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Purpose: Despite the overall benefits of deep brain stimulation (DBS) in Parkinson's disease (PD), its effects on speech production have been mixed when examined using auditory-perceptual and acoustic measures. This study investigated the effects of DBS on the lip and jaw kinematics during sentence production in individuals with dysarthria secondary to PD. Method: Twenty-seven participants from three groups were included in the study: (a) individuals with PD and without DBS (PD group), (b) individuals with PD and with DBS (PD-DBS group), and (c) neurologically healthy control speakers (HC group). Lip and jaw movements during speech were recorded using optical motion capture and analyzed for path distance, speed, duration, articulatory stability, and interarticulator coordination. Results: The PD-DBS group showed (a) increased path distance compared with the PD and HC groups and (b) increased speed compared with the PD group but not the HC group. Both PD and PD-DBS groups exhibited lengthened sentence duration compared with the HC group. Articulatory stability was greater for the two PD groups, PD and PD-DBS, compared with the HC group. Spatial, but not temporal, coordination was lower for the PD group than for the other two groups. The only kinematic changes between the DBS on and off conditions within the PD-DBS group were increases in spatial coordination. Conclusions: These data suggest that DBS primarily affects the amplitude scaling of articulatory movements, but not the temporal scaling, in individuals with PD. The findings are discussed with respect to the DBS-induced neural changes and their effects on speech motor control in PD.

Porous polyethylene (PE) polymer film is a representative material for separators in Li-ion batteries (LIBs). Although PE separators are widely used in commercial LIBs owing to several advantages such as chemical stability, low cost, and good processability, the material still suffers from poor wettability to organic liquid electrolytes and low thermal stability. In this study, a facile surface modification method via the nucleophilic addition of amine in a solution is proposed. To improve the electrolyte wettability and thermal stability of the PE separators, a carbonyl group (C=O) was introduced onto the surface by pretreatment. Then, an imine functional group (R–N=C) was created by the conversion reaction between the carbonyl and amine groups (R-NH2) in a poly(ethylene glycol) bis(amine) solution. By including the formed imine group onto the surface, the surface-modified PE separator exhibited enhanced wettability and thermal stability. The chemical surface treatment transformed the PE separator from hydrophobic to hydrophilic, resulting in the increased ionic conductivity of the electrolyte and rate capability of the cells without any negative effect on the physical and electrochemical properties of the separator.

Purpose: This study aimed to examine the effects of wearing a face mask on speech acoustics and intelligibility, using an acoustic-phonetic analysis of speech. In addition, the effects of speakers' behavioral modification while wearing a mask were examined. Method: Fourteen female adults were asked to read a set of words and sentences under three conditions: (a) conversational, mask-off; (b) conversational, mask-on; and (c) clear, mask-on. Seventy listeners rated speech intelligibility using two methods: orthographic transcription and visual analog scale (VAS). Acoustic measures for vowels included duration, first (F1) and second (F2) formant frequency, and intensity ratio of F1/F2. For consonants, spectral moment coefficients and consonant–vowel (CV) boundary (intensity ratio between consonant and vowel) were measured. Results: Face masks had a negative impact on speech intelligibility as measured by both intelligibility ratings. However, speech intelligibility was recovered in the clear speech condition for VAS but not for transcription scores. Analysis of orthographic transcription showed that listeners tended to frequently confuse consonants (particularly fricatives, affricates, and stops), rather than vowels in the word-initial position. Acoustic data indicated a significant effect of condition on CV intensity ratio only. Conclusions: Our data demonstrate a negative effect of face masks on speech intelligibility, mainly affecting consonants. However, intelligibility can be enhanced by speaking clearly, likely driven by prosodic alterations.

