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Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic reduction of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: Nociplastic pain conditions develop predominantly in women. We recently established a murine nociplastic pain model by applying postinjury thermal (40°C) stimulation to an injured (capsaicin-injected) area, triggering a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. The nociplastic pain state was centrally maintained by spinal microglia in males but peripherally by ongoing afferent activity at the previously injured area in females. Here, we investigated whether gonadal hormones are critical for the development of this peripherally maintained nociplastic pain state in females. Although the transition to a nociplastic pain state still occurred in ovariectomized females, the pain state was maintained neither by ongoing afferent activity at the previously injured area nor by spinal microglia. Estradiol reconstitution a week before the injury plus postinjury stimulation, but not after the transition had already occurred, restored the development of peripherally maintained nociplastic mechanical hypersensitivity in ovariectomized females. G protein-coupled estrogen receptor antagonism during the transition phase mimicked ovariectomy in gonad-intact females, whereas the receptor antagonism after the transition gradually alleviated the nociplastic mechanical hypersensitivity. At the previously injured area, afferents responsive to allyl isothiocyanate (AITC), a TRPA1 agonist, contributed to the maintenance of nociplastic mechanical hypersensitivity in gonad-intact females. In ex vivo skin-nerve preparations, only AITC-responsive afferents from the nociplastic pain model in gonad-intact females showed ongoing activities greater than control. These results suggest that gonadal hormones are critical for peripherally maintained nociplastic pain state in females by sensitizing AITC-responsive afferents to be persistently active., (Copyright © 2022 International Association for the Study of Pain.)

De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic pain is the most common neurological disorder of HIV patients. Multiple neuropathologies were identified in the pain pathway. Among them is the prominent astrocytic reaction (also know an astrogliosis). However, the pathogenic role and mechanism of the astrogliosis are unclear. Here, we show that the astrogliosis is crucial for the pain development induced by a key neurotoxic HIV protein gp120 and that a neuron-to-astrocyte Wnt5a signal controls the astrogliosis. Ablation of astrogliosis blocked the development of gp120-induced mechanical hyperalgesia, and concomitantly the expression of neural circuit polarization in the spinal dorsal horn. We demonstrated that conditional knockout of either Wnt5a in neurons or its receptor ROR2 in astrocytes abolished not only gp120-induced astrogliosis but also hyperalgesia and neural circuit polarization. Furthermore, we found that the astrogliosis promoted expression of hyperalgesia and NCP via IL-1β regulated by a Wnt5a-ROR2-MMP2 axis. Our results shed light on the role and mechanism of astrogliosis in the pathogenesis of HIV-associated pain., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Actin is a multifunctional biomolecule that forms not only basic structural bodies such as filopodia and lamellipodia, but also large microvilli-like organelles like stereocilia. Actin consists of four sub-domains (S1, S2, S3, and S4), and the "target-binding groove" formed between S1 and S3 is the major binding site for various actin binding proteins. Actin filament dynamics are regulated by numerous actin binding proteins with different mechanisms of actin binding, assembly, and disassembly such as actin severing, branching, and bundling. Ectoplasmic specialization protein 1 (espin 1) is an actin binding and bundling protein that is specifically implicated in the elongation and stabilization of stereocilia as a binding partner with myosin III. However, little is known about the molecular structure, actin bundling, and stabilizing mechanism of espin 1; hence, we investigated the interaction between actin and espin 1 through structural data. In this study, we first purified human espin 1 in an E. coli system following a new detergent-free approach and then demonstrated the 2D structure of full-length espin 1 using transmission electron microscopy along with Nickel nitrilotriacetic acid nanogold labeling and 2D averaging using SPIDER. Furthermore, we also determined the espin 1 binding domain of actin using a co-sedimentation assay along with gelsolin and myosin S1. These findings are not only beneficial for understanding the actin binding and bundling mechanism of espin 1, but also shed light on its elongation, stabilization, and tip-localization mechanisms with myosin III. This study thus provides a basis for understanding the molecular structure of espin 1 and can contribute to various hearing-related diseases, such as hearing loss and vestibular dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Kim, Heo, Chung and Jung.)

Identity development-exploring options and making commitments-is an important process related to human functioning across the lifespan. An accurate understanding of identity development processes requires precise measures, but commonly used questionnaires have not been subject to intensive psychometric analyses. We investigated the psychometric properties of two such measures, the Utrecht Management of Identity Commitments Scale and the Dimensions of Identity Development Scale. Previous analyses have treated the response scales as interval rather than ordinal, which may not be reasonable given the measures' Likert-type response scales. Accordingly, we evaluated their measurement precision by conducting multidimensional item response theory analyses of data from six studies of secondary and postsecondary students in The Netherlands and the United States (total N = 4,844; 36.00% boys/men, 63.07% girls/women; 0.02% nonbinary or missing gender data; 62.39% completed the measure in Dutch, 37.61% in English; 52.66% postsecondary school; 47.34% secondary school; racial, ethnic, and nationality information varied across studies). Graded response models showed that a limited range of the latent attributes was precisely measured, and the quality of items varied considerably. The measures functioned mostly similarly between gender groups, but there was substantial differential item functioning based on school level and language of the measure. We originally sought to create shortened versions, but the shortened versions provided no improvement over the low quality of the longer versions. Our analyses suggest that reflection on what these identity processes entail is needed, to develop new items that address different manifestations of the attributes under consideration. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Microtube-like porous carbon (MPC) and tube-like porous carbon-sulfur (MPC-S) composites were synthesized by carbonizing milkweed pappus with sulfur, and they were used as cathodes for lithium-sulfur batteries. The morphology and uniformity of these materials were characterized using X-ray powder diffraction, Raman spectroscopy, scanning electron microscopy, transmission electron microscopy with an energy-dispersive X-ray analyzer, thermogravimetric analysis, and X-ray photoelectron spectrometry. The electrochemical performance of the MPC-S cathodes was measured using the charge/discharge cycling performance, C rate, and AC impedance. The composite cathodes with 93.8 wt.% sulfur exhibited a stable specific capacity of 743 mAh g -1 after 200 cycles at a 0.5 C.

Cryo-electron microscopy (cryo-EM) has become an unrivaled tool for determining the structure of macromolecular complexes. The biological function of macromolecular complexes is inextricably tied to the flexibility of these complexes. Single particle cryo-EM can reveal the conformational heterogeneity of a biochemically pure sample, leading to well-founded mechanistic hypotheses about the roles these complexes play in biology. However, the processing of increasingly large, complex datasets using traditional data processing strategies is exceedingly expensive in both user time and computational resources. Current innovations in data processing capitalize on artificial intelligence (AI) to improve the efficiency of data analysis and validation. Here, we review new tools that use AI to automate the data analysis steps of particle picking, 3D map reconstruction, and local resolution determination. We discuss how the application of AI moves the field forward, and what obstacles remain. We also introduce potential future applications of AI to use cryo-EM in understanding protein communities in cells.

