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This work proposes an adaptive resource orchestration system for a Wireless Local Area Network (WLAN) that is based on the operating principle of Cognitive Radio (CR) technology. By collecting environmental parameters, including the retransmission rate and the channel occupancy rate, the proposed system has “knowledge” of overall transmission behavior and can regulate transmission resources. An Adaptive Connection Assignment (ACA) mechanism is proposed for end devices; it find out target end devices with poor transmission performance, analyzes their alternative Access Point (AP) availability and causes them to change connections to improve transmission performance. An Adaptive Channel Utilization (ACU) mechanism is designed for APs to identify a target AP that is suffering from interference, to analyze its alternative channel availability and to require it to change its working channel to improve transmission efficiency. Results of simulations of various scenarios indicate that the throughput of end devices is increased by 15 to 24%, the throughput of APs is increased by 6 to 47% and the retransmission rate of APs is reduced by 0.4 to 5.3%. &nbsp

Numerous data processing algorithms are available for ground-penetrating radar (GPR) data processing. However, most of the existing processing algorithms are derived from Fourier theory and assume that the system is linear or that data are stationary, which may oversimplify the case. Some nonlinear algorithms are accessible for improvement but generally are for stationary and deterministic systems. To alleviate the dilemma, this study proposes an algorithm fusion scheme that employs standard linear techniques in conjunction with a newer nonlinear and non-stationary method. The linear techniques include linear filtering, migration, and interpolation. The newer method is mainly for nonlinear filtering and image reconstruction. The results can be demonstrated in a two-dimensional single profile (time–distance section) or a 3D visualization if survey lines fulfill the 3D Nyquist sample intervals requirement. Two controlled experiments were conducted to justify the proposed scheme. Then, a field study including two examples was carried out to demonstrate the feasibility of practical applications. Compared with conventional methods, the proposed algorithm fusion provides better visualization and integrative interpretation for GPR imaging.

The super enhancement of silicon band edge luminescence when co-implanted with boron and carbon is reported. The role of boron in the band edge emissions in silicon was investigated by deliberately introducing defects into the lattice structures. We aimed to increase the light emission intensity from silicon by boron implantation, leading to the formation of dislocation loops between the lattice structures. The silicon samples were doped with a high concentration of carbon before boron implantation and then annealed at a high temperature to activate the dopants into substitutional lattice sites. Photoluminescence (PL) measurements were performed to observe the emissions at the near-infrared region. The temperatures were varied from 10 K to 100 K to study the effect of temperature on the peak luminescence intensity. Two main peaks could be seen at ~1112 and 1170 nm by observing the PL spectra. The intensities shown by both peaks in the samples incorporated with boron are significantly higher than those in pristine silicon samples, and the highest intensity in the former was 600 times greater than that in the latter. Transmission electron microscopy (TEM) was used to study the structure of post-implant and post-anneal silicon sample. The dislocation loops were observed in the sample. Through a technique compatible with mature silicon processing technology, the results of this study will greatly contribute to the development of all Si-based photonic systems and quantum technologies.

As the progress of science and technology and its application in medical treatment, the static computer-aided surgical guide for implant surgery is commonly used nowadays. For achieving a more accurate implant position, factors affecting the accuracy of the computer- aided surgical guide are generally concerned. The aim of this article was to perform a comprehensive overview of literatures and assessment of patient-related, guide stent-related and surgery-related factors affecting the accuracy of the static computer-aided implant surgical guide. It could be concluded that the position of guide, types of tissue support, fixation of guide, types of guided surgery (totally or partially guided), the sleeve length, the key height, and the distance between the sleeve and the implant platform might influence the accuracy of static computer-aided implant surgery. Knowledge of factors related to the accuracy of the surgical guide can aid the clinician to place implants precisely and safety, prevent complications and achieve predictable outcomes. &nbsp

To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms.Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease.Likely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology.This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. High-priority candidates were identified in an additional five individuals. WES provides additional support for previously described disease-associated genes and expands their already broad mutational and phenotypic spectrum.

Circular RNAs (circRNAs) are abundantly expressed in cancer. Their resistance to exonucleases enables them to have potentially stable interactions with different types of biomolecules. Alternative splicing can create different circRNA isoforms that have different sequences and unequal interaction potentials. The study of circRNA function thus requires knowledge of complete circRNA sequences. Here we describe psirc, a method that can identify full-length circRNA isoforms and quantify their expression levels from RNA sequencing data. We confirm the effectiveness and computational efficiency of psirc using both simulated and actual experimental data. Applying psirc on transcriptome profiles from nasopharyngeal carcinoma and normal nasopharynx samples, we discover and validate circRNA isoforms differentially expressed between the two groups. Compared with the assumed circular isoforms derived from linear transcript annotations, some of the alternatively spliced circular isoforms have 100 times higher expression and contain substantially fewer microRNA response elements, showing the importance of quantifying full-length circRNA isoforms.

