectomy.

OBJECTIVES: To evaluate the influence of myoma characteristics on cesarean myomectomy and to demonstrate its additional advantages. METHODS: Retrospective data were collected from 292 women with myomas who had undergone cesarean section at Kangnam Sacred Heart Hospital between 2007 and 2019. We performed subgroup analysis according to the type, weight, number, and size of myomas. Preoperative and postoperative hemoglobin levels, operative time, estimated blood loss, length of hospital stay, incidence of transfusion, uterine artery embolization, ligation, hysterectomy, and postoperative complications were compared among subgroups. RESULTS: There were 119 patients who had cesarean myomectomy and 173 who had cesarean section only. An increase in postoperative hospitalization and operation time was observed in the cesarean myomectomy group compared to that in the caesarean section only group (mean difference, 0.7 days, p = 0.01, 13.5 minutes, p <0.001). Estimated blood loss, hemoglobin differences, and transfusion rates were higher in the cesarean myomectomy than in the cesarean section only group. There were no differences in postoperative complications (fever, bladder injury, and ileus) between the two groups. No hysterectomy cases were reported in the cesarean myomectomy group. In subgroup analysis, the larger and heavier the myoma, the higher the risk of bleeding that led to transfusion. Estimated blood loss, differences in hemoglobin, and transfusion rate increased depending on myoma size and weight. A significant increase in postoperative hospitalization was observed in women with larger and heavier myomas. However, there was no statistical difference among the three types of myomas. CONCLUSION: In cesarean myomectomy, larger (≥ 10 cm), and heavier myomas (≥ 500 g), were associated with postoperative outcomes, but not the number or type of myoma. The safety of cesarean myomectomy is not inferior to that of caesarean section only, considering its positive effects such as gynecological symptom relief and avoidance of the next surgery.

Adverse Reactions after BNT162b2 Messenger RNA Vaccination for Coronavirus Disease 2019 in Healthcare Workers Compared with Influenza Vaccination.

This study aimed to compare adverse reactions following BNT162b2 and influenza vaccinations in healthcare workers. This study included healthcare workers who received the BNT162b2 vaccine and/or inactivated influenza vaccine, quadrivalent (IIV4), on 18-29 October 2021 at a tertiary hospital in Korea. IIV4 was administered and BNT162b2 was subsequently administered one week later. The participants responded to a mobile questionnaire regarding adverse events. The overall adverse reaction rates were 90.6% in the BNT162b2 + IIV4 group, 90.4% in the BNT162b2 alone group, and 44.1% in the IIV4 alone group (p < 0.001). Fever occurred in 19.5%, 26.9%, and 3.3% of participants in the BNT162b2 + IIV4, BNT162b2 alone, and IIV4 alone groups, respectively (p < 0.001). The most common local and systemic adverse reactions were injection site pain (65.0%) and fatigue (58.6%), respectively. Injection-site pain was experienced by 88.7%, 88.5%, and 37.5% of the BNT162b2 + IIV4, BNT162b2 alone, and IIV4 alone groups, respectively (p < 0.001). Fatigue was experienced by 74.8%, 78.8%, and 38.6% of the BNT162b2 + IIV4, BNT162b2 alone, and IIV4 alone groups, respectively (p < 0.001). Adverse reactions occurred at a significantly higher frequency after BNT162b2 than after IIV4. The frequency of adverse reactions one week after vaccination with IIV4 and BNT162b2 was not different from that after vaccination with BNT162b2 alone. Therefore, coadministration of influenza vaccine with BNT162b2 can be expected to be safe.

Improving Retention of Diverse Samples in Longitudinal Research on Developmental Disabilities.

Developmental disabilities (DD) research has depended on volunteer and clinical samples, with limited racial/ethnic diversity. This study focused on improving diversity and retention in DD research. The sample included 225 parents with a child with DD and 4,002 parents without children with DD from diverse racial/ethnic groups, drawn from Midlife in the United States, a national longitudinal study. Unexpectedly, parents of children with DD from diverse racial/ethnic groups were more likely to participate longitudinally than other groups. Relative participant payment was a factor that enhanced their likelihood of retention. This research illustrates how large national studies can be leveraged to increase representativeness and ongoing participation of diverse racial/ethnic groups, especially in combination with other factors, such as parenting a child with DD.

Egg Microneedle for Transdermal Delivery of Active Liraglutide.

Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose-dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once-a-day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience. However, there are two fundamental limitations: the low drug delivery due to incomplete insertion and loss of drug activity during DMN fabrication. Here, it is shown that an egg microneedle (EMN) designed with three functional layered structures can maintain the maximum activity of the loaded compound during DMN fabrication and deliver it completely into the skin, with the base layer allowing the complete delivery of liraglutide, and the shell layer maintaining the drug activity by mimicking the role of albumin in eggs. In a diabetic mouse model, liraglutide administration via EMN exhibited similar effect when compared to that of injection. Therefore, EMN-mediated liraglutide administration is a good potential option for replacing liraglutide injections in T2DM treatment.

