CO2 doping of organic interlayers for perovskite solar cells.

In perovskite solar cells, doped organic semiconductors are often used as charge-extraction interlayers situated between the photoactive layer and the electrodes. The π-conjugated small molecule 2,2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9-spirobifluorene (spiro-OMeTAD) is the most frequently used semiconductor in the hole-conducting layer1-6, and its electrical properties considerably affect the charge collection efficiencies of the solar cell7. To enhance the electrical conductivity of spiro-OMeTAD, lithium bis(trifluoromethane)sulfonimide (LiTFSI) is typically used in a doping process, which is conventionally initiated by exposing spiro-OMeTAD:LiTFSI blend films to air and light for several hours. This process, in which oxygen acts as the p-type dopant8-11, is time-intensive and largely depends on ambient conditions, and thus hinders the commercialization of perovskite solar cells. Here we report a fast and reproducible doping method that involves bubbling a spiro-OMeTAD:LiTFSI solution with CO2 under ultraviolet light. CO2 obtains electrons from photoexcited spiro-OMeTAD, rapidly promoting its p-type doping and resulting in the precipitation of carbonates. The CO2-treated interlayer exhibits approximately 100 times higher conductivity than a pristine film while realizing stable, high-efficiency perovskite solar cells without any post-treatments. We also show that this method can be used to dope π-conjugated polymers.

Structural insights into the regulation of protein-arginine kinase McsB by McsA.

In gram-positive bacteria, phosphorylated arginine functions as a protein degradation signal in a similar manner as ubiquitin in eukaryotes. The protein-arginine phosphorylation is mediated by the McsAB complex, where McsB possesses kinase activity and McsA modulates McsB activity. Although mcsA and mcsB are regulated within the same operon, the role of McsA in kinase activity has not yet been clarified. In this study, we determined the molecular mechanism by which McsA regulates kinase activity. The crystal structure of the McsAB complex shows that McsA binds to the McsB kinase domain through a second zinc-coordination domain and the subsequent loop region. This binding activates McsB kinase activity by rearranging the catalytic site, preventing McsB self-assembly, and enhancing stoichiometric substrate binding. The first zinc-coordination and coiled-coil domains of McsA further activate McsB by reassembling the McsAB oligomer. These results demonstrate that McsA is the regulatory subunit for the reconstitution of the protein-arginine kinase holoenzyme. This study provides structural insight into how protein-arginine kinase directs the cellular protein degradation system.

Role of Gasdermin E in the Biogenesis of Apoptotic Cell-Derived Exosomes.

The gasdermins are a family of pore-forming proteins that has recently been suggested to play a central role in pyroptosis. In this study, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell-derived exosomes. In apoptotic human HeLa and HEK293 cells, GSDMA, GSDMC, GSDMD, and GSDME increased the release of apoptotic exosomes. GSDMB and DFNB59, in contrast, negatively affected the release of apoptotic exosomes. GSDME at its full-length and cleaved forms was localized in the exosomes and exosomal membrane. Full-length and cleaved forms of GSDME are suggested to increase Ca2+ influx to the cytosol through endosomal pores and thus increase the biogenesis of apoptotic exosomes. In addition, the GSDME-mediated biogenesis of apoptotic exosomes depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins, that is, annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of apoptotic exosomes begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that GSDME-bearing tumors released apoptotic exosomes to induce inflammatory responses in the in vivo mouse 4T1 orthotropic model of BALB/c breast cancer. The data indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process.

Crystal structure and biochemical analysis suggest that YjoB ATPase is a putative substrate-specific molecular chaperone.

AAA+ ATPases are ubiquitous proteins associated with most cellular processes, including DNA unwinding and protein unfolding. Their functional and structural properties are typically determined by domains and motifs added to the conserved ATPases domain. Currently, the molecular function and structure of many ATPases remain elusive. Here, we report the crystal structure and biochemical analyses of YjoB, a Bacillus subtilis AAA+ protein. The crystal structure revealed that the YjoB hexamer forms a bucket hat-shaped structure with a porous chamber. Biochemical analyses showed that YjoB prevents the aggregation of vegetative catalase KatA and gluconeogenesis-specific glyceraldehyde-3 phosphate dehydrogenase GapB but not citrate synthase, a conventional substrate. Structural and biochemical analyses further showed that the internal chamber of YjoB is necessary for inhibition of substrate aggregation. Our results suggest that YjoB, conserved in the class Bacilli, is a potential molecular chaperone acting in the starvation/stationary phases of B. subtilis growth.