BACKGROUND Healthcare avoidance in the COVID-19 Pandemic has been widely reported. Yet few studies have investigated the dynamics of hospital avoidance behaviour during pandemic waves and inferred its impact on excess non-COVID-19 death toll. OBJECTIVE To measure the impact of hospital avoidance behaviour on excess mortality using emergency department (ED) patient data from 2016 to 2021, during which Hong Kong experienced a unique COVID-19 pandemic with four distinct waves of case number surges. METHODS Our data is taken from the CDARS Hong Kong Hospital Authority administrative database, which oversees all local public hospitals and plays a prominent role in emergency care provision. To estimate excess mortality, two-stage least squares was utilised with daily tallies of ED visit and 28-day mortality. Elderly records were categorised by the residential care home for elderly status (RCHE) and comorbidities were used to explain the demographic and clinical attributes of excess 28-day mortality. RESULTS Compared with the average in 2016-2019 average there was a reduction in total ED visits in 2020 of 25·4%. During the same period, the 28-day mortality of non-COVID-19 ED deaths increased by 7·82% compared with 2016-2019. The estimated total elderly excess non-COVID 28-day death by reduced ED visits throughout 2020 to 2021 is 1,958 (1,100-2,820, no time lag). The actual excess death in 2020 and 2021 are 3,143 and 4,013 respectively, with 2016-2019 average as the benchmark. Death on Arrival (DOA)/ Death before Arrival (DBA) increased by 35·1% in 2020, while non-DOA/DBA mortalities increased only by a moderate 4·65%. In both DOA/DBA and non-DOA/DBA, the increases were higher during wave periods than in non-wave periods. Moreover, non-RCHE patients saw a greater reduction in ED visit than RCHE residents across all waves by more than 10%. Most of the subset comorbidities demonstrated an annualised reduction in visit in 2020. Renal diseases and severe liver diseases saw a notable death increase. CONCLUSIONS We demonstrated a statistical method to estimate hospital avoidance behaviour during a pandemic, and quantified the consequential excess 28-day mortality, with a focus on elderlies, who had high frequencies of ED visit and deaths. This study serves as an informed alert and possible investigation guideline to healthcare professionals about hospital avoidance behaviour and its consequences.

Coccidioides immitis and posadasii are closely related fungal species that cause coccidioidomycosis. These dimorphic organisms cause disease in immunocompetent as well as immunocompromised individuals and as much as 40% of the population is infected in the endemic area. Although most infections resolve spontaneously, the infection can be prolonged and, in some instances, fatal. Coccidioides has been studied for more than 100 years and many aspects of the organism and the disease it causes have been investigated. There are over 500 manuscripts concerning Coccidioides (excluding clinical articles) referenced in PubMed over the past 50 years, so there is a large body of evidence to review. We reviewed the most accurate and informative basic research studies of these fungi including some seminal older studies as well as an extensive review of current research. This is an attempt to gather the most important basic research studies about this fungus into one publication. To focus this review, we will discuss the mycology of the organism exclusively rather than the studies of the host response or clinical studies. We hope that this review will be a useful resource to those interested in Coccidioides and coccidioidomycosis.

Introduction Erythropoiesis-stimulating agents, standard of care for anemia of end-stage kidney disease, are associated with cardiovascular events. We evaluated the efficacy and safety of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. Methods SIERRAS was a phase 3, randomized, open-label, active-controlled study enrolled adults on dialysis for end-stage kidney disease receiving erythropoiesis-stimulating agents for anemia. Patients were randomized (1:1) to thrice-weekly roxadustat or epoetin alfa. Doses were based on previous epoetin alfa dose and adjusted in the roxadustat arm to maintain hemoglobin at ∼11 g/dl during treatment. Epoetin alfa dosing was adjusted per US package insert. Primary efficacy endpoint was mean hemoglobin (g/dl) change from baseline averaged over weeks 28 to 52. Treatment-emergent adverse events were monitored. Results Enrolled patients (roxadustat, n = 370 and epoetin alfa, n = 371) had similar mean (SD) baseline hemoglobin levels (10.30 [0.66] g/dl). Mean (SD) hemoglobin changes for weeks 28 to 52 were 0.39 (0.93) and −0.09 (0.84) in roxadustat and epoetin alfa, respectively. Roxadustat was noninferior (least squares mean difference: 0.48 [95% confidence interval: 0.37, 0.59]; P < 0.001) to epoetin alfa. Tolerability was comparable between treatments. Conclusion In end-stage kidney disease, roxadustat was noninferior to epoetin alfa in up to 52 weeks of treatment in this erythropoietin-stimulating agent conversion study. Roxadustat had an acceptable tolerability profile.

Efficient O2 reduction reaction (ORR) for selective H2O generation enables advanced fuel cell technology. Non-precious metal (NPM) catalysts are viable and attractive alternatives to state-of-the-art Pt-based materials that are expensive. Cu complexes inspired by Cu-containing O2 reduction enzymes in nature have yet to reach their desired ORR catalytic performance. Here, the concept of mechanical interlocking is introduced to the ligand architecture to enforce dynamic spatial restriction on the Cu coordination site unachievable using other structural means. The utility of the kinetic effects from mechanical bond in transition metal catalysis is just about to emerge, and here the catenane ligands govern the O2 adduct binding mode, thereby steering the selectivity to generate H2O as the major product via the 4e– pathway, rivaling the selectivity of Pt. The kinetic effects from the interlocked catenane ligand also promotes product elimination and boosts the onset potential by 130 mV, the mass activity by 1.8 times, and the turnover frequency (TOF) by 1.5 folds as compared to the non-interlocked counterpart. Our Cu catenane complex represents one of the first examples to take advantage of mechanical interlocking to afford electrocatalysts with enhanced activity and selectivity. The mechanistic insights gained through this integrated experimental and theoretical study are envisioned to be of practical value not just to the area of ORR energy catalysis, but also with broad implications on interlocked metal complexes that are of critical importance to the general fields in redox reactions involving proton-coupled electron transfer (PCET) steps

Gout is one of the most common inflammatory arthropathies in the developed world. However, involvement of the spine is relatively rare, and other sinister differential diagnoses will need to be considered. We describe an unusual case of gouty tophi deposition within the spine in an elderly patient presenting with signs and symptoms of acute cord compression. Important differential diagnoses that need to be excluded include bony metastases from underlying malignancy and other infective/inflammatory causes. Early recognition of imaging findings can avoid delayed or inappropriate medical treatment.