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Purpose:Aberrant overexpression of SFN (stratifin) plays an oncogenic role in lung adenocarcinoma. We have shown previously that SKP1, an adapter component of E3 ubiquitin ligase forming an SCF complex, is a unique SFN-binding protein in lung adenocarcinoma cells.Experimental Design:In silico simulation and in vitro mutagenesis analysis were performed to identify the SFN-binding domain on SKP1. We examined expression, localization, and stability of SKP1 after knockdown of SFN using lung adenocarcinoma cells including A549. In silico library screening and experimental validation were used for drug screening. Daily oral administration of each candidate drugs to A549-injected tumor-bearing mice was performed to evaluate their in vivo antitumor efficacy.Results:Suppression of SFN upregulated the stability of SKP1 and accelerated its cytoplasm-to-nucleus translocation. Consistently, IHC analysis revealed that cytoplasmic expression of SKP1 was significantly associated with SFN positivity, tumor malignancy, and poorer patient outcome. After SFN suppression, ubiquitination of oncoproteins, including p-cyclin E1, p-c-Myc, p-c-Jun, and cleaved Notch 1, which are target proteins of SCFFBW7, was strongly induced. These results indicate that SFN–SKP1 binding results in SCFFBW7 dysfunction and allows several oncoproteins to evade ubiquitination and subsequent degradation. Because inhibition of SFN-SKP1 binding was expected to have antitumor efficacy, we next searched for candidate SFN inhibitors. Aprepitant and ticagrelor were finally selected as potential SFN inhibitors that dose dependently reduced SFN-SKP1 binding and tumor progression in vivo.Conclusions:As overexpression of SFN is detectable in most adenocarcinoma, we believe that SFN inhibitors would be novel and promising antitumor drugs for lung adenocarcinoma.

Supplementary material and method and figure legends.

Purpose: The aim of this study was to conduct a scoping review of research on oral and laryngeal diadochokinesis (DDK) in children and adults, either typically developing/developed or with a clinical diagnosis. Method: Searches were conducted with PubMed/MEDLINE, Google Scholar, CINAHL, and legacy sources in retrieved articles. Search terms included the following: DDK, alternating motion rate, maximum repetition rate, sequential motion rate, and syllable repetition rate. Results: Three hundred sixty articles were retrieved and included in the review. Data source tables for children and adults list the number and ages of study participants, DDK task, and language(s) spoken. Cross-sectional data for typically developing children and typically developed adults are compiled for the monosyllables /pʌ/, /tʌ/, and /kʌ/; the trisyllable /pʌtʌkʌ/; and laryngeal DDK. In addition, DDK results are summarized for 26 disorders or conditions. Discussion: A growing number of multidisciplinary reports on DDK affirm its role in clinical practice and research across the world. Atypical DDK is not a well-defined singular entity but rather a label for a collection of disturbances associated with diverse etiologies, including motoric, structural, sensory, and cognitive. The clinical value of DDK can be optimized by consideration of task parameters, analysis method, and population of interest.

Tin-based intermetallic compounds are regarded as a promising alternative for Li secondary battery anodes due to their high specific and volumetric capacity, as well as their low operating potential. However, the materials’ cycling performance still cannot meet the required standards for commercialization. In this study, we designed and synthesized a Sn2Fe-TiOx-C composite as a high-capacity anode material via high-energy mechanical milling and hydrogen treatment. The synthesized material was characterized by several analytical tools. The reaction mechanism of the composite electrode with Li was investigated with ex situ X-ray diffraction analysis, and the conversion of Sn2Fe to Li–Sn alloy and Fe during Li insertion and its reversibility were confirmed. The results of an electrochemical test showed that a reversible capacity of 651 mAh g−1 was retained after 100 cycles. This cycling stability could be attributed to the microstructure in which Sn2Fe was uniformly distributed in the TiOx and carbon matrix. Additionally, there was an improvement in rate performance after hydrogen treatment because titanium oxide produced during mechanical milling was partially reduced, which was helpful for enhancing the electrical conductivity of the composite electrode.

