Correction: Detection of obstructive sleep apnea using Belun Sleep Platform wearable with neural network-based algorithm and its combined use with STOP-Bang questionnaire.

[This corrects the article DOI: 10.1371/journal.pone.0258040.].

Belun Ring (Belun Sleep System BLS-100): Deep learning-facilitated wearable enables obstructive sleep apnea detection, apnea severity categorization, and sleep stage classification in patients suspected of obstructive sleep apnea.

GOAL AND AIMS: Our objective was to evaluate the performance of Belun Ring with second-generation deep learning algorithms in obstructive sleep apnea (OSA) detection, OSA severity categorization, and sleep stage classification. FOCUS TECHNOLOGY: Belun Ring with second-generation deep learning algorithms REFERENCE TECHNOLOGY: In-lab polysomnography (PSG) SAMPLE: Eighty-four subjects (M: F = 1:1) referred for an overnight sleep study were eligible. Of these, 26% had PSG-AHI<5; 24% had PSG-AHI 5-15; 23% had PSG-AHI 15-30; 27% had PSG-AHI ≥ 30. DESIGN: Rigorous performance evaluation by comparing Belun Ring to concurrent in-lab PSG using the 4% rule. CORE ANALYTICS: Pearson's correlation coefficient, Student's paired t-test, diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, Cohen's kappa coefficient (kappa), Bland-Altman plots with bias and limits of agreement, receiver operating characteristics curves with area under the curve, and confusion matrix. CORE OUTCOMES: The accuracy, sensitivity, specificity, and kappa in categorizing AHI ≥ 5 were 0.85, 0.92, 0.64, and 0.58, respectively. The accuracy, sensitivity, specificity, and Kappa in categorizing AHI ≥ 15 were 0.89, 0.91, 0.88, and 0.79, respectively. The accuracy, sensitivity, specificity, and Kappa in categorizing AHI ≥ 30 were 0.91, 0.83, 0.93, and 0.76, respectively. BSP2 also achieved an accuracy of 0.88 in detecting wake, 0.82 in detecting NREM, and 0.90 in detecting REM sleep. CORE CONCLUSION: Belun Ring with second-generation algorithms detected OSA with good accuracy and demonstrated a moderate-to-substantial agreement in categorizing OSA severity and classifying sleep stages.

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.

BACKGROUND: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-ß1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. METHODS: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. RESULTS: We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. CONCLUSION: Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.

Correction to "Optimized CO2 Capture of the Zeolitic Imidazolate Framework ZIF-8 Modified by Solvent-Assisted Ligand Exchange".

[This corrects the article DOI: 10.1021/acsomega.1c01130.].

Detection of obstructive sleep apnea using Belun Sleep Platform wearable with neural network-based algorithm and its combined use with STOP-Bang questionnaire.

Many wearables allow physiological data acquisition in sleep and enable clinicians to assess sleep outside of sleep labs. Belun Sleep Platform (BSP) is a novel neural network-based home sleep apnea testing system utilizing a wearable ring device to detect obstructive sleep apnea (OSA). The objective of the study is to assess the performance of BSP for the evaluation of OSA. Subjects who take heart rate-affecting medications and those with non-arrhythmic comorbidities were included in this cohort. Polysomnography (PSG) studies were performed simultaneously with the Belun Ring in individuals who were referred to the sleep lab for an overnight sleep study. The sleep studies were manually scored using the American Academy of Sleep Medicine Scoring Manual (version 2.4) with 4% desaturation hypopnea criteria. A total of 78 subjects were recruited. Of these, 45% had AHI < 5; 18% had AHI 5-15; 19% had AHI 15-30; 18% had AHI ≥ 30. The Belun apnea-hypopnea index (bAHI) correlated well with the PSG-AHI (r = 0.888, P < 0.001). The Belun total sleep time (bTST) and PSG-TST had a high correlation coefficient (r = 0.967, P < 0.001). The accuracy, sensitivity, specificity in categorizing AHI ≥ 15 were 0.808 [95% CI, 0.703-0.888], 0.931 [95% CI, 0.772-0.992], and 0.735 [95% CI, 0.589-0.850], respectively. The use of beta-blocker/calcium-receptor antagonist and the presence of comorbidities did not negatively affect the sensitivity and specificity of BSP in predicting OSA. A diagnostic algorithm combining STOP-Bang cutoff of 5 and bAHI cutoff of 15 events/h demonstrated an accuracy, sensitivity, specificity of 0.938 [95% CI, 0.828-0.987], 0.944 [95% CI, 0.727-0.999], and 0.933 [95% CI, 0.779-0.992], respectively, for the diagnosis of moderate to severe OSA. BSP is a promising testing tool for OSA assessment and can potentially be incorporated into clinical practices for the identification of OSA. Trial registration: ClinicalTrial.org NCT03997916 https://clinicaltrials.gov/ct2/show/NCT03997916?term=belun+ring&draw=2&rank=1.