Introduction Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and improves iron metabolism. We assessed the efficacy and tolerability of roxadustat in patients with chronic kidney disease (CKD)-related anemia not on dialysis. Methods ANDES was a global Phase 3 randomized study in which adults with stage 3–5 CKD not on dialysis received roxadustat or placebo. Patients were initially dosed thrice weekly; dose was titrated to achieve a hemoglobin level ≥11.0 g/dl, followed by titration for maintenance. The primary endpoints were change in hemoglobin (weeks 28–52) and proportion of patients achieving a hemoglobin response (hemoglobin ≥11.0 g/dl and increase ≥1.0 g/dl [baseline >8.0 g/dl], or increase ≥2.0 g/dl [baseline ≤8.0 g/dl]) (week 24). Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were recorded. Results In roxadustat (n = 616) and placebo (n = 306) groups, hemoglobin mean (SD) change from baseline over weeks 28–52 was significantly larger for roxadustat (2.00 [0.95]) versus placebo (0.16 [0.90]), corresponding to least-squares mean difference of 1.85 g/dl (95% confidence interval [CI] 1.74–1.97; P < 0.0001). The proportion of patients achieving a response at week 24 was larger for roxadustat (86.0%; 95% CI 83.0%–88.7%) versus placebo (6.6%; 95% CI 4.1%–9.9%; P < 0.0001). The proportion of patients receiving rescue therapy at week 52 was smaller for roxadustat (8.9%) versus placebo (28.9%); hazard ratio, 0.19 (95% CI 0.14–0.28; P < .0001). The incidences of TEAEs and TESAEs were comparable. Conclusion This study showed that roxadustat corrected and maintained hemoglobin and was well tolerated in patients with CKD-related anemia not on dialysis (ClinicalTrials.gov NCT01750190)., Graphical abstract

Background We evaluated the efficacy and safety of roxadustat versus epoetin alfa for the treatment of chronic kidney disease-related anemia in patients new to dialysis. Methods HIMALAYAS was a Phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were incident to hemodialysis/peritoneal dialysis for 2 weeks to ≤4 months prior to randomization and had mean hemoglobin (Hb) ≤10.0 g/dL. Primary endpoints were mean Hb (g/dL) change from baseline averaged over Weeks 28–52 regardless of rescue therapy [non-inferiority criterion: lower limit of 95% confidence interval (CI) for treatment difference >−0.75] and percentage of patients achieving an Hb response between Weeks 1 and 24 censored for rescue therapy (non-inferiority margin for between-group difference −15%). Adverse events were monitored. Results The intent-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (standard deviation) Hb changes from baseline averaged over Weeks 28–52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior [least squares mean difference: 0.18 (95% CI 0.08, 0.29)] to epoetin alfa. Percentages of patients with an Hb response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups, respectively. Roxadustat was non-inferior to epoetin alfa [treatment-group difference 3.5% (95% CI −0.7%, 7.7%)]. Adverse event rates were comparable between treatment groups. Conclusions Roxadustat was efficacious for correcting and maintaining Hb levels compared with epoetin alfa. Roxadustat had an acceptable safety profile.

[18 F]β-CFT is a positron emission tomography (PET) ligand for imaging of dopamine transporter. It was proved to be a sensitive PET marker to detect presynaptic dopaminergic hypofunction in Parkinson's disease. In recent years, copper-mediated 18 F-fluorination of aryl boronic esters has been successful in some molecules containing aromatic groups. In this study, we describe the novel synthetic strategy of [18 F]β-CFT by copper-mediated nucleophilic radiofluorination with pinacol-derived aryl boronic esters upon reaction with [18 F]KF/K222 and Cu (OTf)2 (py)4 . The radiolabeling protocol was optimized with [18 F]fluoride elution method and amount of copper catalyst used. [18 F]β-CFT is obtained from boronic ester precursors in 2.2% to 10.6% non-isolated radiochemical yield (RCY). Purified [18 F]β-CFT with >99% radiochemical purity (RCP) and high molar activity was obtained in validation runs. The radiolabeling procedure is straightforward and can easily be adapted for clinical use.

Given a sequence of n numbers and two positive integers L and U with L ≤ U , the maximum sum segment problem is to find a segment of the sequence with length between L and U such that the sum of numbers in this segment is maximized. In this paper, we introduce the concept of uncertainty into the maximum sum segment problem, where each of the n numbers of the sequence is not given as an exact value but as an interval characterizing the possible range of its value. In such a sequence with uncertainty, we are interested in segments that have potentiality to be maximum sum segments. A segment is a potential maximum sum segment if there exists a possible assignment scenario of the uncertain numbers such that the segment has maximum sum under this assignment. We define the maximum sum segment with uncertainty (MSSU) problem, which consists of two sub-problems: (1) reporting all potential maximum sum segments; and (2) counting the total number of those segments. For the case that L = 1 and U = n , we propose an O ( n + K ) -time algorithm for the reporting problem and an O ( n ) -time algorithm for the counting problem, where K is the number of potential maximum sum segments. For general L and U, we give an O ( n ( U − L ) ) -time algorithm for either the reporting or the counting problem. Note that we assume the word-RAM model of computation.