Fascin, a major actin cross-linking protein, is expressed in most vertebrate epithelial tissues. It organizes actin filaments into well-ordered bundles that are responsible for the extension of dynamic membrane protrusions, including microspikes, filopodia, and invadopodia from cell surfaces, which are involved in cell migration and invasion as critical components of cancer metastasis. However, it is not well-understood how fascin-1 induces actin binding/bundling and where fascin-1 localizes along the actin filaments, thus facilitating actin bundle formation. In the present study, we attempted to clarify these problems by using biochemical and electron microscopic analyses using various fascin-1 constructs. Three dimensional structures of actin/fascin-1 complex were obtained by electron microscopy (EM) with iterative helical real-space reconstruction (IHRSR) and tomography. We revealed that the N-terminal region containing the Actin-Binding Site 2 (ABS2) of fascin-1 is responsible for actin bundling and the C-terminal region is important for the dimerization of fascin-1. We also found that the dimerization of fascin-1 through intermolecular interactions of the C-terminal region is essential for actin bundling. Since fascin is an important factor in cancer development, it is expected that the findings of present study will provide useful information for development of therapeutic strategies for cancer.

Background: Contrary to pre-attack symptoms before an individual cluster headache attack, little is known about the pre-cluster symptoms before the onset of cluster bouts. We previously described pre-attack symptoms before cluster headache attacks. The aim of this study was to investigate characteristics of pre-cluster symptoms in patients with episodic cluster headache., Methods: In this multicentre study, 184 patients with episodic cluster headache were recruited between October 2018 and December 2020. They were interviewed by investigators and completed a structured questionnaire. To investigate pre-cluster and pre-attack symptoms, we assessed 20 symptoms and signs using the questionnaire., Results: The upcoming cluster bout was predictable in 35.3% (n = 65/184) of the patients. When present, pre-cluster symptoms occurred at a median duration of 7 days (interquartile range, 2.3-14 days) before the onset of the cluster bout. Patients with pre-cluster symptoms showed a higher proportion of women, prevalence of pre-attack symptoms and seasonal rhythmicity, frequency of cluster headache attacks per day, and total number of cluster bouts compared to patients without pre-cluster symptoms. In univariable and multivariable logistic regression analyses, female sex was associated with the predictability of pre-cluster symptoms (odds ratio = 2.297, p  = 0.016)., Conclusions: The upcoming cluster bout was predicted in approximately 35% of patients with episodic cluster headache, which may allow for an earlier preventive treatment and help understand the pathophysiology.

Membrane-sculpting proteins shape the morphology of cell membranes and facilitate remodeling in response to physiological and environmental cues. Complexes of the monotopic membrane protein caveolin function as essential curvature-generating components of caveolae, flask-shaped invaginations that sense and respond to plasma membrane tension. However, the structural basis for caveolin's membrane remodeling activity is currently unknown. Here, we show that, using cryo-electron microscopy, the human caveolin-1 complex is composed of 11 protomers organized into a tightly packed disc with a flat membrane-embedded surface. The structural insights suggest a previously unrecognized mechanism for how membrane-sculpting proteins interact with membranes and reveal how key regions of caveolin-1, including its scaffolding, oligomerization, and intramembrane domains, contribute to its function.

Controlling behavior to flexibly achieve desired goals depends on the ability to monitor one's own performance. It is unknown how performance monitoring can be both flexible, to support different tasks, and specialized, to perform each task well. We recorded single neurons in the human medial frontal cortex while subjects performed two tasks that involve three types of cognitive conflict. Neurons encoding conflict probability, conflict, and error in one or both tasks were intermixed, forming a representational geometry that simultaneously allowed task specialization and generalization. Neurons encoding conflict retrospectively served to update internal estimates of conflict probability. Population representations of conflict were compositional. These findings reveal how representations of evaluative signals can be both abstract and task-specific and suggest a neuronal mechanism for estimating control demand.

Background: It is quite difficult to distinguish retractile testis from gliding testis, which requires different treatment planning in the clinic setting. We evaluated practice patterns of urologists in Korea regarding the diagnosis and management of retractile and gliding testes., Methods: We mailed or e-mailed self-completion questionnaires consisting of 20 items to 106 urologists practicing in Korean hospitals concerning the diagnosis and treatment of cryptorchidism. We collected and analyzed the responses statistically., Results: Responses were received from 62 urologists. The response rate was 58.5%. Thirty-seven urologists (59.7%) actually felt they had difficulty in distinguishing retractile testis from gliding testis in the clinic setting. This rate was higher for non-pediatric urologists (78.1%) than for pediatric urologists (40.0%) ( P = 0.006). In cases of infant retractile testis, only five urologists (8.1%) said that they would perform orchiopexy immediately, with 54 (87.1%) urologists saying they would do follow-up. In cases of preschool-age children with retractile testis, 17 urologists (27.4%) said that they would perform orchiopexy immediately with 41 (66.1%) urologists saying they would do follow-up. In cases of infant gliding testis, 37 urologists (59.7%) said that they would perform orchiopexy immediately with 24 (38.7%) urologists saying they would do a follow-up., Conclusion: More than half (59.7%) of Korean urologists revealed it challenging to distinguish retractile testis and gliding testis in the clinical setting. The more it was difficult to diagnose retractile testis with certainty, the more frequent surgical correction was chosen for treatment. Therefore, it is essential to prevent unnecessary surgical treatment by establishing a practical guideline., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Abstract: Acute injury-induced pain can transition to chronic nociplastic pain, which predominantly affects women. To facilitate studies on the underlying mechanisms of nociplastic pain, we developed a mouse model in which postinjury thermal stimulation (intermittent 40°C water immersion for 10 minutes at 2 hours postcapsaicin) prolongs capsaicin (ie, experimental injury)-induced transient mechanical hypersensitivity outside of the injury area. Although capsaicin injection alone induced mechanical and thermal hypersensitivity that resolved in ∼7 days (slower recovery in females), the postinjury stimulation prolonged capsaicin-induced mechanical, but not thermal, hypersensitivity up to 3 weeks in both sexes. When postinjury stimulation was given at a lower intensity (30°C) or at later time points (40°C at 1-3 days postcapsaicin), chronification of mechanical hypersensitivity occurred only in females. Similar chronification could be induced by a different postinjury stimulation modality (vibration of paw) or with a different injury model (plantar incision). Notably, the 40°C postinjury stimulation did not prolong capsaicin-induced inflammation in the hind paw, indicating that the prolonged mechanical hypersensitivity in these mice arises without clear evidence of ongoing injury, reflecting nociplastic pain. Although morphine and gabapentin effectively alleviated this persistent mechanical hypersensitivity in both sexes, sexually dimorphic mechanisms mediated the hypersensitivity. Specifically, ongoing afferent activity at the previously capsaicin-injected area was critical in females, whereas activated spinal microglia were crucial in males. These results demonstrate that postinjury stimulation of the injured area can trigger the transition from transient pain to nociplastic pain more readily in females, and sex-dependent mechanisms maintain the nociplastic pain state., (Copyright © 2021 International Association for the Study of Pain.)

