Moreover, it provides a reference for the characterization of the chemical constituents of other Chinese medicine preparations.Cilia are present on most vertebrate cells and play a central role in development, growth, and homeostasis. Thus, cilia dysfunction can manifest into an array of diseases, collectively termed ciliopathies, affecting millions of lives worldwide. Yet, our understanding of the gene regulatory networks that control cilia assembly and functions remain incomplete. With the advances in next-generation sequencing technologies, we can now rapidly predict pathogenic variants from hundreds of ciliopathy patients. While the pace of candidate gene discovery is exciting, most of these genes have never been previously implicated in cilia assembly or function. This makes assigning the disease causality difficult. This review discusses how Xenopus, a genetically tractable and high-throughput vertebrate model, has played a central role in identifying, validating, and characterizing candidate ciliopathy genes. The review is focused on multiciliated cells (MCCs) and diseases associated with MCC dysfunction. MCCs harbor multiple motile cilia on their apical surface to generate extracellular fluid flow inside the airway, the brain ventricles, and the oviduct. In Xenopus, these cells are external and present on the embryonic epidermal epithelia, facilitating candidate genes analysis in MCC development in vivo. The ability to introduce patient variants to study their effects on disease progression makes Xenopus a powerful model to improve our understanding of the underlying disease mechanisms and explain the patient phenotype.The strongest genetic risk factor for idiopathic late-onset Alzheimer’s disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer’s disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or β42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.

The aim of this study is to evaluate the performance of three existing prediction scores which are applicable to adults for identifying nonalcoholic fatty liver disease (NAFLD) in Chinese children.

We used data from routine check-up based medical records of 1845 children to validate the performance of three existing scoring systems including the hepatic steatosis index (HSI), Zhejiang University index (ZJU index), and triglyceride-glucose index (TyG index) in detection of NAFLD in children. Propensity score matching was applied to adjust for potential confounding effects in both training and validation cohorts. The area under the curve (AUC) of the receiver operating characteristic curve analysis was utilized to assess the performance of the three scoring systems.

Children with NAFLD had higher scores of HSI, ZJU index, and TyG index when compared with the control group (children without NAFLD). Elevated HSI, ZJU index, and TyG index scores were significantly associated with the presence of pediatric NAFLD since adjusted odds ratio and 95% CI with per interquartile range elevation of the HSI, ZJU index, and TyG index were 32.81 (20.48, 52.55), 26.31 (16.97, 40.79), and 1.83 (1.57, 2.13), respectively. In terms of discrimination of NAFLD in children, the AUC of the HSI, ZJU index, and TyG index depending on the validation cohort were 0.964, 0.960, and 0.769, respectively.

The HSI and ZJU index could be appropriate noninvasive biomarkers in distinguishing NAFLD in children from their controls with satisfied accuracy, which would emphasize the clinical and public health policy relevance of pediatric NAFLD. Our findings need to be confirmed by additional longitudinal studies.

The HSI and ZJU index could be appropriate noninvasive biomarkers in distinguishing NAFLD in children from their controls with satisfied accuracy, which would emphasize the clinical and public health policy relevance of pediatric NAFLD. Our findings need to be confirmed by additional longitudinal studies.Multiwell plates (MWPs) are the workhorses of the life sciences. However, biophotonics research with MWPs is limited, in part due to the lack of equipment suitable for photo-irradiation of photoactive molecules in a MWP-suitable, high-throughput manner, either commercially or through open-source MWP systems. Here we present „LightBox”, a calibrated controllable MWP illumination system with broad applications including screening of photoactive molecules and characterization of photocatalytic chemicals. LightBox is a high intensity, accurately controllable, uniform illumination system designed for MWPs with electronics and a control unit that provides a simple and intuitive interface. LightBox can reach intensities of 0.23 mW/mm2 at wavelengths of 405 nm with variance between well sites of less then 5%. The usefulness of LightBox is demonstrated by assessing the IC50 of a photosensitizing compound using a live/dead assay following simultaneous irradiation of the sample at a range of concentrations, eliminating uncontrolled variables between concentrations and drastically increasing assessment speed.

The International Study Group on Pancreatic Surgery recommends upfront surgery for resectable pancreatic cancer or borderline resectable-venous (BR-V) disease and neoadjuvant therapy (NAT) among those with arterial involvement (BR-A or locally advanced, LA). Though neoadjuvant therapy (NAT) is a promising strategy, outcomes are rarely reported on intention-to-treat (ITT) basis. This study presents ITT outcomes where pathways to surgery were in line with International Study Group on Pancreatic Surgery guidelines.