Section 301 of the Sarbanes‐Oxley Act (SOX) implicitly assumes that audit committees can independently determine audit fees. Critics of section 301 have questioned this assumption in particular, and the efficacy of section 301 more generally. In response, the SEC issued a concept release in 2015 calling for public disclosure of the process that audit committees follow for determining auditor compensation. Motivated by these calls and the widespread use of stocks and options to compensate firms' independent directors, we examine the relation between equity compensation granted to audit committee members and audit fees. Using a sample of 3,685 firm‐year observations during 2007–2015, we find a negative relation between audit committee equity compensation and audit fees, consistent with larger equity pay inducing audit committee members to compromise independence by paying lower audit fees. These findings are robust to controlling for endogeneity, firm size, alternative measures of equity compensation, alternative samples, and an alternative treatment of extreme values. We further show that larger equity compensation is associated with lower earnings quality. We also find that the negative effect of equity compensation on audit fees is stronger when city‐level audit market competition is high. However, this negative relation disappears when (i) firms face high litigation risk, (ii) auditors have stronger bargaining power, (iii) the audit committee includes a high proportion of accounting experts, and (iv) auditors are industry experts. Our results are relevant for regulators and investors. Y a‐t‐il une relation entre la remuneration en actions des membres d'un comite d'audit et les frais d'audit? L'article 301 de la loi Sarbanes‐Oxley (SOX) suppose implicitement que les comites d'audit peuvent determiner les frais d'audit de facon independante. Les critiques relatives a l'article 301 ont remis en question cette supposition et, de facon plus generale, l'efficacite de l'article 301. En reponse a ces critiques, la SEC a fait paraitre en 2015 un document de consultation demandant que soit rendu public le processus mis en œuvre par les comites d'audit pour determiner la remuneration des auditeurs. Dans la foulee de ces demandes et de l'utilisation repandue des actions et options pour remunerer les administrateurs independants des societes, nous examinons la relation entre la remuneration en actions accordee aux membres des comites d'audit et les frais d'audit. A partir d'un echantillon de 3 685 observations annee‐entreprises portant sur la periode 2007 a 2015, nous constatons une relation negative entre la remuneration en actions des comites d'audit et les frais d'audit, ce qui cadre avec l'hypothese voulant qu'une remuneration en actions plus elevee incite les membres des comites a compromettre leur independance en payant des tarifs d'audit plus faibles. Ces resultats sont robustes pour la prise en compte de l'endogeneite, de la taille des societes, d'autres mesures de remuneration par actions, d'autres echantillons et d'une autre methode de traitement des valeurs extremes. Nous etablissons egalement qu'une remuneration en actions plus importante est associee a des resultats de plus faible qualite. Nous constatons enfin que l'effet negatif de la remuneration en actions sur les frais d'audit est plus marque lorsque la concurrence sur le marche de l'audit a l'echelle de la ville est forte. Toutefois, cette relation negative disparait lorsque i) les societes font face a des risques de litige eleves, ii) les auditeurs disposent d'un plus grand pouvoir de negociation, iii) le comite d'audit comprend une forte proportion d'experts comptables et iv) les auditeurs sont des experts du secteur d'activites. Nos resultats sont pertinents pour les organismes de reglementation et les investisseurs.

The near-surface geophysical methods have been widely applied to investigations of shallow targets for scientific and engineering research. Various data processing algorithms are available to help visualize targets, data interpretation, and finally, achieve research goals.Most of the available algorithms are Fourier-based with linear stationary assumptions. However, the real data are rarely the case and should be treated as nonlinear and non-stationary. In recent decades, a few newer algorithms are proposed for processing non-stationary, or nonlinear and non-stationary data, for instance, wavelet transform, curvelet transform, full-waveform inversion, Hilbert-Huang transform, etc. This progress is encouraging, but conventional algorithms still have many advantages, like strong theoretical bases, fast, and easy to apply, which the newer algorithms are short of.In this study, we try to fuse both conventional and contemporary algorithms in near-surface geophysical methods. A cost-effective ground-penetrating radar (GPR) data processing scheme is introduced in shallow depth structure mapping as an example. The method integrates a nonlinear filtering technique, natural logarithmic transformed ensemble empirical mode decomposition (NLT EEMD), with the conventional pseudo-3D GPR data processing methods including background removal and migration to map the subsurface targets in 2D profile. The finalized pseudo-3D data volume is constructed by conventional linear interpolation. This study shows that the proposed technique could be successfully employed to locate the buried targets with minimal survey effort and affordable computation cost. Furthermore, the application of the proposed method is not limited to GPR data processing, any geophysical/engineering data with the similar data structure are applicable.

The management of chronic wounds in the elderly such as pressure injury (also known as bedsore or pressure ulcer) is increasingly important in an ageing population. Accurate classification of the stage of pressure injury is important for wound care planning. Nonetheless, the expertise required for staging is often not available in a residential care home setting. Artificial-intelligence (AI)-based computer vision techniques have opened up opportunities to harness the inbuilt camera in modern smartphones to support pressure injury staging by nursing home carers. In this paper, we summarise the recent development of smartphone or tablet-based applications for wound assessment. Furthermore, we present a new smartphone application (app) to perform real-time detection and staging classification of pressure injury wounds using a deep learning-based object detection system, YOLOv4. Based on our validation set of 144 photos, our app obtained an overall prediction accuracy of 63.2%. The per-class prediction specificity is generally high (85.1%–100%), but have variable sensitivity: 73.3% (stage 1 vs. others), 37% (stage 2 vs. others), 76.7 (stage 3 vs. others), 70% (stage 4 vs. others), and 55.6% (unstageable vs. others). Using another independent test set, 8 out of 10 images were predicted correctly by the YOLOv4 model. When deployed in a real-life setting with two different ambient brightness levels with three different Android phone models, the prediction accuracy of the 10 test images ranges from 80 to 90%, which highlight the importance of evaluation of mobile health (mHealth) application in a simulated real-life setting. This study details the development and evaluation process and demonstrates the feasibility of applying such a real-time staging app in wound care management.