Objective: Cluster headache (CH) is a rare, primary headache disorder, characterized of excruciating, strictly one-sided pain attacks and ipsilateral cranial autonomic symptoms. Given the debilitating nature of CH, delayed diagnosis can increase the disease burden. Thus, we aimed to investigate the diagnostic delay, its predictors, and clinical influence among patients with CH., Methods: Data from a prospective multicenter CH registry over a 4-year period were analyzed. CH was diagnosed according to the International Classification of Headache Disorders (ICHD)-3 criteria, and diagnostic delay of CH was assessed as the time interval between the year of the first onset and the year of CH diagnosis. Patients were classified into three groups according to the tertiles of diagnostic delay (1st tertile, <1 year; 2nd tertile, 1-6 years; and 3rd tertile, ≥7 years)., Results: Overall, 445 patients were evaluated. The mean duration of diagnosis delay was 5.7 ± 6.7 years, (range, 0-36 years). Regarding the age of onset, majority of young patients (age <20 years) belonged to the third tertile (60%), whereas minority of old patients (>40 years) belonged to the third tertile (9.0%). For year of onset, the proportion of patients in the 3rd tertile was the highest for the groups before the publication year of the ICHD-2 (74.7%) and the lowest for the groups after the publication year of the ICHD-3 beta version (0.5%). Compared with the first CH, episodic CH [multivariable-adjusted odds ratio (aOR) = 5.91, 95% CI = 2.42-14.48], chronic CH (aOR = 8.87, 95% CI = 2.66-29.51), and probable CH (aOR = 4.12, 95% CI = 1.48-11.43) were associated with the tertiles of diagnostic delay. Age of onset (aOR = 0.97, 95% CI = 0.95-0.99) and PHQ-9 score (aOR = 0.96, 95% CI = 0.93-0.99) were inversely associated with the tertile of diagnostic delay. The prevalence of suicidal ideation was highest in the patients of the third tertile. The mean HIT-6 score increased significantly with the diagnostic delay ( p = 0.041)., Conclusions: Patients with a younger onset of CH have a higher risk of diagnostic delay. Nevertheless, the rate of delayed diagnosis gradually improved over time and with the publication of the ICHD criteria, supporting the clinical significance of diagnostic clinical criteria and headache education to reduce the disease burden of CH., Competing Interests: SJC was involved as a site investigator of multicenter trial sponsored Otsuka Korea, Allergan, Ildong Pharmaceutical Co., Ltd., Novartis International AG, Eli Lilly and Company, Hyundaipharm. Co. Ltd., Biohaven Asia Pacific Ltd., H. Lundbeck A/S (Lundbeck), and Parexel Korea Co., Ltd., and received lecture honoraria from Allergan Korea, WhanIn Pharm Co., Ltd., Shinpoong Pharma. Co., Ltd., and SK chemicals in the past 24 months. MC was a site investigator for a multicenter trial sponsored by Otsuka Korea, Novartis International AG, and Eli Lilly and Company. He worked as an advisory member for Teva and has received lecture honoraria from Allergan Korea, Handok-Teva, and Yuyu Pharmaceutical Company in the past 24 months. He received grants from the Yonsei University College of Medicine and the National Research Foundation of Korea (2019R1F1A1053841). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Chung, Kim, Lee, Chu, Ahn, Bae, Song, Sohn, Oh, Kim, Kim, Park, Chung, Moon, Cho, Seo, Kim, Choi, Park, Chung and Cho.)

Veronicastrum sibiricum is a perennial species distributed in Korea, Japan, Manchuria, China, and Siberia. This study aimed to determine the requirements for germination and dormancy break of V. sibiricum seeds and to classify the kind of seed dormancy. Additionally, its class of dormancy was compared with other Veronicastrum and Veronica species. V. sibiricum seeds were permeable to water and had a mature embryo during seed dispersal. In field conditions, germination was prevented by physiological dormancy, which was, however, relieved by March of the next year, allowing the start of germination when suitable environmental conditions occurred. In laboratory experiments, the seeds treated with 0, 2, 4, 8, and 12 weeks of cold stratification (4 °C) germinated to 0, 79, 75, 72, and 66%, respectively. After the GA 3 treatment (2.887 mM), ≥90% of the seeds germinated during the four incubation weeks at 20/10 °C. Thus, 2.887 mM GA 3 and at least two weeks at 4 °C were effective in breaking physiological dormancy and initiating germination. Therefore, the V. sibiricum seeds showed non-deep physiological dormancy (PD). Previous research, which determined seed dormancy classes, revealed that Veronica taxa have PD, morphological (MD), or morphophysiological seed dormancy (MPD). The differences in the seed dormancy classes in the Veronicastrum - Veronica clade suggested that seed dormancy traits had diverged. The results provide important data for the evolutionary ecological studies of seed dormancy and seed-based mass propagation of V. sibiricum .

Background: Nanoparticles have been utilized in brain research and therapeutics, including imaging, diagnosis, and drug delivery, owing to their versatile properties compared to bulk materials. However, exposure to nanoparticles leads to their accumulation in the brain, but drug development to counteract this nanotoxicity remains challenging. To date, concerns have risen about the potential toxicity to the brain associated with nanoparticles exposure via penetration of the brain blood barrier to address this issue., Methods: Here the effect of silica-coated-magnetic nanoparticles containing the rhodamine B isothiocyanate dye [MNPs@SiO 2 (RITC)] were assessed on microglia through toxicological investigation, including biological analysis and integration of transcriptomics, proteomics, and metabolomics. MNPs@SiO 2 (RITC)-induced biological changes, such as morphology, generation of reactive oxygen species, intracellular accumulation of MNPs@SiO 2 (RITC) using transmission electron microscopy, and glucose uptake efficiency, were analyzed in BV2 murine microglial cells. Each omics data was collected via RNA-sequencing-based transcriptome analysis, liquid chromatography-tandem mass spectrometry-based proteome analysis, and gas chromatography- tandem mass spectrometry-based metabolome analysis. The three omics datasets were integrated and generated as a single network using a machine learning algorithm. Nineteen compounds were screened and predicted their effects on nanotoxicity within the triple-omics network., Results: Intracellular reactive oxygen species production, an inflammatory response, and morphological activation of cells were greater, but glucose uptake was lower in MNPs@SiO 2 (RITC)-treated BV2 microglia and primary rat microglia in a dose-dependent manner. Expression of 121 genes (from 41,214 identified genes), and levels of 45 proteins (from 5918 identified proteins) and 17 metabolites (from 47 identified metabolites) related to the above phenomena changed in MNPs@SiO 2 (RITC)-treated microglia. A combination of glutathione and citrate attenuated nanotoxicity induced by MNPs@SiO 2 (RITC) and ten other nanoparticles in vitro and in the murine brain, protecting mostly the hippocampus and thalamus., Conclusions: Combination of glutathione and citrate can be one of the candidates for nanotoxicity alleviating drug against MNPs@SiO 2 (RITC) induced detrimental effect, including elevation of intracellular reactive oxygen species level, activation of microglia, and reduction in glucose uptake efficiency. In addition, our findings indicate that an integrated triple omics approach provides useful and sensitive toxicological assessment for nanoparticles and screening of drug for nanotoxicity., (© 2021. The Author(s).)