Optimized CO2 Capture of the Zeolitic Imidazolate Framework ZIF-8 Modified by Solvent-Assisted Ligand Exchange.

Zeolitic imidazolate frameworks, like ZIF-8 and related structures, have shown great potential for the capture of carbon dioxide. Modifying their structure by exchanging part of the constituent organic ligands is a proven method for enhancing the capacity to absorb CO2. In this work, we performed solvent-assisted ligand exchange (SALE) on nanosized ZIF-8 (nZIF-8) with a series of functionalized imidazole derivatives (exchange percentages, after 24 h): 2-bromoimidazole (19%), 2-chloroimidazole (29%), 2-trifluoromethylbenzimidazole (4%), 2-mercaptobenzimidazole (4%), and 2-nitroimidazole (54%). The sodalite topology and porosity of nZIF-8 were maintained with all SALE modifications. Low-pressure CO2 adsorption of nZIF-8 (38.5 cm3 g-1) at STP was appreciably enhanced with all mixed-linker SALE products. Using halogenated (-Cl, -Br, and -CF3) imidazole derivatives in a 24 h SALE treatment resulted in increases between 11 and 22% in CO2 adsorption, while the thiol (-SH)- and nitro (-NO2)-functionalized SALE products led to 32 and 100% increases in CO2 uptakes, respectively. These CO2 uptakes were further optimized by varying the SALE treatment time. The SHbIm- and NO2Im-exchanged SALE products of nZIF-8 show 87 and 98 cm3 g-1 of CO2 uptakes after 60 and 120 h of SALE, respectively. These are record high CO2 adsorptions for all reported ZIF derivatives at low-pressure conditions.

ApoE4 Accelerates Early Seeding of Amyloid Pathology.

Accumulation and aggregation of amyloid-ß (Aß) in the brain is an initiating step in the pathogenesis of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (apoE) gene is the strongest genetic risk factor for late-onset AD. Although there is strong evidence showing that apoE4 enhances amyloid pathology, it is not clear what the critical stage(s) is during amyloid development in which apoE4 has the strongest impact. Using apoE inducible mouse models, we show that increased expression of astrocytic apoE4, but not apoE3, during the seeding stage of amyloid development enhanced amyloid deposition and neuritic dystrophy in amyloid model mice. ApoE4, but not apoE3, significantly increased brain Aß half-life measured by in vivo microdialysis. Furthermore, apoE4 expression increased whereas apoE3 reduced amyloid-related gliosis in the mouse brains. Together, our results demonstrate that apoE4 has the greatest impact on amyloid during the seeding stage, likely by perturbing Aß clearance and enhancing Aß aggregation.

Base-Mediated Cyclization Reaction of 2-(5-Hydroxy-1-pentynyl)benzonitriles to 4-Amino-2,3-dihydronaphtho[2,3-b]furanes and Synthesis of Furanonaphthoquinones.

An efficient transformation of 2-(5-hydroxy-1-pentynyl)benzonitriles 5 to furanonaphthoquinones 11 is presented. Treatment of 5 with 1.5 equiv of NaOMe in DMSO at 140 °C for 0.5 h gave 6 in good yields. Conversion of 6 to 11 was carried out by oxidation of 6 with Fremy's salt and KH2PO4 in acetone and water, followed by dehydrogenation using palladium on charcoal in diphenylether at reflux temperature.

Neuronal LRP1 regulates glucose metabolism and insulin signaling in the brain.

Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-ß (Aß) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aß in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor ß in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy.

Great fraction of dissolved organic C and N in the primary per-humid Chamaecyparis forest soil.

BACKGROUND: Labile organic matter plays a crucial role in a variety of forest functions, however, our understanding to its quality and quantity across various forests is limited, particularly primary forests. We investigated soil labile C and N (i.e. microbial biomass C and N, dissolved organic carbon (DOC) and nitrogen (DON), associated ammonium, and nitrate) at three topographic locations (i.e. summit, footslope and lakeshore) in a primary Chamaecyparis forest of Taiwan. The following hypotheses are tested in this study: (1) This undisturbed Chamaecyparis forest shows the great size of soil labile C and N; (2) there is an evident topographic effect on the distribution of soil labile C and N and the associated inorganic N over seasons. RESULTS: Fulfilling with our first hypothesis, the considerable size of labile C and N in this forest soil was quantified. Abundant C availability and the acidity of soils in this forest favoured ammonium production over nitrate. The undisturbed environment with per-humid and acidic soil was linked to the high concentrations of soil DOC and DON as the dominant form in N dynamics. In contrast to our second hypothesis, topographic effects on soil labile C and N were generally not evident, suggesting the homogeneous soil environment across various topographic locations in this Chamaecyparis forest. CONCLUSIONS: This study illustrates the sustainable importance of primary montane forests for being sources of DOC and DON.

Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential coreceptor for Wnt signaling, and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-ß. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-ß. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Aß synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.

Solid-phase synthesis of diverse spiroisoxazolinodiketopiperazines.

A convenient, efficient protocol to prepare diverse spiroisoxazolino-diketopiperazines via a parallel solid-supported synthesis was developed. The key steps are (1) a coupling reaction of an amino acid; (2) tosylation with concomitant ß-elimination to form an α, ß-unsaturated ester; (3) a 1,3-dipolar cycloaddition with an oxime to form isoxazoline rings; and (4) cyclic cleavage to release the product from the resin. All reaction steps and workup procedures were modified to allow the use of automated or semiautomated equipment. A 100-member demonstration library with two diversity sites was prepared in good purity and acceptable overall yields.

Study of coupling loss on strongly-coupled, ultra compact microring resonators.

Small-radius microring resonators with large free spectral range (FSR) are of great interest for optical communication and optical interconnect applications. The resonator loss of a waveguide-coupled ring resonator, if the gap width between the microring and the bus waveguide is extremely small, can be significantly influenced by the coupling loss which corresponds to the microring operated in a strong coupling regime. This effect is particularly prominent for small radius microrings. We have studied the coupling loss with respect to the gap width on a waveguide-coupled microring both experimentally and theoretically, using two-dimensional (2D) finite difference time domain (FDTD) and effective index method (EIM).The coupling loss was confirmed by measuring transmission spectra of Si microring filters fabricated on silicon-on-insulator (SOI) wafers. Our experimental data show that the ring loss increases rapidly as the coupling gap decreases to less than 200 nm. The measured results show that the ring loss of a silicon microring with a radius of 2.75 µm is around 0.01382 dB/circumference as the gap width is greater than 325 nm, referred to as the intrinsic ring loss. However, for a smaller gap of 150 nm, the loss of the microring increases to 0.07084dB/circumference. The added ring loss is attributed to the coupling loss at small coupling gap for small radius ring.

A unique glycine-rich motif at the N-terminal region of Bamboo mosaic virus coat protein is required for symptom expression.

The coat proteins (CP) of many plant viruses are multifunctional proteins. We used N-terminal sequencing and mass spectrometry/mass spectrometry analysis to identify a truncated form of the Bamboo mosaic virus (BaMV) CP missing the N-terminal 35 amino acids (N35). The N35 region is unique in the potexviruses by its containing a glycine-rich motif (GRM) not present in databases but highly conserved among BaMV isolates. Results from site-directed mutagenesis and deletion mutational analysis showed that loss of this region converted necrotic local lesions to chlorotic local lesions on Chenopodium quinoa leaves. Furthermore, this region is required for successful development of mosaic symptoms on Nicotiana benthamiana leaves but is dispensable for BaMV replication and cell-to-cell and long-distance movement as well as virion assembly. This unique GRM-containing region of BaMV CP may be a symptom determinant in specific hosts.

Enantioselective total synthesis of (+)-conicol via cascade three-component organocatalysis.

The first asymmetric total synthesis of (+)-conicol has been achieved via a key step reaction involving the organocatalytic domino oxa-Michael-Michael-Michael-aldol condensation of 2-((E)-2-nitrovinyl)benzene-1,4-diol and alpha,beta-unsaturated aldehydes. Structures of the three-component domino reaction adducts, 20 and 21, including their absolute configurations, were confirmed unambiguously by X-ray analysis. Through this work, the absolute configuration of (+)-conicol was thereby elucidated.

Organocatalytic enantioselective cascade Michael-Michael-Wittig reactions of phosphorus ylides: one-pot synthesis of the all-cis trisubstituted cyclohexenecarboxylates via the [1 + 2 + 3] annulation.

The stereoselective synthesis of all-cis 5-nitro-4,6-diphenylcyclohex-1-enecarboxylic ester has been achieved by an organocatalytic asymmetric Michael-Michael-Wittig cascade reaction of phosphorus ylides, nitroolefins, and alpha,beta-unsaturated aldehydes with excellent enantioselectivities (up to >99% ee).