Background:: Epigenetic dysfunction is implicated in many neurologic, psychiatric and oncologic diseases. Consequently, histone deacetylases (HDACs) inhibitors have been developed as therapeutic and imaging agents for these diseases. However, only a few radiotracers have been developed as HDACs imaging agents for the central nervous system (CNS). We report herein the synthesis and evaluation of [18F]INER-1577-3 ([18F]5) as an HDACs imaging agent for CNS. Methods:: [18F]INER-1577-3 ([18F]5) was synthesized by two methods: one-step (A) and two-step (B) methods. Briefly, radiofluorination of the corresponding precursors (11, 12) with K[18F]/K2.2.2 followed by purifications with HPLC gave ([18F]5). The quality of [18F]INER- 1577-3 synthesized by these methods was verified by HPLC and TLC as compared to an authentic sample. The inhibitions of [18F]INER-1577-3 and related HDACs inhibitors on tumor cells growth were carried out with breast cancer cell line 4T1 and MCF-7. The whole-body and brain uptake of [18F]INER-1577-3 in rats and AD mice were determined using a micro-PET scanner and the data was analyzed using PMOD. Results: : The radiochemical yield of [18F]INER-1577-3 synthesized by these two methods was 1.4 % (Method A) and 8.8% (Method B) (EOB), respectively. The synthesis time was 115 min and 100 min, respectively, from EOB. The inhibition studies showed that INER-1577-3 has a significant inhibitory effect in HDAC6 and HDAC8 but not HDAC2. PET studies in rats and AD mice showed a maximum at about 15 min postinjection for the whole brain of a rat (0.47 ± 0.03 %ID/g), SAMP8 mice (5.63 ± 1.09 %ID/g) and SAMR1 mice (7.23 ± 1.21 %ID/g). Conclusion:: This study showed that INER-1577-3 can inhibit tumor cell growth and is one of a few HDACs inhibitors that can penetrate the blood-brain barrier (BBB) and monitor HDAC activities in AD mice. Thus, [18F]INER-1577-3 may be a potent HDACs imaging agent, especially for CNS.

Binita Shrestha,1 Lijun Wang,1 Hao Zhang,2 Chiung Yu Hung,2 Liang Tang1 1Department of Biomedical Engineering, The University of Texas at San Antonio, San Antonio, TX, USA; 2Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USACorrespondence: Liang TangDepartment of Biomedical Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USATel +1 210-458-7995Email Liang.Tang@utsa.eduBackground: Cancer is a complex heterogeneous disease to which singular modes of treatment mostly fail to produce a desired therapeutic efficacy. Targeting different cellular pathways using combinational therapies has been gaining popularity in cancer treatment, with the added benefit of reducing dosage and side effects.Methods: A gold nanoparticle-mediated drug delivery nanoplatform was developed for co-delivery of doxorubicin and polo-like kinase 1 (PLK1) siRNA. Gold nanoparticles were coated with polyethyleneimine to facilitate assembly of PLK1 on the surface. Doxorubicin was loaded on nanoparticles through a pH-sensitive linker with a thiol group at one terminal end for controlled release.Results: The therapeutic efficiency of this co-delivery system was evaluated in 2D and 3D cultured systems. The reduced IC50 value clearly demonstrated the synergistic effect of combined drug and gene delivery over their individual delivery in a cancer treatment model.Conclusion: This study may provide an adaptable, facile platform to investigate drug-siRNA combinations for cancer inhibition.Keywords: nanomedicine, cancer therapy, pH-responsive, co-delivery, PLK1

The transforming growth factor β (TGF-β) signaling pathway is evolutionarily conserved and widely used in the animal kingdom to regulate diverse developmental processes. Prior studies have shown that Baboon (Babo), a Drosophila type I TGF-β receptor, plays essential roles in brain development and neural circuit formation. However, the expression pattern for Babo in the developing brain has not been previously reported. We generated a knock-in fly with a human influenza hemagglutinin (HA) tag at the C-terminus of Babo and assessed its localization. Babo::HA was primarily expressed in brain structures enriched with neurites, including the mushroom body lobe and neuropils of the optic lobe, where Babo has been shown to instruct neuronal morphogenesis. Since the babo 3' untranslated region contains a predicted microRNA-34 (miR-34) target sequence, we further tested whether Babo::HA expression was affected by modulating the level of miR-34. We found that Babo was upregulated by mir-34 deletion and downregulated by miR-34 overexpression, confirming that it is indeed a miR-34 target gene. Taken together, our results demonstrate that the baboHA fly permits accurate visualization of endogenous Babo expression during brain development and the construction of functional neural circuits.

This preliminary study aims to prepare porous extractant-incorporated membranes (EIMs) containing base polymer cellulose triacetate (CTA), tri-n-octylphosphine oxide (TOPO), and trioctylammonium chloride (Aliquat 336) prepared by non-solvent induced phase inversion for selective removal of p-cresol from simulated serum. The surface morphology and pore structure of the EIMs were investigated using a field emission scanning electron microscope (FE-SEM) and nitrogen sorptiometer, respectively. The functional groups and chemical composition of the EIMs were characterized by the Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) and X-ray photoelectron spectrometry (XPS), respectively. The interactions between uremic toxins (p-cresol, creatinine, and urea) and TOPO or Aliquat 336, studied independently by liquid-liquid extraction, were ascribed to hydrogen bonding. Batch tests showed that the addition of TOPO strongly favored p-cresol adsorption; for example, an adsorption capacity of 2.08 mmol/g of the EIM composed of 54.5 wt% CTA, 27.3 wt% Aliquat 336, and 18.2 wt% TOPO was obtained at 37 °C, compared to a negligibly small capacity for creatinine and urea. Cross-flow dynamic experiments revealed that the maximum adsorption of p-cresol in a multi-component serum was 0.75 mmol/g of the EIM under the conditions studied. The high adsorption selectivity for p-cresol may make the prepared EIMs promising and potential for efficient removal of p-cresol from simulated serum.