Opioids are widely used for pain relief; however, chronic opioid use causes a paradoxical state of enhanced pain sensitivity, termed "Opioid-induced hyperalgesia (OIH)." Despite the clinical importance of OIH, the detailed mechanism by which it enhances pain sensitivity remains unclear. In this study, we tested whether repeated morphine induces a neuronal circuit polarization in the mouse spinal dorsal horn (SDH). Transgenic mice expressing GFP to neurokinin 1 receptor-expressing neurons (sNK1Rn) and GABAergic interneurons (sGABAn) that received morphine [20 mg/kg, once daily for four consecutive days (i.p.)] developed mechanical hypersensitivity. Repeated morphine altered synaptic strengths in the SDH as a specific cell-type but not in a gender-dependent manner. In sNK1Rn and non-tonic firing neurons, repeated morphine treatment significantly increased frequency of spontaneous excitatory postsynaptic current (sEPSC) and evoked EPSC (eEPSC). In addition, repeated morphine treatment significantly decreased evoked inhibitory postsynaptic current (eIPSC) in sNK1Rn. Conversely, in sGABAn and tonic firing neurons, repeated morphine treatment significantly decreased sEPSC frequency and eEPSC, but had no change of eIPSC in sGABAn. Interestingly, repeated morphine treatment significantly decreased neuronal rheobase of sNK1Rn but had no effect on sGABAn. These findings suggest that spinal neuronal circuit polarization maybe the mechanism of OIH and identify a potential therapeutic mechanism to prevent or treat opioid-induced pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kearns, Jayasi, Liu, Wang, Shi, Chung, La, Tang and Bae.)

Mutual crosstalk among poly(ADP-ribose) (PAR), activated PAR polymerase 1 (PARP1) metabolites, and DNA repair machinery has emerged as a key regulatory mechanism of the DNA damage response (DDR). However, there is no conclusive evidence of how PAR precisely controls DDR. Herein, six deubiquitinating enzymes (DUBs) associated with PAR-coupled DDR were identified, and the role of USP39, an inactive DUB involved in spliceosome assembly, was characterized. USP39 rapidly localizes to DNA lesions in a PAR-dependent manner, where it regulates non-homologous end-joining (NHEJ) via a tripartite RG motif located in the N-terminus comprising 46 amino acids (N46). Furthermore, USP39 acts as a molecular trigger for liquid demixing in a PAR-coupled N46-dependent manner, thereby directly interacting with the XRCC4/LIG4 complex during NHEJ. In parallel, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner. These findings provide mechanistic insights into how PAR chains precisely control DNA repair processes in the DDR., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Charonia lampas sauliae (triton snails, triton shells or tritons; Mollusca, Caenogastropoda, Littorinimorpha, Ranellidae) is a marine species with a wide distribution. In Korea, this species is listed as vulnerable and is regionally protected as an endangered species. Here, we report the first comprehensive transcriptome dataset of C. lampas sauliae obtained using the Illumina HiSeq 2500 platform. In total, 97.68% of raw read sequences were processed as clean reads. Of the 577,478 contigs obtained, 146,026 sequences were predicted to contain coding regions. About 89.34% of all annotated unigene sequences showed homologous matches to protein sequences in PANM DB (Protostome database). Further, about one-third of the unigene sequences were annotated using the UniGene, Swiss-Prot, Clusters of Orthologous Groups (COG) and Gene Ontology (GO) databases. In total, 190 enzymes were predicted under key metabolic pathways under stood through Kyoto Encyclopedia of Genes and Genomes (KEGG) database annotation. Repetitive elements such as long terminal repeats (LTRs), short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs), and DNA elements were enriched in the unigene sequences. Among the identified transcripts were the channel proteins, some of which were blocked by tetrodotoxin, which is thought to be synthesized by symbiotic bacteria inhabiting the shells. In addition, conotoxin superfamily peptides, such as B-conotoxin, conotoxin superfamily T and alpha-conotoxin, were identified, which may have relevance to biomedical and evolutionary research. A transcriptome-wide search for polymorphic loci identified 21,568 simple sequence repeats (SSRs) in the unigene sequences. Most SSRs were dinucleotides, among which AC/GT was the dominant SSR type. The molecular and genetic resources revealed in this study could be utilized for investigations on the fitness of the species in the marine environment and sustainability in a changing habitat., (Copyright © 2021. Published by Elsevier B.V.)

Legionella pneumophila is an opportunistic pathogen that causes the potentially fatal pneumonia known as Legionnaires' disease. The pathology associated with infection depends on bacterial delivery of effector proteins into the host via the membrane spanning Dot/Icm type IV secretion system (T4SS). We have determined sub-3.0 Å resolution maps of the Dot/Icm T4SS core complex by single particle cryo-EM. The high-resolution structural analysis has allowed us to identify proteins encoded outside the Dot/Icm genetic locus that contribute to the core T4SS structure. We can also now define two distinct areas of symmetry mismatch, one that connects the C18 periplasmic ring (PR) and the C13 outer membrane cap (OMC) and one that connects the C13 OMC with a 16-fold symmetric dome. Unexpectedly, the connection between the PR and OMC is DotH, with five copies sandwiched between the OMC and PR to accommodate the symmetry mismatch. Finally, we observe multiple conformations in the reconstructions that indicate flexibility within the structure., Competing Interests: MS, CD, JC, LC, JR, MS, DL, MO No competing interests declared, (© 2021, Sheedlo et al.)