The Na+/H+ antiporter SALT OVERLY SENSITIVE 1 regulates salt compensation of circadian rhythms by stabilizing GIGANTEA in Arabidopsis.

The circadian clock is a timekeeping, homeostatic system that temporally coordinates all major cellular processes. The function of the circadian clock is compensated in the face of variable environmental conditions ranging from normal to stress-inducing conditions. Salinity is a critical environmental factor affecting plant growth, and plants have evolved the SALT OVERLY SENSITIVE (SOS) pathway to acquire halotolerance. However, the regulatory systems for clock compensation under salinity are unclear. Here, we show that the plasma membrane Na+/H+ antiporter SOS1 specifically functions as a salt-specific circadian clock regulator via GIGANTEA (GI) in Arabidopsis thaliana. SOS1 directly interacts with GI in a salt-dependent manner and stabilizes this protein to sustain a proper clock period under salinity conditions. SOS1 function in circadian clock regulation requires the salt-mediated secondary messengers cytosolic free calcium and reactive oxygen species, pointing to a distinct regulatory role for SOS1 in addition to its function as a transporter to maintain Na+ homeostasis. Our results demonstrate that SOS1 maintains homeostasis of the salt response under high or daily fluctuating salt levels. These findings highlight the genetic capacity of the circadian clock to maintain timekeeping activity over a broad range of salinity levels.

Sleep parameter characteristics of patients with OSA who have retropalatal circumferential narrowing and the clinical significance of lateral pharyngeal wall collapse during sleep.

BACKGROUND: The lateral pharyngeal wall (LPW) is a critical anatomic structure in patients with obstructive sleep apnea (OSA). Resolving the retropalatal circumferential (RC) narrowing caused by combination of both LPW collapse and antero-posterior (AP) narrowing holds promise for surgical treatment of OSA. We sought to determine the clinical characteristics and distinctive alterations in sleep parameters of patients with OSA who have RC narrowing and LPW collapse. METHODS: Drug-induced sleep endoscopy (DISE), polysomnography findings, and sleep questionnaires were reviewed retrospectively in patients with OSA. RESULTS: Of the 106 OSA patients examined, 48% showed RC narrowing and 44% showed AP narrowing at the oropharynx level during sleep while 8% of the patients showed only LPW collapse. Patients with RC narrowing with LPW collapse exhibited a higher BMI than those with AP narrowing only. In addition, patients with RC narrowing showed more aggravated sleep parameters including apneic events than patients with AP narrowing alone. The degree of RC narrowing correlated significantly with the severity of OSA as shown by a higher apnea index and lower oxygen desaturations. CONCLUSIONS: Our clinical findings suggest that the presence of RC narrowing with LPW collapse in OSA is closely related to increased apneic and oxygen desaturation events. RC narrowing with LPW collapse may be targets for surgical correction in patients with OSA to improve therapeutic outcomes.

DIX domain containing 1 (DIXDC1) modulates VEGFR2 level in vasculatures to regulate embryonic and postnatal retina angiogenesis.

BACKGROUND: In sprouting angiogenesis, VEGFR2 level is regulated via a fine-tuned process involving various signaling pathways. Other than VEGF/VEGFR2 signaling pathway, Wnt/ ß-catenin signaling is also important in vascular development. However, the crosstalk between these two signaling pathways is still unknown to date. In this study, we aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ ß-catenin signaling pathways. RESULTS: In mice, DIXDC1 deficiency delayed angiogenesis at the embryonic stage and suppressed neovascularization at the neonatal stage. DIXDC1 knockdown inhibited VEGF-induced angiogenesis in endothelial cells in vitro by downregulating VEGFR2 expression. DIXDC1 bound Dishevelled Segment Polarity Protein 2 (Dvl2) and polymerized Dvl2 stabilizing VEGFR2 protein via its direct interaction. The complex formation and stability of VEGFR2 was potentiated by Wnt signaling. Moreover, hypoxia elevated DIXDC1 expression and likely modulated both canonical Wnt/ß-catenin signaling and VEGFR2 stability in vasculatures. Pathological angiogenesis in DIXDC1 knockout mice was decreased significantly in oxygen-induced retinopathy (OIR) and in wound healing models. These results suggest that DIXDC1 is an important factor in developmental and pathological angiogenesis. CONCLUSION: We have identified DIXDC1 as an important factor in early vascular development. These results suggest that DIXDC1 represents a novel regulator of sprouting angiogenesis that links Wnt signaling and VEGFR2 stability and may have a potential role in pathological neovascularization.