Significance To understand the value and clinical impact of surveying genome-wide disease-causing genes and variants, we used a prospective cohort study design that enrolled volunteers who agreed to have their whole genome sequenced and to participate in deep phenotyping using clinical laboratory tests, metabolomics technologies, and advanced noninvasive imaging. The genomic results are integrated with the phenotype results. Approximately 1 in 6 adult individuals (17.3%) had genetic findings and, when integrated with deep phenotyping data, including family/medical histories with genetic findings, 1 in 9 (11.5%) had genotype and phenotype associations. Genomics and metabolomics association analysis revealed 5.1% of heterozygotes with phenotype manifestations affecting serum metabolite levels. We report observations from our study in which health outcomes and benefits were not measured., Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

Neurogenesis in the Drosophila central brain progresses dynamically in order to generate appropriate numbers of neurons during different stages of development. Thus, a central challenge in neurobiology is to reveal the molecular and genetic mechanisms of neurogenesis timing. Here, we found that neurogenesis is significantly impaired when a novel mutation, Nuwa, is induced at early but not late larval stages. Intriguingly, when the Nuwa mutation is induced in neuroblasts of olfactory projection neurons (PNs) at the embryonic stage, embryonic-born PNs are generated, but larval-born PNs of the same origin fail to be produced. Through molecular characterization and transgenic rescue experiments, we determined that Nuwa is a loss-of-function mutation in Drosophila septin interacting protein 1 (sip1). Furthermore, we found that SIP1 expression is enriched in neuroblasts, and RNAi knockdown of sip1 using a neuroblast driver results in formation of small and aberrant brains. Finally, full-length SIP1 protein and truncated SIP1 proteins lacking either the N- or C-terminus display different subcellular localization patterns, and only full-length SIP1 can rescue the Nuwa-associated neurogenesis defect. Taken together, these results suggest that SIP1 acts as a crucial factor for specific neurogenesis programs in the early developing larval brain.

Simple Summary Immunotherapy is approved in selected cases of gastric cancer, and durable responses have been observed in exceptional responders. Several potential predictive biomarkers have been identified in gastric cancer, such as microsatellite instability-high (MSI-H), Epstein–Barr virus (EBV), and programmed death ligand 1 (PD-L1). We explored the real-world evidence of these biomarkers and their outcomes. When only combined positive score (CPS) ≥ 1 was used as the biomarker, the overall response rate (ORR) and progression-free survival (PFS) were not statistically significant. CPS ≥ 1 was commonly combined with MSI-H (75%) and Epstein–Barr encoding region (EBER) (80%). MSI-H and CPS ≥ 5 were prognostic biomarkers associated with better ORR and PFS. In patients with EBER, better ORR and PFS were observed only in patients with CPS ≥ 1. These results could transform clinical practice and can be used to formulate more precise treatment suggestions for patients with gastric cancer. Abstract Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers—microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein–Barr encoding region (EBER)—were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.

Additional file 1: Table S1. Primer sequences of PCR, real-time PCR, and genotyping.

This study investigated whether patients with history of dental caries are associated with an increased risk of newly-onset systemic lupus erythematosus (SLE). A total of 501,461 carious patients and 258,918 controls without carious teeth were enrolled between 1997 and 2013 from the National Health Insurance Research Database. Subgroup analyses were conducted based on restorative materials included amalgam, composite resins, or both. The cumulative incidence and hazard ratios (HRs) of SLE development were derived after adjusting for age, sex, socioeconomic status, income, insured classification, comorbidities, and frequency of dental visit in a multivariable model. The risk of SLE was significantly higher in carious patients (HR= 1.98, 95% confidence interval [CI] = 1.65-2.38) compared to controls. Dose-dependent relationship between caries and risk of SLE was identified. The risk of SLE was higher among those who had dental visits ≧11 (HR= 2.53, 95% CI = 1.86-3.43), followed by those with 3-10 dental visits (HR= 1.86, 95% CI= 1.36-2.54), when compared to those with 1-2 visits, and was higher among those who had carious teeth extractions ≧5 (HR= 1.88, 95% CI= 1.19-2.97), followed by those with 1-4 carious teeth extractions (HR= 1.36, 95% CI = 1.17-1.59) than those without extraction. The risk of SLE for dental caries management among different restorative materials, including amalgam, composite resins, or both, was not statistically difference. Patients with dental caries were associated with higher SLE risks. The relationship between dental caries and risk of SLE was dose-dependent, regardless of the material used for the restoration.