Objective: Impaired memory is a common comorbidity of refractory temporal lobe epilepsy (TLE) and often perceived by patients as more problematic than the seizures themselves. The objective of this study is to understand what the relationship of these behavioral impairments is to the underlying pathophysiology, as there are currently no treatments for these deficits, and it remains unknown what circuits are affected., Methods: We recorded single neurons in the medial temporal lobes (MTLs) of 62 patients (37 with refractory TLE) who performed a visual recognition memory task to characterize the relationship between behavior, tuning, and anatomical location of memory selective and visually selective neurons., Results: Subjects with a seizure onset zone (SOZ) in the right but not left MTL demonstrated impaired ability to recollect as indicated by the degree of asymmetry of the receiver operating characteristic curve. Of the 1973 recorded neurons, 159 were memory selective (MS) and 366 were visually selective (VS) category cells. The responses of MS neurons located within right but not left MTL SOZs were impaired during high-confidence retrieval trials, mirroring the behavioral deficit seen both in our task and in standardized neuropsychological tests. In contrast, responses of VS neurons were unimpaired in both left and right MTL SOZs. Our findings show that neuronal dysfunction within SOZs in the MTL was specific to a functional cell type and behavior, whereas other cell types respond normally even within the SOZ. We show behavioral metrics that detect right MTL SOZ-related deficits and identify a neuronal correlate of this impairment., Significance: Together, these findings show that single-cell responses can be used to assess the causal effects of local circuit disruption by an SOZ in the MTL, and establish a neural correlate of cognitive impairment due to epilepsy that can be used as a biomarker to assess the efficacy of novel treatments., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This study aimed to investigate the risk factors of fistula recurrence after primary urethrocutaneous fistulectomy in children with hypospadias., Material and Methods: The study included 63 children who underwent fistulectomy for urethrocutaneous fistula (UCFs) that occurred after urethroplasty for hypospadias, between February 2009 and December 2018. The patients were divided into 2 groups: successful group 1 and failed group 2. For data analysis, we included the demographics of the patients, the details of the previous urethroplasty (the type of hypospadias and the location of the meatus after complete chordectomy), the presence of meatal stenosis or urethral stricture after urethroplasty, and the size of the UCFs. The Student t-test and the chi-square test were performed to analyze the data using the Statistical Package for Social Sciences software., Results: The overall success rate of primary urethrocutaneous fistulectomy was 81.0% (51/63 children). The most common location of a secondary fistula was the penoscrotal area 5 (41.6%). There were no statistically significant differences in age (p=0.501), weight (p=0.063), body mass index (p=0.924), history of low birth weight (p=0.454), and history of prematurity (p=0.381). The type of hypospadias (p=0.007) and urethral defect length (p=0.021) were identified as independent risk factors for failed urethrocutaneous fistulectomy. There were no statistically significant differences in meatal stenosis (p=0.431), postoperative stricture (p=0.587), fistula location (p=0.173), multiplicity (p=0.588), and fistula size (p=0.530)., Conclusion: The type of hypospadias and the length of the urethral defect are the significant risk factors for secondary fistula recurrence after primary urethrocutaneous fistulectomy.

Purpose: To determine references for penile circumference according to age in prepubertal children and whether this measurement can be used as a basic penile parameter along with stretched penile length in prepubertal children., Materials and Methods: A total of 750 children (mean age, 4.2±3.4 years) aged under 14 years without penile problems were enrolled in this study. Children with penile or testicular abnormalities were excluded. All data were gathered at the outpatient clinic by a single pediatric urologist from July 2017 to April 2020. Penile parameters (baseline and stretched penile length, penile circumference) and testicular volumes were measured by using an elastic ruler and a Prader orchidometer, respectively., Results: Mean baseline and stretched penile lengths were 3.0±1.0 cm and 4.2±1.0 cm, respectively. The mean penile circumference was 4.2±0.9 cm. The stretched penile length was similar to penile circumference (p=0.425). This similarity was found for each age group except for the 0-1-year-old and 3-4-year-old age groups (p=0.001 and p=0.034, respectively). As children grow into adolescence, stretched penile length increases significantly compared to penile circumference., Conclusions: Penile circumference increased with age like stretched penile length and testicular volume in prepubertal children. Stretched penile length and penile circumference were found to be similar. This study can be used as a basic reference for penile circumference values in prepubertal children., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Background and Purpose: Epidemiologic data suggest that cluster headache (CH) is significantly associated with cigarette smoking. The aim of this study was to determine differences in features between patients with a smoking history and those who are never-smokers, using data from a prospective multicenter registry., Methods: Data used in this study were obtained from the Korean Cluster Headache Registry that collected data from consecutive patients diagnosed with CH. We compared clinical and demographic features between ever-smokers (current or former smokers) and never-smokers., Results: This study enrolled 250 patients who were diagnosed with CH, of which 152 (60.8%) were ever-smokers and 98 (39.2%) were never-smokers. The age at CH onset was significantly lower in the never-smoker group than in the ever-smoker group [27.1±12.9 years vs. 30.6±10.9 years (mean±standard deviation), p =0.024]. Seasonal rhythmicity (58.1% vs. 44.7%, p =0.038) and triptan responsiveness (100% vs. 85.1%, p =0.001) were higher in never-smokers, while other clinical features such as pain severity, duration, attack frequency, and associated autonomic symptoms did not differ significantly between the groups. The male-to-female ratio was markedly higher in ever-smokers (29.4:1) than in never-smokers (1.7:1)., Conclusions: Most of the clinical features did not differ significantly between patients with a smoking history and never-smokers. However, the age at CH onset, sex ratio, and seasonal rhythmicity were significantly associated with smoking history., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2021 Korean Neurological Association.)

Background: Lung cancer screening (LCS) is broadly accepted. Screening also identifies incidental cardiac findings (S findings) that need follow-up. We report the magnitude of the potential downstream revenue generated by appropriate S finding management after 4 years of our free LCS program., Materials and Methods: A retrospective database and chart review of a single-center free LCS program in the underserved southeast were performed. All patients who were enrolled in the screening required a primary care physician (PCP) as part of the decision-making model. Referrals to cardiac specialists for S findings found on LCS were recorded. Cost analysis was performed to track potential downstream revenue generated for the institution based upon Medicare allowable or Diagnosis-related group calculations., Results: One thousand one hundred thirty-two scans were reviewed with 262 (23%) yielding positive S findings for 1 or more organ systems. 181/262 (69%) patients had cardiac findings, only 64/181 (35%) of these patients were referred to cardiology specialists by the PCP. The total Medicare billable amount for all cardiac referrals/interventions was $284 379, representing 35% of the potential billable amount of $804 260. Percutaneous coronary intervention (PCI) was the highest billable amount at $18 568. Eight percent of the patients undergoing appropriate cardiac evaluation required a PCI. If not for the screening and cardiac specialist referral, this patient group may not have received appropriate cardiovascular diagnosis and treatment., Discussion: Lung cancer screening also identifies patients with significant cardiac disease, many of whom may not be appropriately referred. Identification and treatment of incidentally noted cardiovascular findings may both improve patient care and justify supporting free LCS programs.

Although cranial autonomic symptoms (CAS) are typical in cluster headache (CH), some individuals with CH show no CAS during their headache attacks. Probable cluster headache (PCH) is a subtype of CH that fulfils all but one criterion of CH. This study aimed to investigate the frequency and clinical features of CH and PCH without CAS in comparison to those with CAS. We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals. Of the 216 participants with CH and 26 with PCH, 19 (8.8%) and 7 (26.9%), respectively, did not have CAS. Participants with CH without CAS exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0-6.0] vs 8.0 [3.0-12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0-7.0] vs 7.0 [3.0-11.0], p = 0.042) than those with CAS. Among participants with PCH, headache intensity was less severe in participants without CAS than in those with CAS (numeric rating scale, 8.0 [7.0-8.0] vs 9.5 [8.0-10.0], p = 0.015). In conclusion, a significant proportion of participants with CH and PCH did not have CAS. Some clinical features of CH and PCH differed based on the presence of CAS.