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

BACKGROUND: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear. OBJECTIVE: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model. METHODS: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery. RESULTS: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice. CONCLUSIONS: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.

Crystal structure of a tandem B-box domain from Arabidopsis CONSTANS.

CONSTANS is a central protein in the regulation of photoperiodic flowering, which is expressed in response to day length and promotes the expression of Flowering Locus T. The tandem B-box domain in CONSTANS mediates interactions with various proteins to regulate the expression of Flowering Locus T. Although most plants, including Arabidopsis, have multiple B-box proteins, their B-box structures have not been elucidated. Here, we report the crystal structure of a tandem B-box domain from Arabidopsis CONSTANS. The crystal structure shows that each B-box adopts a canonical B-box fold and coordinates two zinc atoms. Furthermore, the crystal structure reveals that the B-box domain has a unique structure that distinguishes it from animal B-boxes at the monomer and dimer level.

Optimal application of soft-palate webbing flap pharyngoplasty combined with nasal surgery for surgical treatment of primary snoring and obstructive sleep apnea.

BACKGROUND: Excessive collapse of the soft palate and lateral pharyngeal wall narrowing are established causes of loud snoring and sleep apnea in subjects with obstructive sleep apnea (OSA). Therefore, delicate surgical techniques are needed to reshape the soft palate and create sufficient tension in the lateral pharyngeal wall. This study aimed to determine the therapeutic outcome and favorable indications of soft-palate webbing flap pharyngoplasty in subjects with OSA and primary snoring. METHODS: A total of 174 subjects who underwent soft-palate webbing flap pharyngoplasty combined with uvulopalatal flap and septoturbinoplasty from August 2015 to February 2020 were included in this study. Medical records, including pre- and postoperative sleep parameters, were retrospectively reviewed. The primary outcome measure was the degree of improvement in AHI after surgery. Other outcomes were differences in surgical response rates, subjective visual analog score (VAS) for snoring, sleep quality, and complications. RESULTS: Polysomnographic results showed that apnea-hypopnea index (AHI) scores were significantly reduced from 39.6 ± 6.1 to 22.9 ± 3.6 following soft-palate webbing flap pharyngoplasty in 59 subjects, and overall success and response rates of this technique were analyzed with 71%. We found that the successful outcomes were observed in 50% of mild (n = 12) and 56% of moderate (n = 16) subjects with OSA subjects due to lateral pharyngeal wall collapse. The success rate of soft-palate webbing flap pharyngoplasty was relatively higher in subjects with mild and moderate OSA than those with severe OSA. Additionally, the mean VAS snoring scale was 4.7 and subjects' primary snoring intensity significantly improved to 2.9 after soft-palate webbing flap pharyngoplasty. Subjective symptoms such as daytime sleepiness and sleep quality also showed improvement. Most complications were found to be minimal and improved by 1 month after the operation. CONCLUSION: Our data demonstrate that soft-palate webbing flap pharyngoplasty is an effective treatment for OSA and primary snoring and may be a promising technique to reduce lateral pharyngeal wall collapse.

Controlling Gas Generation of Li-Ion Battery through Divinyl Sulfone Electrolyte Additive.