Background: People with dysarthria often present with reduced speech intelligibility (Yorkston et al., 1992). Given its link with other communication outcomes (Borrie et al., 2022; Spencer et al., 2020; Yorkston & Beukelman, 1981), improving speech intelligibility is often the target in dysarthria management (Cannito et al., 2012; Wenke et al., 2008). However, speech intelligibility is not the sole predictor of communication outcomes in dysarthria (Hustad, 2008; McAuliffe et al., 2010). Additionally, much of the dysarthria literature has focused on investigating the speaker-specific acoustic and perceptual sources of intelligibility deficits (Fletcher et al., 2017; Thompson et al., 2023; Tjaden et al., 2014; Weismer et al., 2001), despite the importance of the listener in perception. Thus, there is a need to investigate other listener-based perceptual outcomes in dysarthria, such as listening effort. Defined as the cognitive energy a listener expends to engage in a listening situation (Pichora-Fuller et al., 2016), listening effort is a potentially relevant, albeit underexamined, listener-based perceptual outcome in dysarthria. A few studies have found that listening effort is greater while listening to a speaker with dysarthria compared to a healthy speaker (Fletcher et al., 2019, 2022). Although the intelligibility of dysarthric speech and listening effort has been observed in some studies (Coté-Reschny & Hodge, 2010; Fletcher et al., 2019; Whitehill & Wong, 2006), a relationship between these constructs are not always found (Fletcher et al., 2022). Indeed, a recent study found increased listening effort during accented speech perception compared to native speech perception, even when speech intelligibility was preserved (McLaughlin & Van Engen, 2020). Thus, it is plausible that listening effort is increased during perception of dysarthric speech, even if the speaker is intelligible to the listener. Current Study: The overall objective of this study is to investigate listening effort during perception of dysarthric speech. Listening effort will be measured using two methods, pupil dilation and subjective listener ratings. The overall objective of this study is to model listening effort in dysarthric speech perception.

Purpose: This study sought to determine if alternative vowel space area (VSA) measures (i.e., novel trajectory-based measures: vowel space hull area and vowel space density) predicted speech intelligibility to the same extent as two traditional vowel measures (i.e., token-based measures: VSA and corner dispersion) in speakers with dysarthria. Additionally, this study examined if the strength of the relationship between acoustic vowel measures and intelligibility differed based on how intelligibility was measured (i.e., orthographic transcriptions [OTs] and visual analog scale [VAS] ratings). Method: The Grandfather Passage was read aloud by 40 speakers with dysarthria of varying etiologies, including Parkinson's disease ( n = 10), amyotrophic lateral sclerosis ( n = 10), Huntington's disease ( n = 10), and cerebellar ataxia ( n = 10). Token- and trajectory-based acoustic vowel measures were calculated from the passage. Naïve listeners ( N = 140) were recruited via crowdsourcing to provide OTs and VAS intelligibility ratings. Hierarchical linear regression models were created to model OTs and VAS intelligibility ratings using the acoustic vowel measures as predictors. Results: Traditional VSA was the sole significant predictor of speech intelligibility for both the OTs ( R 2 = .259) and VAS ( R 2 = .236) models. In contrast, the trajectory-based measures were not significant predictors of intelligibility. Additionally, the OTs and VAS intelligibility ratings conveyed similar information. Conclusions: The findings suggest that traditional token-based vowel measures better predict intelligibility than trajectory-based measures. Additionally, the findings suggest that VAS methods are comparable to OT methods for estimating speech intelligibility for research purposes.

Ovarian carcinoma immunoreactive antigen domain 2 (OCIAD2) has been reported to show significantly higher expression in invasive lung adenocarcinoma than in lung adenocarcinoma in situ, and its abnormal expression is associated with poorer prognosis of the patients. However, the cellular function of OCIAD2 in this tumor remains poorly understood. In the present study, we first validated that OCIAD2 showed higher expression in human lung adenocarcinoma tissues or cell lines than in normal lung tissue or immortalized normal bronchial epithelial cells. OCIAD2 was localized predominantly at the mitochondrial membrane in lung adenocarcinoma cells. Interestingly, suppression of OCIAD2 led to loss of mitochondrial structure and a reduction in the number of mitochondria. Moreover, OCIAD2 suppression led to downregulation of cellular growth, proliferation, migration, and invasion, and upregulation of mitochondria‐related apoptosis. We also showed that OCIAD2 suppression induced a decrease in mitochondrial membrane potential and release of cytochrome c. Transcriptional profiling using RNA sequencing revealed a total of 137 genes whose expression was commonly altered after OCIAD2 knockdown in three lung adenocarcinoma cell lines (A549, HCC827, and PC9). Pathway enrichment analysis of those genes demonstrated significant enrichment in apoptotic signaling or endoplasmic reticulum (ER) stress pathways. Our data suggest that OCIAD2 inhibits the mitochondria‐initiated apoptosis and thus promotes the survival of lung cancer cells. Therefore, OCIAD2 may be an effective target for treatment of lung adenocarcinoma., In lung adenocarcinoma, OCIAD2 maintains the mitochondria integrity and promotes tumor progression by acting as an antiapoptotic factor. However, inhibition of OCIAD2 causes fatal defects in the mitochondria and also induces mitochondrial apoptosis by depolarizing the mitochondrial membrane potential, releasing cytochrome c, and activating caspase cascades in lung adenocarcinoma cells.