Purpose: The concealed penis (CP) is a congenital or acquired genital anomaly that requires surgical correction. To construct an objective CP severity index, we compared the penile parameters of a CP with a normal penis (NP) and postoperative outcomes of CP patients., Materials and Methods: In this retrospective study, 391 boys under 14 years who visited our hospital between September 2017 and February 2020 were included. Among these boys, 105 patients had a CP and 286 boys had a NP without CP. The stretched penile length (SPL), penile circumference (PC), and penile length above baseline skin level (BPL) were measured using a ruler (cm), and the testicular volume was measured using an orchidometer (mL). We defined the concealed index according to SPL (CIs) as BPL/SPL and the concealed index according to circumference (CIc) as BPL/PC. A repair of the CP was performed in the CP patients. All parameters were measured before surgery and after three months., Results: The CP had significantly shorter SPL and BPL, and smaller CIs, and CIc than the NP. The cutoff values for the CIs and CIc were 0.68 and 0.58, respectively (sensitivity 86.7% and 86.7%; specificity 65.0% and 88.5%, respectively). After repair of the CP, all penile parameters were significantly improved., Conclusions: The CIs and CIc are useful and objective parameters for checking the severity of CP, and evaluating the postoperative outcome of CP repair. We newly introduced cutoff values for the CIs (0.68) and CIc (0.58) for diagnosing and evaluating CP repair., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Objective: Post-traumatic growth typically refers to enduring positive psychological change experienced as a result of adversity, trauma, or highly challenging life circumstances. Critics have challenged insights from much of the prior research on this topic, pinpointing its significant methodological limitations. In response to these critiques, we propose that post-traumatic growth can be more accurately captured in terms of personality change-an approach that affords a more rigorous examination of the phenomenon., Method: We outline a set of conceptual and methodological questions and considerations for future work on the topic of post-traumatic growth., Results: We provide a series of recommendations for researchers from across the disciplines of clinical/counseling, developmental, health, personality, and social psychology and beyond, who are interested in improving the quality of research examining resilience and growth in the context of adversity., Conclusion: We are hopeful that these recommendations will pave the way for a more accurate understanding of the ubiquity, durability, and causal processes underlying post-traumatic growth., (© 2020 Wiley Periodicals LLC.)

Background: Nasal polyps in the nasal cavity and mucous discharge inside the maxillary sinus exhibit compressive stress on the nasal mucosal epithelium. However, there have been only a few studies on how compressive stress impacts the human nasal mucosal epithelium., Methodology: We investigated the effect of compressive stress on collective migration, junctional proteins, transepithelial electri- cal resistance, epithelial permeability, and gene expression in well-differentiated normal human nasal epithelial (NHNE) cells and human nasal polyp epithelial (HNPE) cells., Results: NHNE cells barely showed collective migration at compressive stress up to 150 mmH20. However, HNPE cells showed much greater degree of collective migration at a lower compressive stress of 100 mmH20. The cell migration of HNPE cells sub- jected to 100 mmH2O compression was significantly decreased at day 3 and was recovered to the status prior to the compressive stress by day 7, indicating that HNPE cells are relatively more sensitive to mechanical pressure than NHNE cells. Compressive stress also increased transepithelial electrical resistance and decreased epithelial permeability, indicating that the compressive stress disturbed the structural organization rather than physical interactions between cells. In addition, we found that compressive stress induced gene expressions relevant to airway inflammation and tissue remodelling in HNPE cells., Conclusion: Taken together, these findings demonstrate that compressive stress on nasal polyp epithelium is capable of inducing collective migration and induce increased expression of genes related to airway inflammation, innate immunity, and polyp remo- delling, even in the absence of inflammatory mediators.

Background: Previous studies have reported notable differences in demographic and clinical features of cluster headache between Western and Asian populations, including lower prevalence of the chronic type and in women. Recently, prodromal symptoms of migraine and pre-attack symptoms of cluster headache have drawn attention regarding their potential pathophysiological implications and pre-emptive treatment. However, pre-attack symptoms of cluster headache have not been studied in the Asian population., Methods: A total of 136 patients with cluster headache (21 first-onset, 110 episodic, and five chronic cases) were recruited in this multi-center study between October 2018 and December 2019. We evaluated the characteristics of pre-attack symptoms in a current bout using a structured questionnaire. Univariable and multivariable logistic regression analyses were performed to evaluate the factors associated with presence of pre-attack symptoms., Results: Pre-attack symptoms were reported in 71.3% of our patients with cluster headache. When present, pre-attack symptoms occurred at a median of 20 minutes (range 1-120) before the attack. The prevalence of local and painful, local and painless sensory, autonomic, and general symptoms was 58.8%, 14.7%, 11.0%, and 30.1%, respectively. Multivariable logistic regression analysis revealed that higher number of bouts was associated with higher prevalence of pre-attack symptoms (OR = 1.464, p  = 0.044)., Conclusions: Pre-attack symptoms were frequently observed in Korean patients with cluster headache, which was consistent with previous Western studies.

Research on the longitudinal association between self-esteem and satisfaction with social relationships has led to ambiguous conclusions regarding the temporal order and strength of this relation. Existing studies have examined this association across intervals ranging from days to years, leaving it unclear as to what extent differences in timing may explain differences across studies. In the present study, we used continuous time structural equation models (i.e., CT-SEM) to examine cross-lagged relations between the constructs, and also distinguished between-person differences from within-person processes (i.e., RI-CT-SEM). We analyzed 10 years of annual data from the Longitudinal Internet Studies of the Social Sciences ( N = 14,741). When using CT-SEM, we found a bidirectional positive relation between self-esteem and satisfaction with social relationships, with larger effects over longer intervals. When using RI-CT-SEM, we found the largest effects of self-esteem and satisfaction with social relationships across intervals of 1 year, with smaller effect sizes at both shorter and longer intervals. In addition, the effect of fluctuations in people's satisfaction with social relationships on fluctuations in their self-esteem was greater than the reverse effect. Our results highlight the importance of considering time when examining the relation between self-esteem and interpersonal outcomes and likely psychological constructs in general. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

HIV-sensory neuropathy (HIV-SN) is a debilitating complication in HIV patients with or without anti-retroviral treatment (ART). Common symptoms of HIV-SN include pain, decreased sensation, paresthesias, and dysesthesias in a symmetric stocking-glove distribution. While HIV-1 protein such as gp120 is implicated in HIV-SN (e.g. impaired large-diameter fiber), ART itself was recently shown to contribute to HIV-SN in HIV patients and impair thin fiber. Multiple host mechanisms may play roles during the pathogenesis of HIV-SN, including neuron-glia interactions in the spinal dorsal horn (SDH), inflammation, mitochondrial dysfunction and endoplasmic reticulum stress. Concurrent infections, such as tuberculosis, also carry a higher likelihood of HIV-SN as well as environmental or genetic predisposition. Pro-inflammatory cytokines such as IL-1, IL2 receptor-alpha, and tumor necrosis factor (TNF) along with abnormal lactate levels have been identified as potential players within the complex pathophysiology of this condition. In this paper, we review the pathophysiology of HIV neuropathy, focusing on the various treatment options available or under investigation. Although several treatment options are available e.g., the capsaicin patch and spinal cord stimulation, symptomatic control of HIV-SN are often challenging. Alternative approaches such as self-hypnosis, resistance exercise, cannabinoids, and acupuncture have all shown promising results, but need further investigation.