The focus of mainstream lithium-ion battery (LIB) research is on increasing the battery's capacity and performance; however, more effort should be invested in LIB safety for widespread use. One aspect of major concern for LIB cells is the gas generation phenomenon. Following conventional battery engineering practices with electrolyte additives, we examined the potential usage of electrolyte additives to address this specific issue and found a feasible candidate in divinyl sulfone (DVSF). We manufactured four identical battery cells and employed an electrolyte mixture with four different DVSF concentrations (0%, 0.5%, 1.0%, and 2.0%). By measuring the generated gas volume from each battery cell, we demonstrated the potential of DVSF additives as an effective approach for reducing the gas generation in LIB cells. We found that a DVSF concentration of only 1% was necessary to reduce the gas generation by approximately 50% while simultaneously experiencing a negligible impact on the cycle life. To better understand this effect on a molecular level, we examined possible electrochemical reactions through ab initio molecular dynamics (AIMD) based on the density functional theory (DFT). From the electrolyte mixture's exposure to either an electrochemically reductive or an oxidative environment, we determined the reaction pathways for the generation of CO2 gas and the mechanism by which DVSF additives effectively blocked the gas's generation. The key reaction was merging DVSF with cyclic carbonates, such as FEC. Therefore, we concluded that DVSF additives could offer a relatively simplistic and effective approach for controlling the gas generation in lithium-ion batteries.

Asia-Pacific survey of physicians' perceptions and managements of chronic rhinosinusitis.

BACKGROUND: The diagnosis and management of patients with chronic rhinosinusitis (CRS) may vary between otolaryngologists and allergists. Moreover, the adherence of different practitioners to European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 guideline recommendations has not been previously ascertained in Asia-Pacific regions. OBJECTIVE: Different specialists' perceptions and managements of CRS in Asia-Pacific regions were assessed in an attempt to gauge these practices against EPOS 2020 guidelines. METHODS: A transregional, cross-sectional survey was conducted to assess otolaryngologists' and allergists' perceptions and managements of CRS with regard to diagnosis, management and adherence to EPOS 2020 guidelines. RESULTS: Sixteen physicians in Asia-Pacific regions responded to the questionnaire. A total of 71.4% of otolaryngologists preferred to diagnose CRS with a combination of positive nasal symptoms and nasal endoscopy plus sinus CT, whereas 22.2% of allergists took such criterion to diagnose CRS. Compared to allergists, otolaryngologists more often considered the endotype classification (85.8% versus 55.5%). For the preferred first-line treatment, in addition to intranasal corticosteroids recommended by all respondents, 66.7% of allergists preferred antihistamines, whereas 71.4% of otolaryngologists preferred nasal saline irrigation. Regarding the proper timing of surgery, 71.5% of otolaryngologists reported 8-12 weeks of treatment after the initiation of medication, while more than half of the allergists recommended 4-6 weeks of medical treatment. CONCLUSIONS: This survey shows that variable perceptions and practices for CRS may exist between physicians with different specialties and highlights the need for increased communication and awareness between otolaryngologists and allergists to improve the diagnosis and treatment of CRS.

An online survey of clinical practice for allergic rhinitis among the Asia-Pacific representatives.

BACKGROUND: Physicians' knowledge and practice which are consistent with evidence-based guidelines can improve allergic rhinitis (AR) patients' care. Compared with western countries, the available literature about Asian doctors' perceptions and clinical practices regarding Allergic Rhinitis and its Impacts on Asthma (ARIA) guidelines is limited. OBJECTIVE: To collect detailed information about the practical management patterns specific for AR patients and investigate compliance with ARIA in the clinical practice of Asian physicians and elucidate the possible inadequacy in the existing ARIA guidelines. METHODS: An e-mail with a structured questionnaire was sent to members of the Asia-Pacific Association of Allergy, Asthma and Clinical Immunology. The questionnaire consisted of doctors' characteristics, environment of medical practice, routine clinical practice following ARIA guidelines and patients' adherence to the prescription. RESULTS: Physicians from 14 countries and regions sent valid questionnaires back, 94.12% of whom were senior doctors with more than 10 years of experience. 88.24% of doctors diagnosed AR depending on the history combined with allergy tests. 82.35% of participants employed the classification criteria by ARIA. 94.12%, 88.24% and 41.8% of respondents recommended intranasal corticosteroids, oral antihistamines and leukotriene receptor antagonists as first-line medications. 5.88% treated perennial AR by intranasal corticosteroids alone. 11.76% of clinicians recommended no allergen immunotherapy (AIT) or biologics and 58.82% of interviewees reported AR patients occasionally or sometimes agreed with the recommendation of AIT. CONCLUSIONS: There was high compliance with ARIA guidelines in Asian senior physicians' actual notion and practice in the management of AR. New-generation ARIA guidelines are imperative for unmet needs.