The expression of Ras-specific guanine nucleotide-releasing factor 2 (RasGRF2) in lung adenocarcinomas was examined using immunohistochemistry in relation to clinicopathological characteristics and prognosis. In comparison to low expression, high expression of RasGRF2 was more closely associated with poor prognosis. Interestingly, expression of phosphorylated epithelial cell transforming 2 (pECT2), which - like RasGRF2 - is also a guanine-nucleotide exchange factor, was also associated with prognosis, and patients with high expression of both RasGRF2 and pECT2 had a much poorer outcome than those who were negative for both.

The field of sports has traditionally been a domain that practices and reinforces masculinity. However, in contemporary literature, observations and experiences of males in sports have expanded their ideas on masculinity as well as gender identity. Furthermore, there is an increase in males participating in non-orthodox masculine physical activities, most of which are known as “gender appropriate” for females such as cheerleading, dance, gymnastics, etc. Recently, pole dance – a stigmatized female-oriented activity – has become a newly introduced activity in the sports scene and one in which males are gradually engaging in worldwide. In the case of Korea, the phenomenon of men taking part in female-concentrated activities is not common; however, there are a rising number of male pole dancers visible through national competitions and media sources. Therefore, this study explores the experiences of Korean male exotic pole dance practitioners to understand how they define gender identity whilst participating in a highly female-oriented activity. It was found that research participants articulated beyond their biological sex and practice not to conform to social gender roles, and rather emphasized their manifested identity of individual self. Despite Korea’s cultural and traditional aspects of gender norms, this study establishes a broader segment of gender ideas and expands the understanding of various identities spoken among male polers.

We assessed the feasibility of a hybrid monitoring system (minimal on-site monitoring + strategic central monitoring) used at the academic research office at Asan Medical Center (Seoul, Korea) in monitoring investigator-sponsored oncology trials.Monitoring findings in three oncology trials conducted between 2014 and 2017 were compared. A confirmatory source data verification (SDV) was carried out in the low-risk trial and compared with the central monitoring findings. The economic advantages of central monitoring were tested by calculating the monitoring hours per patient.A total of 50, 118, 228 patients were enrolled in the high-, intermediate-, and low-risk trials, respectively. The high-risk trial was monitored through 42 on-site visits (1299 findings); the intermediate-risk trial had 79 monitorings (on-site, 24%; central, 76%; 1464 findings); the low-risk trial had 197 monitorings (on-site, 4%; central, 96%; 3364 findings). Central monitoring was more effective than on-site monitoring in revealing minor errors such as "missing case report forms" and "data outliers" (both P 0.0001), and showed comparable results in revealing major issues such as investigational product compliance and delayed reporting of serious adverse events (both P 0.05). Confirmatory SDV in the low-risk trial revealed more findings than central monitoring in the "inconsistent data" and "inappropriate adverse event" categories. The total monitoring hours per patient were lower in the intermediate- and low-risk trials than in the high-risk trial (8.1 and 7.3 vs. 14.3 h, respectively).Our hybrid monitoring system showed acceptable feasibility in revealing both major and minor issues in multi-center oncology investigator-sponsored trials.

This study examined the acoustic characteristics of American English liquids /ɹ/, /l/, and /ɹl/ produced by 14 adult learners of English (L2) and 13 native speakers of English. Several temporal and spectral measures were examined, including a novel measure to describe the relative timing of the maximum constriction during liquid production. The results indicated that L2 speakers rely more on duration contrasts to distinguish the three liquids than spectral contrasts. Reduced spectral differences among the liquids in L2 speakers are discussed concerning the influence of the native language of L2 speakers.

