Clustering of resting state networks

BACKGROUND: The goal of the study was to demonstrate a hierarchical structure of resting state activity in the healthy brain using a data-driven clustering algorithm. METHODOLOGY/PRINCIPAL FINDINGS: The fuzzy-c-means clustering algorithm was applied to resting state fMRI data in cortical and subcortical gray matter from two groups acquired separately, one of 17 healthy individuals and the second of 21 healthy individuals. Different numbers of clusters and different starting conditions were used. A cluster dispersion measure determined the optimal numbers of clusters. An inner product metric provided a measure of similarity between different clusters. The two cluster result found the task-negative and task-positive systems. The cluster dispersion measure was minimized with seven and eleven clusters. Each of the clusters in the seven and eleven cluster result was associated with either the task-negative or task-positive system. Applying the algorithm to find seven clusters recovered previously described resting state networks, including the default mode network, frontoparietal control network, ventral and dorsal attention networks, somatomotor, visual, and language networks. The language and ventral attention networks had significant subcortical involvement. This parcellation was consistently found in a large majority of algorithm runs under different conditions and was robust to different methods of initialization. CONCLUSIONS/SIGNIFICANCE: The clustering of resting state activity using different optimal numbers of clusters identified resting state networks comparable to previously obtained results. This work reinforces the observation that resting state networks are hierarchically organized

RP-HPLC-DAD metoda za određivanje olmesartan medoksomila kao čiste supstancije i u tabletama izloženih razgradnji

A simple, sensitive and precise RP-HPLC-DAD method was developed and validated for the determination of olmesartan medoxomil (AT-II receptor blocker) in the presence of its degradation products. Olmesartan medoxomil and all the degradation products were resolved on a C18 column with the mobile phase composed of methanol, acetonitrile and water (60:15:25, V/V/V, pH 3.5 by orthophosphoric acid) at 260 nm using a photodiode array detector. The method was linear over the concentration range of 1–18 µg mL 1 and precise with RSD 2.0 for each peak and sensitive with LOD 0.03 µg mL−1 and LOQ 0.1 µg mL−1. The method was used to study the drug degradation behavior under forced conditions. Four degradation products (DP-I, II, III, IV) were formed during the degradation study in 0.1 mol L−1 HCl whereas only DP-I, II and III were formed in water, 0.01 mol L−1 NaOH and 3 % H2O2. No significant thermal or photolytic degradation was observed in solid drug. The method was applied successfully for the assay of olmesartan medoxomil in the tablet dosage form.U ovom radu razvijena je i validirana jednostavna, osjetljiva i precizna RP-HPLC-DAD metoda za određivanje olmesartan medoksomila (inhibitor AT-II receptora) u prisutnosti njegovih razgradnih produkata. Olmesartan medoksomil i razgradni produkti kromatografirani su na C18 koloni uz mobilnu fazu metanol/ acetonitril/vo da (60:15:25 V/V/V; pH 3,5 podešen ortofosfornom kiselinom) pri 260 nm uz detektor s fotodiodnim nizom. Metoda je linearna u koncentracijskom rasponu 1–18 µg mL 1 i precizna s RSD < 1 % tijekom ispitivanja repetabilnosti i intermedijarne ponovljivosti. Povrat od 99,3 ± 0,9 do 100,8 ± 1,2 % dokazuje točnost metode. Razvijena metoda je specifična na što ukazuje kromatografsku rezoluciju veću od 2,0 i osjetljiva (LOD = 0,03 µg mL−1 i LOQ = 0,1 µg mL−1). Metoda je upotrebljena za praćenje razgradnje olmesartan medoksomila u uvjetima potencirane razgradnje. U 0,1 mol L−1 HCl detektirana su četiri razgradna produkta (DP-I, II, III, IV), a u vodi, 0,01 mol L−1 NaOH i 3 % H2O2 samo DP-I, II i III. U čvrstom agregatnom stanju nije primjećena značajna termička ni fotolitička razgradnja ljekovite tvari. Metoda je uspješno primijenjena za određivanje olmesartan medoksomila u tabletama