Spousal loss and cognitive function: the importance of gender and multiple dimensions of marital quality.

Objectives: Research suggests that the death of a spouse has an adverse effect on a widow(er)'s cognition. However, little research has examined how the marital context before widowhood and gender influence this association. Guided by the social ambivalence and disease (SAD) model, this study examined the associations between spousal loss and cognition , with moderating effects of gender and pre-loss marital quality.Method: We analyzed a national longitudinal data, Midlife in the United States (MIDUS), specifically MIDUS 2 (2004-2005) and MIDUS 3 (2013-2014). The analytic sample consisted of (1) 146 participants who experienced the death of their spouse between MIDUS 2 and MIDUS 3 and (2) 144 age- and gender-matched comparison participants who did not lose their spouse during the period.Results: Adverse influence of widowhood on cognition was more pronounced among bereaved men than bereaved women. Widowed individuals whose relationships with their deceased spouse were ambivalent had poorer cognition than widowed individuals who had aversive relationships with their deceased spouse.Conclusion: Findings suggest that the influence of spousal death on cognitive functioning depends on gender and pre-loss marital quality, emphasizing the importance of considering pre-loss marital relationship and gender dynamics in developing efficient interventions for the widowed.

Physical Examination-Indicated Cerclage in Singleton and Twin Pregnancies and Risk Factors for Predicting Preterm Birth < 28 Weeks.

We compare the outcomes of physical examination-indicated cerclage (PEIC) between singleton and twin pregnancies and analyze predictive factors for preterm birth < 28 weeks of gestation. Patients who underwent PEIC at our center were reviewed. We compared perinatal outcomes between singleton and twin pregnancies. The primary outcome was delivery before 28 weeks of gestation. Also, we analyzed perioperative clinical, laboratory, and sonographic findings to determine the risk factors for predicting preterm birth < 28 weeks. The rate of preterm birth < 28 weeks was not significantly different. Also, neonatal outcomes were not different. Also, we compared the outcomes according to GA (gestational age) at delivery before (Group A) or after (Group B) 28 weeks, which is the primary outcome. In perioperative findings, group A was likely to have more advanced cervical dilatation, bulging membranes into the vagina, positive fFN or IGFBP-1, and shorter postoperative CL (cervical length) than group B. Also, positive fFN or IGFBP-1 and postoperative CL < 21.6 mm were independently associated with a higher risk of preterm birth < 28 weeks. These findings provide the effectiveness of PEIC with twin pregnancy as well as singleton pregnancy and helpful predictive methods that might effectively identify women at high risk of preterm birth < 28 weeks following PEIC.

Multi-MicroRNA Analysis Can Improve the Diagnostic Performance of Mammography in Determining Breast Cancer Risk.

The objective of this study was to determine whether multi-microRNA analysis using a combination of four microRNA biomarkers (miR-1246, 202, 21, and 219B) could improve the diagnostic performance of mammography in determining breast cancer risk by age group (under 50 vs. over 50) and distinguish breast cancer from benign breast diseases and other cancers (thyroid, colon, stomach, lung, liver, and cervix cancers). To verify breast cancer classification performance of the four miRNA biomarkers and whether the model providing breast cancer risk score could distinguish between benign breast disease and other cancers, the model was verified using nonlinear support vector machine (SVM) and generalized linear model (GLM) and age and four miRNA qRT-PCR analysis values (dCt) were input to these models. Breast cancer risk scores for each Breast Imaging-Reporting and Data System (BI-RADS) category in multi-microRNA analysis were analyzed to examine the correlation between breast cancer risk scores and mammography categories. We generated two models using two classification algorithms, SVM and GLM, with a combination of four miRNA biomarkers showing high performance and sensitivities of 84.5% and 82.1%, a specificity of 85%, and areas under the curve (AUCs) of 0.967 and 0.965, respectively, which showed consistent performance across all stages of breast cancer and patient ages. The results of this study showed that this multi-microRNA analysis using the four miRNA biomarkers was effective in classifying breast cancer in patients under the age of 50, which is challenging to accurately diagnose. In addition, breast cancer and benign breast diseases can be classified, showing the possibility of helping with diagnosis by mammography. Verification of the performance of the four miRNA biomarkers confirmed that multi-microRNA analysis could be used as a new breast cancer screening aid to improve the accuracy of mammography. However, many factors must be considered for clinical use. Further validation with an appropriate screening population in large clinical trials is required. This trial is registered with (KNUCH 2022-04-036).

Ultrasound-Indicated Cerclage in Twin Pregnancies: A Cohort Study.