Purpose: This study presents the results of acoustic and kinematic analyses of word-initial semivowels (/ɹ, l, w/) produced by second-language (L2) speakers of English whose native language is Korean. In addition, the relationship of acoustic and kinematic measures to the ratings of foreign accent was examined by correlation analyses. Method: Eleven L2 speakers and 10 native speakers (first language [L1]) of English read The Caterpillar passage. Acoustic and kinematic data were simultaneously recorded using an electromagnetic articulography system. In addition to speaking rate, two acoustic measures (ratio of third-formant [F3] frequency to second-formant [F2] frequency and duration of steady states of F2) and two kinematic measures (lip aperture and duration of lingual maximum hold) were obtained from individual target sounds. To examine the degree of contrast among the three sounds, acoustic and kinematic Euclidean distances were computed on the F2–F3 and x – y planes, respectively. Results: Compared with L1 speakers, L2 speakers exhibited a significantly slower speaking rate. For the three semivowels, L2 speakers showed a reduced F3/F2 ratio during constriction, increased lip aperture, and reduced acoustic Euclidean distances among semivowels. Additionally, perceptual ratings of foreign accent were significantly correlated with three measures: duration of steady F2, acoustic Euclidean distance, and kinematic Euclidean distance. Conclusions: The findings provide acoustic and kinematic evidence for challenges that L2 speakers experience in the production of English semivowels, especially /ɹ/ and /w/. The robust and consistent finding of reduced contrasts among semivowels and their correlations with perceptual accent ratings suggests using sound contrasts as a potentially effective approach to accent modification paradigms.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus. IL-23 is essential for their accumulation, and ablation of IL-23 or IL-17 signalling rectifies the reduced survival of female PTEN-haploinsufficient mice that model human patients with PTEN mutations. Single-cell transcriptome and network analyses revealed the dynamic regulation of PTEN, mTOR and metabolic activities that accompanied type-17 cell programming. Furthermore, deletion of mTORC1 or mTORC2 blocks PTEN loss-driven type-17 cell accumulation, and this is further shaped by the Foxo1 and Stat3 pathways. Collectively, our study establishes developmental and metabolic signalling networks underpinning type-17 cell fate decisions and their functional effects at coordinating PTEN-dependent tissue homeostasis.

Purpose This case study traced speech deterioration in an individual before and after the time of diagnosis of amyotrophic lateral sclerosis (ALS). Our participant was diagnosed with spinal-onset, familial ALS in 2017. The speaker's occupation, a professional newscaster for 37 years, allowed a retrospective examination of her speech during news segments over 37 months around the diagnosis, including prediagnosis. Method A total of 6 time points were selected to track auditory-perceptual and acoustic speech deterioration (2 years, 14 months, and 7 months prior to diagnosis; the month of diagnosis; and 7 months and 12 months after diagnosis). For perceptual ratings, 2 experts in motor speech disorders rated 17 speech dimensions on a 7-point scale. Four acoustic parameters were chosen for measurement: articulation rate, utterance duration, second formant frequency slope, and acoustic vowel space. Additionally, kinematic data were obtained from 1 time-point (8 months postdiagnosis) and descriptively compared to the movement of other individuals with ALS and to healthy speakers. Results As expected, both perceptual and acoustic results indicated a decline in the selected speech measures as the disease progressed. More interestingly, the measures showed a consistent curvilinear appearance in which the speech parameters exhibit an improvement until immediately before and around the diagnosis, followed by sudden, drastic deterioration. Kinematic results indicated a greater degree of movement and speed compared to healthy speakers, probably due to the speaker's occupation. Conclusions Based on the findings, the time around diagnosis is considered a critical period with respect to speech deterioration in ALS wherein a dynamic, increasing–decreasing pattern of changes occur. This finding appears to reflect the patient's compensatory strategies and the speech deficits associated with bulbar involvement.