Coordinating healthcare networks

Current healthcare reforms advocate significantly to improve the coordination of services around a patient-centric model, with an overarching goal to maximize patient outcomes with lower cost, i.e. a value-based care. With most patient care delivered through outpatient services, the need to coordinate different services and their patient appointment scheduling decisions becomes central to successful reform. Currently, outpatient services are particularly fragmented with minimal coordination among different providers, and the coordination is left to the patient. This approach causes compromised patient health outcomes, an increase in missed appointments and unacceptable access delays. Therefore, the potential impact of coordinating outpatient services is great, in terms of improving patient outcomes and satisfaction, optimizing providers’ utilization and reducing operational costs. In the first study, we investigate how to coordinate the delivery of care in the preoperative process for surgical outpatient. Based on the concept of the Perioperative Surgical Home proposed by the American Society of Anesthesiologists, we develop a Patient-Centered Surgical Home (PCSH) model. Using statistical analysis and simulation, we demonstrate how this can be implemented and reveal the potential benefits on cooperation of the referring clinics and integrating patient in- formation early in the preoperative process. The second study proposes a multi-station network model that sequentially schedules patient appointments in a network of stations with stochastic service times, no-show possibilities, and overbooking. We propose a myopic coordinated policy and present evidence that the policy yields a solution that is close to optimal and is computationally feasible. However, the solution is not simple enough for practical implementation. Hence, we explore a sequence of approximations and find one that offers a tremendous computational advantage. We also provide several managerial insights and discuss how network structures affect complexity. In the third study, we focuses on the cost perspective of coordination. We formulate a multi-server, multi-clinic model that represents the current practice at the PCSH and develop a coordinated scheduling method that dynamically balances the utilizations of all services as patients are sequentially scheduled in the PCSH. We compare our proposed policy against other policies found in the practice and the results shed light on the risk of improper coordination in our increasingly interdependent healthcare system.Information, Risk, and Operations Management (IROM

Bacterial endosymbiont Cardinium cSfur genome sequence provides insights for understanding the symbiotic relationship in Sogatella furcifera host

Background: Sogatella furcifera is a migratory pest that damages rice plants and causes severe economic losses. Due to its ability to annually migrate long distances, S.furcifera has emerged as a major pest of rice in several Asian countries. Symbiotic relationships of inherited bacteria with terrestrial arthropods have significant implications. The genus Cardinium is present in many types of arthropods, where it influences some host characteristics. We present a report of a newly # identified strain of the bacterial endosymbiont Cardinium cSfur in S. furcifera. Result: From the whole genome of S. furcifera previously sequenced by our laboratory, we assembled the whole genome sequence of Cardinium cSfur. The sequence comprised 1,103,593 bp with a GC content of 39.2%. The phylogenetic tree of the Bacteroides phylum to which Cardinium cSfur belongs suggests that Cardinium cSfur is closely related to the other strains (Cardinium cBtQ1 and cEper1) that are members of the Amoebophilaceae family. Genome comparison between the host-dependent endosymbiont including Cardinium cSfur and freeliving bacteria revealed that the endosymbiont has a smaller genome size and lower GC content, and has lost some genes related to metabolism because of its special environment, which is similar to the genome pattern observed in other insect symbionts. Cardinium cSfur has limited metabolic capability, which makes it less contributive to metabolic and biosynthetic processes in its host. From our findings, we inferred that, to compensate for its limited metabolic capability, Cardinium cSfur harbors a relatively high proportion of transport proteins, which might act as the hub between it and its host. With its acquisition of the whole operon related to biotin synthesis and glycolysis related genes through HGT event, Cardinium cSfur seems to be undergoing changes while establishing a symbiotic relationship with its host. Conclusion: A novel bacterial endosymbiont strain (Cardinium cSfur) has been discovered. A genomic analysis of the endosymbiont in S. furcifera suggests that its genome has undergone certain changes to facilitate its settlement in the host. The envisaged potential reproduction manipulative ability of the new endosymbiont strain in its S. furcifera host has vital implications in designing eco-friendly approaches to combat the insect pest

Development of a Highly Sensitive Enzyme-Linked Immunosorbent Assay for Mouse Soluble Epoxide Hydrolase Detection by Combining a Polyclonal Capture Antibody with a Nanobody Tracer