Additional file 2: Figure S1. UIRI causes prominent renal damage and development of fibrosis. (a) Diagram illustrates the timeline of the experiment. The left kidney of male C57BL/6 mice was subjected to renal ischemia/reperfusion injury (UIRI) and then sacrificed at different days as indicated. UDx: x days after UIRI. (b) PAS staining represents the accumulation of debris in the tubular lumen after UIRI. The arrowhead in the lower panel indicates debris. Scale bar indicates 200 μm in 40x, 50 μm in 200x. (c) qPCR assessment of the relative expression level of Kim-1 mRNA. (d) Masson’s trichrome staining shows the increased fibrosis fraction in kidney section after UIRI. Scale bar indicates 50 μm in 200x. (e) Quantitative scores of interstitial fibrosis were assessed. (f and g) The expression of α-SMA was examined with western blot analysis and quantified. Data are expressed as means ± SEM, n = 3 ~ 6 in each group. * P < 0.05 and *** P < 0.001, as compared with sham group. Figure S2. Loss of XBP1 expression is a universal characteristic in renal fibrosis models. (a) Western blot analysis showed the protein expression of α-SMA, XBP1u and XBP1s in UUO mice model. GAPDH was used as an internal control. (b-d) Quantification of relative protein expression levels of α-SMA, XBP1u and XBP1s. (e) Western blot analysis showed the protein expression of α-SMA, XBP1u and XBP1s in adenine diet mice model. GAPDH was used as an internal control. (f–h) Quantification of relative protein expression levels of α-SMA, XBP1u and XBP1s. N = 3–4 for each group, * P < 0.05, ** P < 0.01, and *** P < 0.001, as compared with sham or chow diet group. Figure S3. Proximal tubular conditional knockout mice blocked XBP1s activation. (a) Diagram illustrates SLC5aCreERT2; XBP1fl/fl mice. (b) After tamoxifen administration, mice were subjected to IP injection of 500 ng/g of Tunicamycin for 12 h. Western blot analysis showed protein expression of XBP1s after Tunicamycin induction in XBP1fl/fl or XBP1cKO mice. GAPDH was used as an internal control. (c) Immunofluorescence staining demonstrated XBP1 expression in Tunicamycin treated mice kidneys. Scale bar: 250 μm. (d) XBP1s mRNA expression level was determined by semi-quantitative PCR. (e) qPCR assessment of the relative expression level of XBP1s mRNA. Figure S4. Proximal tubular XBP1 specific knockout mice were vulnerable to UIRI-induced kidney injury. (a) Diagram illustrates the experimental timeline of tamoxifen administration and UIRI with contralateral nephrectomy (Nx) surgery in XBP1fl/fl and XBP1cKO mice. (b and c) Blood urea nitrogen (BUN) and serum creatinine (Scr) levels were measured after 1 day of contralateral Nx. N = 3 for each group. ** P < 0.01, and *** P < 0.001, as compared with XBP1fl/fl Sham group. Figure S5. UIRI induces cell cycle arrest in G2/M phase. (a-d) The expression of chk1 and p21 in mice kidneys was evaluated with western blotting and quantified. GAPDH was used as an internal control. Data are expressed as means ± SEM, n = 3 ~ 6 in each group. * P < 0.05, ** P < 0.01, and *** P < 0.001, as compared with sham group. (e and f) Representative images of Ki67+ pHH3+ renal sections in (e) WT mice or (f) XBP1cKO and XBP1fl/fl mice subjected to UIRI or Sham operation. Selected areas indicated highly expressed double-positive tubules. Scale bar: 50 μm. (g) Number of Ki67+pHH3+ tubular cells. Data are expressed as means ± SEM. * P < 0.05, ** P < 0.01, and *** P < 0.001, as compared with XBP1fl/fl sham group. ### P < 0.001 compared between indicated groups.

Similarity in facial characteristics between relatives suggests a strong genetic component underlies facial variation. While there have been numerous studies of the genetics of facial abnormalities and, more recently, single nucleotide polymorphism (SNP) genome-wide association studies (GWASs) of normal facial variation, little is known about the role of genetic structural variation in determining facial shape. In a sample of Bantu African children, we found that only 9% of common copy number variants (CNVs) and 10-kb CNV analysis windows are well tagged by SNPs (r2 ≥ 0.8), indicating that associations with our internally called CNVs were not captured by previous SNP-based GWASs. Here, we present a GWAS and gene set analysis of the relationship between normal facial variation and CNVs in a sample of Bantu African children. We report the top five regions, which had p values ≤ 9.35 × 10−6 and find nominal evidence of independent CNV association (p < 0.05) in three regions previously identified in SNP-based GWASs. The CNV region with strongest association (p = 1.16 × 10−6, 55 losses and seven gains) contains NFATC1, which has been linked to facial morphogenesis and Cherubism, a syndrome involving abnormal lower facial development. Genomic loss in the region is associated with smaller average lower facial depth. Importantly, new loci identified here were not identified in a SNP-based GWAS, suggesting that CNVs are likely involved in determining facial shape variation. Given the plethora of SNP-based GWASs, calling CNVs from existing data may be a relatively inexpensive way to aid in the study of complex traits.

Background Nanoliposomal irinotecan (nal-IRI), accompanied by 5-fluorouracil (5-FU) and leucovorin (LV), is an effective and safe therapy for patients in whom metastatic pancreatic ductal adenocarcinoma has progressed after gemcitabine-based chemotherapy. Our aim was to evaluate the effectiveness and safety of a nal-IRI + 5-FU/LV regimen for patients with metastatic pancreatic cancer and gemcitabine-based treatment failure in the real world. Methods We retrospectively collected the baseline characteristics, treatment courses and dosage, treatment response, overall survival, progression-free survival, and adverse effects of patients treated with the nal-IRI-based regimen at Taipei Veterans General Hospital. Results Sixty-seven patients who received the nal-IRI + 5-FU/LV regimen from August 2018 to June 2019 were identified. Their median age was 65 years and 52% were male. Most patients had an Eastern Cooperative Oncology Group performance status (ECOG) of 0 to 1, but patients with an ECOG status of 2 to 4 before initiation of the nal-IRI regimen were also enrolled (31%). The median dose intensity was 40.4 mg/m2 and the median treatment duration was 8.3 weeks (range: 5 days - 75.7 weeks). Objective response and disease control rates were 10.4% and 38.8%, respectively. The median overall survival (OS) was 7.9 months (95% confidence interval (CI): 5.6 - 10.1 months) and the median progression-free survival (PFS) was 2.9 months (95% CI: 1.6 - 4.1 months). Elevated total bilirubin (hazard ratio: 4.31, 95% CI: 1.21 -15.30, p = 0.024), carcinomatosis (HR: 3.75, 95% CI: 1.46 - 9.66, p = 0.006), and previous treatment with irinotecan (HR: 4.86, 95% CI: 1.67 - 14.10, p = 0.004) were associated with a worse OS. Previous treatment with irinotecan (HR: 3.03, 95% CI: 1.22 - 7.49, p = 0.02) was associated with a worse PFS. The most common all-grade adverse effects were anemia (73.9%), nausea (66.2%), and fatigue (61.5%). The most common grade 3 - 4 adverse effects were neutropenia (21.5%), anemia (18.5%), and diarrhea (15.4%). Conclusion Clinically, nal-IRI + 5-FU/LV is effective and tolerable at reduced doses in patients with metastatic pancreatic adenocarcinoma that has progressed after gemcitabine-based therapy.

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.