The magnetite particles were synthesized by reverse coprecipitation of mill scale (iron oxide waste). The particle characterization was done and confirmed by SEM, EDS, BET, XRF, FTIR and XRD. Scherrer equation determined 11.64 nm single crystalline size of the magnetite and the BET surface area was found nearly 75.77 m2 g−1. The expected stoichiometry (3:4) of Fe:O was confirmed by elemental analysis. The magnetite particles were proven as effective adsorbent for phosphate ions from the contaminated water. The phosphate removal efficiency was inspected with several experimental setups including column reactor fed from top to bottom, from bottom to top and sequencing batch reactor. The maximum P-adsorption capacity of magnetite was determined 11.78 mg g−1. The P-carrying adsorbent is regenerated with different concentrations of NaOH and NH4OH solutions for 1, 2 and 5 days. Though both solutions were appeared effective for regeneration of used particles, NaOH was appeared more efficacious than that of NH4OH. The regeneration competence of magnetite particles is also evaluated with repetitive regeneration of used particles with 0.1 N NaOH. As compared with initial value, almost 20% of the adsorption capacity was reduced after 12 successive rounds of phosphate adsorption and desorption onto the surface of magnetite. The obtained results have established fine potentiality for the magnetite particles synthesized by reverse coprecipitation to be applied as phosphate adsorbent in wastewater treatment.

The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen‐induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non‐small‐cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN‐transgenic (Tg‐SPC‐SFN +/−) mice, which express human SFN (hSFN) only in the lung. Here, we have found that carcinogen nicotine‐derived nitrosaminoketone (NNK)‐induced tumors developing in Tg‐SPC‐SFN +/− mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg‐SPC‐SFN +/− tumors and human lung adenocarcinoma, the former were subjected to whole‐exome sequencing. Interestingly, Tg‐SPC‐SFN +/− tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg‐SPC‐SFN +/− tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg‐SPC‐SFN +/− tumors were closely associated with key canonical pathways such as PI3K/AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg‐SPC‐SFN +/− tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg‐SPC‐SFN +/− mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis.

Purpose: Aberrant overexpression of SFN (stratifin) plays an oncogenic role in lung adenocarcinoma. We have shown previously that SKP1, an adapter component of E3 ubiquitin ligase forming an SCF complex, is a unique SFN-binding protein in lung adenocarcinoma cells. Experimental Design: In silico simulation and in vitro mutagenesis analysis were performed to identify the SFN-binding domain on SKP1. We examined expression, localization, and stability of SKP1 after knockdown of SFN using lung adenocarcinoma cells including A549. In silico library screening and experimental validation were used for drug screening. Daily oral administration of each candidate drugs to A549-injected tumor-bearing mice was performed to evaluate their in vivo antitumor efficacy. Results: Suppression of SFN upregulated the stability of SKP1 and accelerated its cytoplasm-to-nucleus translocation. Consistently, IHC analysis revealed that cytoplasmic expression of SKP1 was significantly associated with SFN positivity, tumor malignancy, and poorer patient outcome. After SFN suppression, ubiquitination of oncoproteins, including p-cyclin E1, p-c-Myc, p-c-Jun, and cleaved Notch 1, which are target proteins of SCFFBW7, was strongly induced. These results indicate that SFN–SKP1 binding results in SCFFBW7 dysfunction and allows several oncoproteins to evade ubiquitination and subsequent degradation. Because inhibition of SFN-SKP1 binding was expected to have antitumor efficacy, we next searched for candidate SFN inhibitors. Aprepitant and ticagrelor were finally selected as potential SFN inhibitors that dose dependently reduced SFN-SKP1 binding and tumor progression in vivo. Conclusions: As overexpression of SFN is detectable in most adenocarcinoma, we believe that SFN inhibitors would be novel and promising antitumor drugs for lung adenocarcinoma.