Enzyme-linked immunosorbent assays (ELISA) for the detection of soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of fatty acids and a biomarker, may increasingly represent an important diagnostic tool. However, there is a lack of ELISAs for mouse sEH quantification, thus resulting in a bottleneck in understanding the pathogenesis of many diseases related to sEH based on mouse models. In this work, nanobodies recognizing mouse sEH were obtained through rebiopanning against mouse sEH in the previous phage display library of human sEH. Later, we developed four ELISAs involving a combination of anti-mouse sEH polyclonal antibodies (pAbs) and nanobodies. It was found that the double antibodies worked as dual filters and had a huge impact on both the sensitivity and selectivity of sandwich immunoassays. The switch from anti-human sEH pAbs to anti-mouse sEH pAbs led to over a 100-fold increase in the sensitivity and a dramatic decrease of the limit of detection to a picogram per milliliter range in format B (pAb/biotin-VHH/streptavidin-poly-horseradish peroxidase). Moreover, we found that the four sandwich ELISAs might demonstrate excellent selectivities to mouse sEH, despite the antibodies alone showing significant cross-reactivity to the matrix, indicating the enhanced selectivity of double antibodies as dual filters. Eventually, for the first time, the ELISA (format B) was successfully used to measure the mouse sEH level in cancer cells with ultralow abundances. The ELISAs proposed here represent a sensitive tool for tracking sEH in various biological processes and also provide deep insights into developing sandwich immunoassays against various targets in terms of both the sensitivity and selectivity

Nanobody-Based Immunoassays for the Detection of Food Hazards—A Review

Food safety remains a significant global challenge that affects human health. Various hazards, including microbiological and chemical threats, can compromise food safety throughout the supply chain. To address food safety issues and ensure public health, it is necessary to adopt rapid, accurate, and highly specific detection methods. Immunoassays are considered to be an effective method for the detection of highly sensitive biochemical indicators and provide an efficient platform for the identification of food hazards. In immunoassays, antibodies function as the primary recognition elements. Nanobodies have significant potential as valuable biomolecules in diagnostic applications. Their distinctive physicochemical and structural characteristics make them excellent candidates for the development of reliable diagnostic assays, and as promising alternatives to monoclonal and polyclonal antibodies. Herein, we summarize a comprehensive overview of the status and prospects of nanobody-based immunoassays in ensuring food safety. First, we begin with a historical perspective on the development of nanobodies and their unique characteristics. Subsequently, we explore the definitions and boundaries of immunoassays and immunosensors, before discussing the potential applications of nanobody-based immunoassays in food safety testing that have emerged over the past five years, and follow the different immunoassays, highlighting their advantages over traditional detection methods. Finally, the directions and challenges of nanobody-based immunoassays in food safety are discussed. Due to their remarkable sensitivity, specificity and versatility, nanobody-based immunoassays hold great promise in revolutionizing food safety testing and ensuring public health and well-being

Enhanced thermally activated delayed fluorescence through bridge modification in sulfone-based emitters employed in deep blue organic light-emitting diodes

The authors are grateful to the Engineering and Physical Sciences Research Council (EPSRC) for support from grants EP/P010482/1 and EP/R035164/1. P. Rajamalli acknowledges support from a Marie Skłodowska-Curie Individual Fellowship (MCIF; No. 749557). Dongyang Chen and Wenbo Li thank the China Scholarship Council (grant numbers 201603780001 and 201708060003).Two thermally activated delayed fluorescence (TADF) emitters bearing a new dipyridyl sulfone core as the electron-accepting unit and di-tert-butyl carbazoles as electron-donating units are reported. The two emitters, pDTCz-2DPyS and pDTCz-3DPyS , differ in the regiochemistry of the substitution about the pyridine rings [ pDTCz-2DPyS = 9,9'-(sulfonylbis(pyridine-6,3- diyl))bis(3,6-di-tert-butyl-9H-carbazole); pDTCz-3DPyS = 9,9'-(sulfonylbis(pyridine-5,2-diyl))bis(3,6-di-tert-butyl-9H- carbazole)]. Both compounds show blue emission in the range of 450-465 nm, which is in line with theoretical calculations. They have very similar singlet-triplet energy (ΔEST) gaps (ΔEST = 0.22 eV and 0.21 eV for pDTCz-3DPyS and pDTCz-2DPyS , respectively). pDTCz-2DPyS has a much larger proportion of delayed emission (26.2%) than pDTCz-3DPyS (1.2%)]. The two compounds show comparable photoluminescence quantum yields of 60% in 2,8- bis(diphenylphosphoryl)dibenzo[b,d]thiophene (PPT) doped films. The performance of organic light-emitting diodes (OLEDs) depends on the host used. The maximum external quantum efficiency (EQE) in the PPT host of pDTCz-3DPyS is 7.0%, whilst for pDTCz-2DPyS it is 12.4%. High performance is obtained for both materials when bis[2-(diphenylphosphino)phenyl] ether oxide (DPEPO) is used as the host, with a maximum EQE of 13.4% for pDTCz-3DPyS and 11.4% for pDTCz-2DPyS . In addition, pDTCz-3DPyS shows pure blue electroluminescence with CIE color coordinates of (0.15, 0.12) compared to pDTCz- 2DPyS with coordinates of (0.15, 0.19).PreprintPostprintPeer reviewe