Personality is not the most popular subfield of psychology. But, in one way or another, personality psychologists have played an outsized role in the ongoing "credibility revolution" in psychology. Not only have individual personality psychologists taken on visible roles in the movement, but our field's practices and norms have now become models for other fields to emulate (or, for those who share Baumeister's (2016, https://doi.org/10.1016/j.jesp.2016.02.003) skeptical view of the consequences of increasing rigor, a model for what to avoid). In this article we discuss some unique features of our field that may have placed us in an ideal position to be leaders in this movement. We do so from a subjective perspective, describing our impressions and opinions about possible explanations for personality psychology's disproportionate role in the credibility revolution. We also discuss some ways in which personality psychology remains less-than-optimal, and how we can address these flaws., Competing Interests: Competing Interests: Brent Donellan, David Funder, Brent Roberts, Julia Rohrer, Luke Smillie, and Simine Vazire are members of the editorial board of the journal.

Prevalence of pelvic ectopic kidney with obstruction is not common. Associated anomalies may produce technical difficulties and surgical challenges in treatment. Diagnostic tools such as USG KUB, renal scintigraphic studies (DMSA, DTPA), MRI, and preoperative RGP are very informative examinations to properly decide the timing of the operation and method of it. The patient was under close surveillance from the detection of antenatal hydronephrosis until the development of UPJ obstruction. Herein, we report the case of a patient with this anomaly who successfully underwent laparoscopic reconstruction., Competing Interests: None., (© 2020 The Authors. Published by Elsevier Inc.)

Abnormally increased neuronal activity in the lateral habenula (LHb) is closely associated with depressive-like behavior. Despite the emphasis on the pathological importance of NMDA receptor (NMDAR)-dependent long-term depression (LTD) and the involvement of calcium permeable AMPA receptor (CP-AMPAR) as major Ca 2+ source, the functions of NMDAR and CP-AMPAR on LTD modulation in the LHb still have not been fully investigated. Here, we found that NMDAR-dependent LTD by low frequency stimulation was induced in both synaptic and extrasynaptic regions in the LHb. In addition, CP-AMPAR was necessary for the activation of NMDAR in the induction phase of NMDAR-dependent LTD. The acute stress, which induced depressive behavior, had a blocked effect on synaptic NMDAR-dependent LTD but left extrasynaptic NMDAR-dependent LTD intact. These findings show that NMDAR-dependent LTD in LHb plays an important role in regulating neuronal activity, which is probable to be excessively increased by repeated stress, via maintaining homeostasis in both synaptic and extrasynaptic regions of the LHb. Moreover, NMDAR and CP-AMPAR may serve as a depression-related modulator and be regarded as a promising therapeutic target for treatment of psychopathology such as depression.

The pathogenesis of Helicobacter pylori -associated gastric cancer is dependent on delivery of CagA into host cells through a type IV secretion system (T4SS). The H. pylori Cag T4SS includes a large membrane-spanning core complex containing five proteins, organized into an outer membrane cap (OMC), a periplasmic ring (PR) and a stalk. Here, we report cryo-EM reconstructions of a core complex lacking Cag3 and an improved map of the wild-type complex. We define the structures of two unique species-specific components (Cag3 and CagM) and show that Cag3 is structurally similar to CagT. Unexpectedly, components of the OMC are organized in a 1:1:2:2:5 molar ratio (CagY:CagX:CagT:CagM:Cag3). CagX and CagY are components of both the OMC and the PR and bridge the symmetry mismatch between these regions. These results reveal that assembly of the H. pylori T4SS core complex is dependent on incorporation of interwoven species-specific components., Competing Interests: MS, JC, NS, CD, TC, MO, DL No competing interests declared

Legionella pneumophila is an opportunistic pathogen that causes the potentially fatal pneumonia Legionnaires' Disease. This infection and subsequent pathology require the Dot/Icm Type IV Secretion System (T4SS) to deliver effector proteins into host cells. Compared to prototypical T4SSs, the Dot/Icm assembly is much larger, containing ~27 different components including a core complex reported to be composed of five proteins: DotC, DotD, DotF, DotG, and DotH. Using single particle cryo-electron microscopy (cryo-EM), we report reconstructions of the core complex of the Dot/Icm T4SS that includes a symmetry mismatch between distinct structural features of the outer membrane cap (OMC) and periplasmic ring (PR). We present models of known core complex proteins, DotC, DotD, and DotH, and two structurally similar proteins within the core complex, DotK and Lpg0657. This analysis reveals the stoichiometry and contact interfaces between the key proteins of the Dot/Icm T4SS core complex and provides a framework for understanding a complex molecular machine., Competing Interests: CD, MS, JC, BB, MS, TK, MS, DL, MO No competing interests declared, (© 2020, Durie et al.)

Background: Dimples on the cheeks can make the smile look more cheerful and attractive. Therefore, some people who do not have dimples may choose to undergo dimple creation surgery. Although dimple surgery is quite common, those desiring this procedure often lack information about it. Therefore, we conducted the present study to share our surgical tips and clinical experiences regarding safe dimple creation surgery., Methods: This study included 2,048 patients who underwent dimple creation surgery at our plastic surgery clinic between April 2010 and June 2014. These patients were selected from those who displayed no scarring from injury or tumor removal in the central face during the presurgical evaluation. Medical records were used to identify the age and sex of each patient, the location of dimple creation, any postoperative complications, reoperation, and the reason for reoperation., Results: Of the 2,048 patients, 159 (7.7%) underwent reoperation. The reason for reoperation was undercorrection in 78 cases (49.0%), disappearance of the dimple in 62 cases (38.9%), and overcorrection in nine cases (5.6%). Five patients (3.1%) had their stitches removed to eliminate the created dimple because they changed their minds, and five patients (3.1%) had their stitches removed because of infection. No patients reported complications after reoperation, and no other complications, such as hyperpigmentation or foreign body reaction, were observed., Conclusions: Safe surgery with minimal complications and satisfying cosmetic results can be achieved via accurate knowledge of the relevant anatomy and its relationship with dimples, as well as appropriate surgical methodology.

An 11-month-old boy with unilateral Wilms tumor had an unusual presentation, with dilated hypertensive cardiomyopathy, acute myocarditis, pulmonary edema, and congestive heart failure secondary to the Wilms tumor and requiring intensive care. After surgery, all of the findings were normalized. According to the literature review there were reported previously in only seven cases with dilated cardiomyopathy. Wilms tumor should be included in the differential diagnosis of any child with dilated cardiomyopathy and an abdominal mass, regardless of the presence of hypertension, especially less than one year old. Also, vasoactive mediators including renin should be evaluated in the case of hypertension., (© 2020 The Authors.)

Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.