A simple Raman spectroscopic scheme for on-line detection of microplastics (MPs) in water is demonstrated. Instead of using a conventional physical filter for MP separation, perfluorohexane (PFH, C6F14) was deployed as an MP-capturing medium in this study. When PFH was added into a water-filled L-shape tube, it formed a firm droplet at the bottom of the 90° curve due to its strong hydrophobicity and high density. When a tap water sample containing dispersed polyethylene (PE) particles was flowed through the L-tube, the contained PFH droplet effectively captured the PE particles, with an average recovery of 95.9%. Next, for reliable quantitative analysis, it was necessary to measure the entire PE particle captured PFH droplet in Raman spectral acquisition without partial spectroscopic sampling. Therefore, a wide area illumination (WAI) scheme providing a laser illumination diameter of 6 mm was adopted for sampling of the whole droplet. The intensity ratios of PE and PFH peaks in the collected spectra clearly increased with elevated quantities of dispersed PE particles. When samples of PE particles were measured in sea water, which possesses much higher ionic strength than does tap water, the shapes of PE particle-captured PFH droplets did not change, and the accuracy was maintained. Based on these results, the demonstrated analytical scheme is feasible for field analysis; further study is required to strengthen its utility.

BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.

Patient-derived xenograft (PDX) murine models are employed for preclinical research on cancers, including non-small cell lung cancers (NSCLCs). Even though lung squamous cell carcinomas (LUSCs) show the highest engraftment rate among NSCLCs, half of them nevertheless show PDX failure in immunodeficient mice. Here, using immunohistochemistry and RNA sequencing, we evaluated the distinct immunohistochemical and gene expression profiles of resected LUSCs that showed successful engraftment. Among various LUSCs, including the basal, classical, secretory, and primitive subtypes, those in the non-engrafting (NEG) group showed gene expression profiles similar to the pure secretory subtype with positivity for CK7, whereas those in the engrafting (EG) group were similar to the mixed secretory subtype with positivity for p63. Pathway analysis of 295 genes that demonstrated significant differences in expression between NEG and EG tumors revealed that the former had enriched expression of genes related to the immune system, whereas the latter had enriched expression of genes related to the cell cycle and DNA replication. Interestingly, NEG tumors showed higher infiltration of B cells (CD19+) and follicular dendritic cells (CD23+) in lymph follicles than EG tumors. Taken together, these findings suggest that the PDX cancer model of LUSC represents only a certain population of LUSCs and that CD19- and CD23-positive tumor-infiltrating immune cells in the original tumors may negatively influence PDX engraftment in immunodeficient mice.

We use factor-augmented predictive regressions to analyze the relation between nominal exchange rates and macroeconomic variables. Using a panel of 121 US macroeconomic time series, we estimate eight factors through principal component analysis. Those estimated factors have significant predictive power and can substantially improve the predictive power of purchasing power parity through both in-sample and out-of-sample analyses. The estimated macroeconomic factor, which co-moves with US stock market variables, has strong predictive power for nominal exchange rate fluctuations in the short run, while estimated factors, co-moving with interest rate spreads, government-issued bond yields and employment variables, have strong predictive power in the long run. Moreover, optimal factors selected by the BIC in the out-of-sample analysis differ greatly depending on the time points when forecasts are made. Finally, we show that factors extracted from a panel of 121 US time series data and those extracted from a panel of 215 Korean macroeconomic series together can predict a substantial portion of movements in the Korea–US bilateral exchange rate.

The clinicopathological implications of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) in lung adenocarcinoma were investigated. The expression of OCIAD2 in 191 surgically resected lung adenocarcinomas was examined using immunohistochemistry. OCIAD2 expression was quantified using the H-score and dichotomized as high or low. High OCIAD2 protein expression was significantly correlated with vascular invasion (P = 0.0018), lymphatic permeation (P = 0.049), T factor (P = 0.0024), and pathological stage (P = 0.0003). High OCIAD2 expression was significantly associated with poorer overall survival (OS) (n = 191, P = 0.0325). In peripheral-type lung adenocarcinomas (n = 161), high OCIAD2 expression was significantly associated with both poorer OS (P = 0.0214) and poorer disease-free survival (P = 0.0496). Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) showed weaker OCIAD2 expression than invasive adenocarcinoma. Among small adenocarcinomas measuring 2 cm or less in greatest dimension classified according to the Noguchi's classification (n = 79), invasive adenocarcinomas showed significantly higher OCIAD2 expression than non-invasive adenocarcinomas (P = 0.0007). Interestingly, OCIAD2 was expressed heterogeneously even within a tumor, and its expression was higher in areas of invasion than in areas of in situ spread. Our results suggest that OCIAD2 could be a useful prognostic biomarker of lung adenocarcinoma.