RP-LC and HPTLC Methods for the Determination of Olmesartan Medoxomil and Hydrochlorothiazide in Combined Tablet Dosage Forms

Two new, rapid, precise, accurate and specific chromatographic methods were described for the simultaneous determination of olmesartan medoxomil and hydrochlorothiazide in combined tablet dosage forms. The first method was based on reversed phase liquid chromatography using an Eurosphere 100 RP C18 column (250 × 4.6 mm ID, 5 μm). The mobile phase was methanol–0.05% o-phosphoric acid (60:40 v/v) at a flow rate of 1.0 mL min−1. Commercially available tablets and laboratory mixtures containing both drugs were assayed and detected using a UV detector at 270 nm. The second method involved silica gel 60 F254 high performance thin layer chromatography and densitometric detection at 254 nm using acetonitrile–ethyl acetate–glacial acid (7:3:0.4 v/v/v) as the mobile phase. Calibration curves ranged between 200–600 and 125–375 ng spot−1 for olmesartan and hydrochlorothiazide, respectively

Pharmaceutical Effects of Inhibiting the Soluble Epoxide Hydrolase in Canine Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease that causes pain and bone deterioration driven by an increase in prostaglandins (PGs) and inflammatory cytokines. Current treatments focus on inhibiting prostaglandin production, a pro-inflammatory lipid metabolite, with NSAID drugs; however, other lipid signaling targets could provide safer and more effective treatment strategies. Epoxides of polyunsaturated fatty acids (PUFAs) are anti-inflammatory lipid mediators that are rapidly metabolized by the soluble epoxide hydrolase (sEH) into corresponding vicinal diols. Interestingly, diol levels are increased in the synovial fluid of humans with OA, warranting further research on the biological role of this lipid pathway in the progression of OA. sEH inhibitors (sEHI) stabilize these biologically active, anti-inflammatory lipid epoxides, resulting in analgesia in both neuropathic, and inflammatory pain conditions. Most experimental studies testing the analgesic effects of sEH inhibitors have used experimental rodent models, which do not completely represent the complex etiology of painful diseases. Here, we tested the efficacy of sEHI in aged dogs with natural arthritis to provide a better representation of the clinical manifestations of pain. Two sEHI were administered orally, once daily for 5 days to dogs with naturally occurring arthritis to assess efficacy and pharmacokinetics. Blinded technicians recorded the behavior of the arthritic dogs based on pre-determined criteria to assess pain and function. After 5 days, EC1728 significantly reduced pain at a dose of 5 mg/kg compared to vehicle controls. Pharmacokinetic evaluation showed concentrations exceeding the enzyme potency in both plasma and synovial fluid. In vitro data showed that epoxyeicosatrienoic acid (EETs), epoxide metabolites of arachidonic acid, decreased inflammatory cytokines, IL-6 and TNF-α, and reduced cytotoxicity in canine chondrocytes challenged with IL1β to simulate an arthritic environment. These results provide the first example of altering lipid epoxides as a therapeutic target for OA potentially acting by protecting chondrocytes from inflammatory induced cytotoxicity. Considering the challenges and high variability of naturally occurring disease in aged dogs, these data provide initial proof of concept justification that inhibiting the sEH is a non-NSAID, non-opioid, disease altering strategy for treating OA, and warrants further investigation