Background: To report the pregnancy and neonatal outcomes in patients with twin pregnancies who underwent ultrasound-indicated cerclage (UIC) and to compare them to patients with singleton pregnancies undergoing the same procedures. Methods: Patients who underwent UIC between January 2010 and December 2020 at Kangnam Sacred Heart Hospital were reviewed. We compared characteristics, pregnancy, and neonatal outcomes between patients with singleton and twin pregnancies. Results: A total of 94 women (56 singleton and 38 twin pregnancies) underwent UIC were included. The mean gestational age (GA) at cerclage and preoperative cervical length (CL) were not significantly different. Twin pregnancies were more likely to deliver at earlier median gestations than singletons (singleton, 36 + 1 weeks vs twin, 32 + 6 weeks, and p = 0.004). The frequency of preterm delivery <34 weeks in twin group was higher than in singleton group (15 (26.8%) vs 20 (52.6%) and p =0.016). However, the frequency of preterm delivery <32, <28, and <24 weeks was not significantly different between two groups. Although neonatal weights in singleton pregnancies were heavier than twin pregnancies, neonatal mortality and morbidities were not significantly different between two groups. Among various factors contributing to preterm birth, preoperative CL ≤ 15 mm was independently associated with a higher risk of preterm delivery before 34 weeks. Furthermore, pregnancy and neonatal outcomes of twin pregnancies with cervical length ≤ 15 mm are comparable with those of singleton pregnancies (GA at delivery, singleton, 35 + 1 weeks vs twin, 32 + 5 weeks, and p = 0.24; neonatal mortality, singleton, 3.4% vs twin, 4.8%, and p = 0.64). Conclusion: The pregnancy and neonatal outcomes of UIC in twin pregnancies were comparable to those in singleton pregnancies, especially when CL is ≤15 mm. UIC might be considered a safe procedure for twin pregnancies.

Tissue-specific requirement of sodium channel and clathrin linker 1 (Sclt1) for ciliogenesis during limb development.

Primary cilia have essential roles as signaling centers during development and adult homeostasis. Disruption of ciliary structure or function causes congenital human disorders called ciliopathies. Centriolar distal appendage (DAP) proteins are important for anchoring cilia to the membrane. However, the exact functions of DAP during in vivo ciliogenesis and animal development remain poorly understood. Here, we showed that the DAP component sodium channel and clathrin linker 1 (Sclt1) mutant mice had abnormal craniofacial and limb development with postnatal lethality. In mutant embryos, most of the affected tissues had defects in DAP recruitment to the basal body and docking to the membrane that resulted in reduced ciliogenesis and disrupted hedgehog (Hh) signaling in limb bud mesenchymal cells. However, limb digit formation and ciliogenesis in Sclt1 mutant mice were differentially affected between the fore- and hindlimb buds. The forelimbs developed normally in Sclt1 mutants, but the hindlimbs had preaxial polydactyly. Heterozygous loss of Cep83, another core DAP component, in Sclt1 mutant mice, caused forelimb and hindlimb polydactyly. These findings revealed the tissue-specific differential requirement of DAPs. Taken together, these results indicated that during limb development the ciliary base components, DAPs, play an essential role in ciliogenesis and Hh signaling in vivo in a position-dependent manner.

KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency-Related Polycystic Kidney Disease.

BACKGROUND: Ciliogenesis-associated kinase 1 (CILK1) is a ciliary gene that localizes in primary cilia and regulates ciliary transport. Mutations in CILK1 cause various ciliopathies. However, the pathogenesis of CILK1-deficient kidney disease is unknown. METHODS: To examine whether CILK1 deficiency causes PKD accompanied by abnormal cilia, we generated mice with deletion of Cilk1 in cells of the renal collecting duct. A yeast two-hybrid system and coimmunoprecipitation (co-IP) were used to identify a novel regulator, kinesin light chain-3 (KLC3), of ciliary trafficking and cyst progression in the Cilk1-deficient model. Immunocytochemistry and co-IP were used to examine the effect of KLC3 on ciliary trafficking of the IFT-B complex and EGFR. We evaluated the effects of these genes on ciliary trafficking and cyst progression by modulating CILK1 and KLC3 expression levels. RESULTS: CILK1 deficiency leads to PKD accompanied by abnormal ciliary trafficking. KLC3 interacts with CILK1 at cilia bases and is increased in cyst-lining cells of CILK1-deficient mice. KLC3 overexpression promotes ciliary recruitment of IFT-B and EGFR in the CILK1 deficiency condition, which contributes to the ciliary defect in cystogenesis. Reduction in KLC3 rescued the ciliary defects and inhibited cyst progression caused by CILK1 deficiency. CONCLUSIONS: Our findings suggest that CILK1 deficiency in renal collecting ducts leads to PKD and promotes ciliary trafficking via increased KLC3.