Background: Our aim was to investigate the relationship between coexisting cluster headache (CH) and migraine with anxiety and depression during active cluster bouts, and how symptoms change during remission., Methods: We analyzed data from 222 consecutive CH patients and 99 age- and sex-matched controls using a prospective multicenter registry. Anxiety or depression was evaluated using the Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9), respectively. Moderate-to-severe anxiety or depression was defined as a score of ≥10 at baseline (during a cluster bout). We assessed for changes in anxiety and depression during CH remission periods., Results: Among the CH patients, the prevalence of moderate-to-severe anxiety and depression was seen in 38.2% and 34.6%, respectively. Compared with controls, CH patients were associated with moderate-to-severe anxiety and depression (multivariable-adjusted odds ratio [aOR] = 7.32, 95% confidence intervals [CI] = 3.35-15.99 and aOR = 4.95, 95% CI = 2.32-10.57, respectively). CH patients with migraine were significantly more likely to have moderate-to-severe anxiety and depression (aOR = 32.53, 95% CI = 6.63-159.64 and aOR = 16.88, 95% CI = 4.16-68.38, respectively), compared to controls without migraine. The GAD-7 and PHQ-9 scores were significantly reduced between cluster bout and remission periods (from 6.8 ± 5.6 to 1.6 ± 2.8; P < 0.001, and from 6.1 ± 5.0 to 1.8 ± 2.4; P < 0.001, respectively)., Conclusions: Our results indicate that CH patients are at increased risk of anxiety and depression, especially in the presence of coexisting migraine. However, the anxiety and depression can improve during remission periods.

Individuals' political stances tend to place them into the conservative "right," the liberal "left," or the moderate "middle." What might explain this pattern of division? Moral Politics Theory (Lakoff, 1996) holds that political attitudes arise from moral worldviews that are conceptually anchored in contrasting family models-the strict-father and nurturant-parent models-while the political middle is morally "biconceptual," endorsing both models simultaneously. The present research examined these postulations empirically. Studies 1 and 2 tested the conceptual and predictive validity of the theorized models by developing an instrument assessing strict and nurturant parenting beliefs (the Moral Politics Scale [MPT]), and examining its power to predict political stances on issues seemingly unrelated to parenting attitudes (e.g., abortion, taxes, and same-sex marriage). Studies 3a and 3b explored construct validity while testing whether the family models translate into more general moral worldviews, which then serve as a foundation of political attitudes. Studies 4a through 4c tested generalizability, examining the relationship between the family models and political stances across different countries, data-collection modalities, and a representative American sample. Finally, Studies 5-7 explored biconceptualism and the tendency for these individuals to shift political attitudes as a consequence of situational factors, particularly moral framing, such that strict-father frames lead to increased support for conservative stances while nurturant-parent frames lead to increased support for liberal stances. Overall, we found support for each of MPT's assertions, suggesting that an important aspect of the conceptual and experiential basis of people's political attitudes lies in the strict-father and nurturant-parent family models. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

The molecular chaperone TRAP1 is the mitochondrial paralog of Hsp90 and is overexpressed in many cancer cells. The orthosteric ATP-binding site of TRAP1 has been considered the primary inhibitor binding location, but TRAP1 allosteric modulators have not yet been investigated. Here, we generated and characterized the Hsp90 inhibitor PU-H71, conjugated to the mitochondrial delivery vehicle triphenylphosphonium (TPP) with a C 10 carbon spacer, named SMTIN-C10, to enable dual binding to orthosteric and allosteric sites. In addition to tight binding with the ATP-binding site through the PU-H71 moiety, SMTIN-C10 interacts with the E115 residue in the N-terminal domain through the TPP moiety and subsequently induces structural transition of TRAP1 to a tightly packed closed form. The data indicate the existence of a druggable allosteric site neighboring the orthosteric ATP pocket that can be exploited to develop potent TRAP1 modulators.

A challenge for data sharing in systems neuroscience is the multitude of different data formats used. Neurodata Without Borders: Neurophysiology 2.0 (NWB:N) has emerged as a standardized data format for the storage of cellular-level data together with meta-data, stimulus information, and behavior. A key next step to facilitate NWB:N adoption is to provide easy to use processing pipelines to import/export data from/to NWB:N. Here, we present a NWB-formatted dataset of 1863 single neurons recorded from the medial temporal lobes of 59 human subjects undergoing intracranial monitoring while they performed a recognition memory task. We provide code to analyze and export/import stimuli, behavior, and electrophysiological recordings to/from NWB in both MATLAB and Python. The data files are NWB:N compliant, which affords interoperability between programming languages and operating systems. This combined data and code release is a case study for how to utilize NWB:N for human single-neuron recordings and enables easy re-use of this hard-to-obtain data for both teaching and research on the mechanisms of human memory.

Objective: To investigate the temporal changes of circadian rhythmicity in relation to the disease course in patients with cluster headache., Methods: In this multicenter study, patients with cluster headache were recruited between September 2016 and July 2018. We evaluated the patients for circadian rhythmicity and time of cluster headache attacks in the current bout and any experience of bout-to-bout change in circadian rhythmicity. We analyzed the patterns of circadian rhythmicity in relation to the disease progression (the number of total lifetime bouts, grouped into deciles)., Results: Of the 175 patients in their active, within-bout period, 86 (49.1%) had circadian rhythmicity in the current bout. The prevalence of circadian rhythmicity in the active period was overall similar regardless of disease progression. Sixty-three (46.3%) out of 136 patients with ≥2 bouts reported bout-to-bout changes in circadian rhythmicity. The most frequent time of cluster headache attacks was distributed evenly throughout the day earlier in the disease course and dichotomized into hypnic and midday as the number of lifetime bouts increased ( p  = 0.037 for the homogeneity of variance). When grouped into nighttime and daytime, nighttime attacks were predominant early in the disease course, while daytime attacks increased with disease progression (up to 7th deciles of total lifetime bouts, p  = 0.001) and decreased in patients with the most advanced disease course ( p  = 0.013 for the non-linear association)., Conclusions: Circadian rhythmicity is not a fixed factor, and changes according to the disease course. Our findings will be valuable in providing a new insight into the stability of functional involvement of the suprachiasmatic nucleus in the pathophysiology of cluster headache.

Although many patients with cluster headaches (CH) are disabled by their condition, few studies have examined this in detail. This cross-sectional, multicenter observational study prospectively collected demographic and clinical questionnaire data from 224 consecutive patients with CH. We assessed headache impact using the six-item Headache Impact Test (HIT-6) and evaluated the factors associated with the impact of CH. Participants with a HIT-6 score ≥ 60 were classified into a severe impact group. The majority (190, 84.8%) of the participants were classified into the severe impact group. These patients were characterized by younger age, earlier onset of CH, longer duration of each headache attack, higher pain intensity, more cranial autonomic symptoms, a higher proportion of depression or anxiety, higher score of stress, and lower score of quality of life. The anxiety (OR = 1.19, 95% CI: 1.08-1.31, p = 0.006), greater pain intensity (OR = 1.06, 95% CI: 1.02-1.10, p = 0.002), and age (OR = 0.99, 95% CI: 0.99-1.00, p = 0.008) were significant predictors for a severe impact of CH patients. According to the HIT-6 results, most of the CH patients were significantly affected by CH. As well as pain intensity, anxiety and age modulated CH's impact on their lives.