Angiotensin AT1 receptor antagonism by losartan stimulates adipocyte browning via induction of apelin.

Adipocyte browning appears to be a potential therapeutic strategy to combat obesity and related metabolic disorders. Recent studies have shown that apelin, an adipokine, stimulates adipocyte browning and has negative cross-talk with angiotensin II receptor type 1 (AT1 receptor) signaling. Here, we report that losartan, a selective AT1 receptor antagonist, induces browning, as evidenced by an increase in browning marker expression, mitochondrial biogenesis, and oxygen consumption in murine adipocytes. In parallel, losartan up-regulated apelin expression, concomitant with increased phosphorylation of protein kinase B and AMP-activated protein kinase. However, the siRNA-mediated knockdown of apelin expression attenuated losartan-induced browning. Angiotensin II cotreatment also inhibited losartan-induced browning, suggesting that AT1 receptor antagonism-induced activation of apelin signaling may be responsible for adipocyte browning induced by losartan. The in vivo browning effects of losartan were confirmed using both C57BL/6J and ob/ob mice. Furthermore, in vivo apelin knockdown by adeno-associated virus carrying-apelin shRNA significantly inhibited losartan-induced adipocyte browning. In summary, these data suggested that AT1 receptor antagonism by losartan promotes the browning of white adipocytes via the induction of apelin expression. Therefore, apelin modulation may be an effective strategy for the treatment of obesity and its related metabolic disorders.

Crystal structure of the DNA-binding domain of Bacillus subtilis CssR.

Bacteria utilize two-component systems to regulate gene expression in response to changes in environmental stimuli. CssS/CssR, a two-component system in Bacillus subtilis, is responsible for overcoming envelope stresses caused by heat shock and secretion overload. During stress, the sensor component CssS is auto-phosphorylated and transfers the phosphoryl group to the response regulator CssR. Phosphorylated CssR then directly regulates the transcription of genes required to counteract the stress. Here, the crystal structure of the DNA-binding domain of CssR, determined at 1.07 Å resolution, is reported. The structure shows that the DNA-binding domain of CssR harbors a winged helix-turn-helix motif that is conserved in the OmpR/PhoB subfamily of response regulators. Based on the crystal structure, the dimeric architecture of the full-length CssR and its DNA-binding mode were suggested.

CBFß stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression.

The HIV-1 accessory protein Vif hijacks a cellular Cullin-RING ubiquitin ligase, CRL5, to promote degradation of the APOBEC3 (A3) family of restriction factors. Recently, the cellular transcription cofactor CBFß was shown to form a complex with CRL5-Vif and to be essential for A3 degradation and viral infectivity. We now demonstrate that CBFß is required for assembling a well-ordered CRL5-Vif complex by inhibiting Vif oligomerization and by activating CRL5-Vif via direct interaction. The CRL5-Vif-CBFß holoenzyme forms a well-defined heterohexamer, indicating that Vif simultaneously hijacks CRL5 and CBFß. Heterodimers of CBFß and RUNX transcription factors contribute toward the regulation of genes, including those with immune system functions. We show that binding of Vif to CBFß is mutually exclusive with RUNX heterodimerization and impacts the expression of genes whose regulatory domains are associated with RUNX1. Our results provide a mechanism by which a pathogen with limited coding capacity uses one factor to hijack multiple host pathways.

Correlation of site of obstruction between two dynamic evaluation modalities in obstructive sleep apnea patients: drug-induced sleep endoscopy and sleep videofluoroscopy.