Cytomegalovirus (CMV) disease is relatively uncommon in nontransplant hematological patients. Moreover, cutaneous manifestations of CMV diseases have scarcely been reported and are probably under-recognized.We describe a patient with large B-cell lymphoma who developed a band-form, erythematous lesion over his left abdomen soon after the second course of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone chemotherapy.The lesion was initially mistaken for bacterial cellulitis or herpes zoster and was histologically confirmed as cutaneous CMV infection. Subsequent work-up also detected CMV viremia and the presence of CMV meningoencephalitis.The patient was treated with ganciclovir plus CMV immune globulin followed by foscarnet.Although the patient's cutaneous lesion resolved, his cognitive impairment did not recover, and he developed a fatal multi-organ failure 1 month later.Cutaneous CMV disease can herald multisystem involvement and an unfavorable prognosis in immunocompromised hosts. It should be ruled out with biopsy in patients with hematological malignancy who have cutaneous lesions refractory to antibacterial therapy.

International audience; Introduction - Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy.Methods - MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors.Results - Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p

Epstein-Barr virus (EBV) has been recently found to generate novel circular RNAs (circRNAs) through backsplicing. However, comprehensive catalogs of EBV circRNAs in other cell lines and their functional characterization are still lacking. In this study, we have identified a list of putative EBV circRNAs in GM12878, an EBV-transformed lymphoblastoid cell line, with a significant majority encoded from the EBV latent genes. A novel EBV circRNA derived from the exon 5 of LMP-2 gene which exhibited highest prevalence, was further validated using RNase R assay and Sanger sequencing. This circRNA, which we term circLMP-2_e5, can be universally detected in a panel of EBV-positive cell lines modelling different latency programs. It ranges from lower expression in nasopharyngeal carcinoma (NPC) cells to higher expression in B cells, and is localized to both the cytoplasm and the nucleus. We provide evidence that circLMP-2_e5 is expressed concomitantly with its cognate linear LMP-2 RNA upon EBV lytic reactivation, and may be produced as a result of exon skipping, with its circularization possibly occurring without the involvement of cis elements in the short flanking introns. Furthermore, we show that circLMP-2_e5 is not involved in regulating cell proliferation, host innate immune response, its linear parental transcripts, or EBV lytic reactivation. Taken together, our study expands the current repertoire of putative EBV circRNAs, broadens our understanding of the biology of EBV circRNAs, and lays the foundation for further investigation of their function in the EBV life cycle and disease development.

Shiou-Shiow Farn,1,2 Kang-Wei Chang,3 Wan-Chi Lin,1 Hung-Man Yu,1 Kun-Liang Lin,1 Yu-Chin Tseng,1 Yu Chang,1 Chung-Shan Yu,2,4 Wuu-Jyh Lin1 1Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, 32546, Taiwan; 2Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu, 300, Taiwan; 3Laboratory Animal Center, Office of Research and Development, Taipei Medical University, Taipei, 11031, Taiwan; 4Institute of Nuclear Engineering and Science, College of Nuclear Science, National Tsing-Hua University, Hsinchu, 300, TaiwanCorrespondence: Wuu-Jyh Lin; Chung-Shan Yu Email WJLin@seecurellc.com; csyu@mx.nthu.edu.twIntroduction: Novel radiotracer development for imaging dopamine transporters is a subject of interest because although [99mTc]TRODAT-1, [123I]β-CIT, and [123I]FP-CIT are commercially available; 99Mo/99mTc generator is in short supply and 123I production is highly dependent on compact cyclotron. Therefore, we designed a novel positron emission tomography (PET) tracer based on a tropane derivative through C-2 modification to conjugate NOTA for chelating 68Ga, a radioisotope derived from a 68Ge/68Ga generator.Methods: IPCAT-NOTA 22 was synthesized and labeled with [68Ga]GaCl4− at room temperature. Biological studies on serum stability, LogP, and in vitro autoradiography (binding assay and competitive assay) were performed. Furthermore, ex vivo autoradiography, biodistribution, and dynamic PET imaging studies were performed in Sprague Dawley rats.Results: [68Ga]IPCAT-NOTA 24 obtained had a radiochemical yield of ≥ 90% and a specific activity of 4.25 MBq/nmol. [68Ga]IPCAT-NOTA 24 of 85% radiochemical purity (RCP%) was stable at 37°C for up to 60 minutes in serum with a lipophilicity of 0.88. The specific binding ratio (SBR%) reached 15.8 ± 6.7 at 60 minutes, and the 85% specific uptake could be blocked through co-injection at 100- and 1000-fold of the cold precursor in in vitro binding studies. Tissue regional distribution studies in rats with [68Ga]IPCAT-NOTA 24 showed striatal uptake (0.02% at 5 minutes and 0.007% at 60 minutes) with SBR% of 6%, 25%, and 62% at 5– 15, 30– 40, and 60– 70 minutes, respectively, in NanoPET studies. The RCP% of [68Ga]IPCAT-NOTA 24 at 30 minutes in vivo remained 67.65%.Conclusion: Data described here provide new information on the design of PET probe of conjugate/pendent approach for DAT imaging. Another chelator or another direct method of intracranial injection must be used to prove the relation between [68Ga]IPCAT-NOTA 24 uptake and transporter localization.Keywords: Parkinson disease, dopamine transporter, Ga-68

The performance of InAs/GaSb core-shell nanowire TFET is systematically investigated for the effects of intrinsic device parameters such as channel doping, shell thickness, spacer length and source offset. Device ON-current (ION) was chosen as the key figure of merit. It is found that ION improves due to improved electrostatic control achieved by the TFET with optimum shell diameter. The maximum ION obtained for a shell thickness of 2 nm was 33.65 μA/μm and a Subthreshold Swing (SS) of 12.9 mV/decade with an ION/IOFF ratio of 1.49 × 108 for our device. Device ION can be further improved by adding an optimum spacer at the source-channel junction. It was also found that device ON-current is almost constant and does not get much affected by having a larger shell offset.