PURPOSE: Drug-induced sleep endoscopy (DISE) and sleep videofluoroscopy (SVF) are two dynamic modalities for evaluating the upper airway in patients with obstructive sleep apnea (OSA). We evaluated the correlation of obstructive sites determined by DISE and SVF in OSA patients and elucidate findings that can improve the accuracy of upper airway assessment. METHODS: A consecutive series of 63 patients with OSA who underwent DISE and SVF were the subjects of this study. The DISE and SVF findings were divided according to the anatomical structure responsible for the collapse, including the soft palate (SP), oropharyngeal lateral walls (LW), tongue base (TB), and larynx (LX). The obstruction was graded on the three-point scale: 0, no obstruction; 1, partial obstruction; or 2, complete obstruction. Additionally, grade 1.5 TB obstruction was designated when the posterior displacement of the anterior tongue was detected during simultaneous retropalatal obstruction. The agreement rate and Cohen's kappa test between the two modalities were also assessed. RESULTS: The agreement rate between the two modalities was highest in LX (88.9%) followed by SP (85.7%), TB (76.1%), and LW (74.6%) (Cohen's kappa value = 0.757 in LX, 0.642 in SP, 0.637 in TB, 0.612 in LW, respectively). When grade 1.5 and 2 TB obstructions were combined, the agreement rate increased to 88.9% (Cohen's kappa value = 0.757). CONCLUSIONS: We found a good overall agreement between the two dynamic airway evaluation modalities during drug-induced sleep, and this correlation may be improved if the posterior displacement of the anterior tongue during DISE is used as a sign of TB obstruction.

Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects.

Neurodegenerative disorders, such as Huntington's diseases and spinocerebellar ataxias (SCAs), are driven by proteins with expanded polyglutamine (polyQ) tracts. Recently, coiled-coil structures in polyQ regions of such proteins were shown to facilitate aggregate formation and ultimately lead to cell death. However, the molecular mechanism linking these structural domains to neuronal toxicity of polyQ proteins remains elusive. Here, we demonstrate that coiled-coil structures in the Q repeat region of SCA type 3 (SCA3) polyQ proteins confer protein toxicity in Drosophila neurons. To functionally characterize coiled-coil structures in the Q repeat regions, we generated three structural variants of SCA3 polyQ proteins: (i) MJDtr-76Q, containing both α-helical coiled-coil and ß-sheet hairpin structures in the Q repeat region; (ii) MJDtr-70Q_cc0, possessing only α-helical coiled-coil structures due to the incorporation of ß-sheet-breaking residues (Q-to-N or Q-to-E mutations); and (iii) MJDtr-70Q_pQp, with no secondary structure due to the introduced proline residues (Q-to-P mutations). Through comparative analysis of these variants, we found that coiled-coil structures facilitated nuclear localization of SCA3 polyQ proteins and induced dendrite defects in Drosophila dendritic arborization neurons. Furthermore, genetic and functional screening identified the transcription factor Foxo as a target of polyQ proteins, and coiled-coil-mediated interactions of Foxo and polyQ proteins in the nucleus resulted in the observed dendrite and behavioral defects in Drosophila These results demonstrate that coiled-coil structures of polyQ proteins are crucial for their neuronal toxicity, which is conferred through coiled-coil to coiled-coil interactions with the nuclear targets of these proteins.

Long-term Outcome of Microscopic Transsphenoidal Surgery for Prolactinomas as an Alternative to Dopamine Agonists.

BACKGROUND: Although long-term dopamine agonist (DA) therapy is recommended as a first-line treatment for prolactinoma, some patients may prefer surgical treatment because of the potential adverse effects of long-term medication, or the desire to become pregnant. This study aimed to determine whether surgical treatment of prolactinomas could be an alternative to DA therapy. METHODS: In this retrospective study, 96 consecutive patients (74 female, 22 male) underwent primary pituitary surgery without long-term DA treatment for prolactinomas at a single institution from 1990 to 2010. All patients underwent primary surgical treatment in the microscopic transsphenoidal approach (TSA). RESULTS: The median age and median follow-up period were 31 (16-73) years and 139.1 (12.2-319.6) months, respectively. An initial overall remission was accomplished in 47.9% (46 of 96 patients, 33 macroadenomas, and 13 microadenomas) of patients. DA dose reduction was achieved in all patients after TSA. A better remission rate was independently predicted by lower diagnostic prolactin levels and by a greater extent of surgical resection. Overall remission at the last follow-up was 33.3%, and the overall recurrence rate was 30.4%. The permanent complication rate was 3.1%, and there was no mortality. CONCLUSION: TSA can be considered a safe and potentially curative treatment for selective microprolactinomas as an alternative to treatment with a long-term DA.