Patients recommended for potentially curative treatment with PDAC between 2012 and 2017 (n = 345) were classified as resectable, BR-A/BR-V or LA, according to NCCN criteria. The primary outcome was overall survival. Secondary outcomes were resection rates, positive margins and toxicity among patients receiving NAT.

At surgery, the resection rates were 78% (172/221), 65% (35/54) and 54% (21/39) for those with resectable, BR-V and BR-A/LA disease, respectively (P < 0.0001). The median survival of those resected in the BR-A/LA cohort was 31 months. However, on an ITT basis, there was no significant difference in survival between resectable, BR-V and BR-A/LA disease (median 19 versus 15 versus 19 months; P = 0.585). On review, some 31 (44%) patients of the BR-A/LA cohort either did not receive or did not complete NAT.

To realize benefits of NAT, more patients need to complete NAT and to undergo resection. Upfront resection for BR-V disease is associated with equivalent outcomes to upfront surgery for resectable disease or NAT for BR-A/LA disease. Strategies to increase the proportion of patients who complete NAT and undergo resection are needed.

To realize benefits of NAT, more patients need to complete NAT and to undergo resection. Upfront resection for BR-V disease is associated with equivalent outcomes to upfront surgery for resectable disease or NAT for BR-A/LA disease. Strategies to increase the proportion of patients who complete NAT and undergo resection are needed.

Appendicitis is the most frequent aetiology of acute abdominal pain requiring surgical treatment, with an estimated lifetime risk between 7% and 8%. Antibiotics play a substantial role in treatment, and there is considerable debate regarding the duration of antibiotics in treating appendicitis.

We searched multiple databases from inception until June 2019 for peer-reviewed studies that compared different durations of antibiotic treatment after appendicectomy for acute complicated appendicitis in adults. We dichotomized reported data into short- and extended-term antibiotic use and controlled for different definitional thresholds in the meta-analysis. We generated risk ratios using restricted maximum likelihood methods and mixed effects modelling for each outcome of interest.

Four observational studies involving 847 participants were included in the meta-analysis. For the primary outcomes of intra-abdominal infection, we did not find a statistically significant difference between extended- and short-termerogeneity between studies and underpowered trials. Further large randomized controlled trials are needed to confirm these findings.LysR-type transcription regulators (LTTRs) comprise one of the largest families of transcriptional regulators in bacteria. They are typically homo-tetrameric proteins and interact with promoter DNA of ~ 50-60 bp. Earlier biochemical studies have suggested that LTTR binding to promoter DNA bends the DNA and, upon inducer binding, the bend angle of the DNA is reduced through a quaternary structure change of the tetrameric LTTR, leading to the activation of transcription. To date, crystal structures of full-length LTTRs, DNA-binding domains (DBD) with their target DNAs, and the regulatory domains with and without inducer molecules have been reported. However, these crystal structures have not provided direct evidence of the quaternary structure changes of LTTRs or of the molecular mechanism underlying these changes. Here, we report the first crystal structure of a full-length LTTR, CbnR, in complex with its promoter DNA. The crystal structure showed that, in the absence of bound inducer molecules, the four DBDs of the tetrameric CbnR interact with the promoter DNA, bending the DNA by ~ 70°. Structural comparison between the DNA-free and DNA-bound forms demonstrates that the quaternary structure change of the tetrameric CbnR required for promoter region-binding arises from relative orientation changes of the three domains in each subunit. The mechanism of the quaternary structure change caused by inducer binding is also discussed based on the present crystal structure, affinity analysis between CbnR and the promoter DNA, and earlier mutational studies on CbnR. DATABASE Atomic coordinates and structure factors for the full-length Cupriavidus necator NH9 CbnR in complex with promoter DNA are available in the Protein Data Bank under the accession code 7D98.A trifluoromethyl sulfur-chelated ruthenium benzylidene, Ru-S-CF3 -I, was synthesized and characterized. This latent precatalyst provides a distinct activity and selectivity profiles for olefin metathesis reactions depending on the substrate. For example, 1,3-divinyl-hexahydropentalene derivatives were efficiently obtained by ring-opening metathesis (ROM) of dicyclopentadiene (DCPD). Ru-S-CF3 -I also presented a much more effective photoisomerization process from the inactive cis-diiodo to the active trans-diiodo configuration after exposure to 510 nm (green light), allowing for a wide scope of photoinduced olefin metathesis reactions. DFT calculations suggest a faster formation and enhanced stability of the active trans-diiodo species of Ru-S-CF3 -I compared with Ru-S-Ph-I, explaining its higher reactivity. In addition, the photochemical release of chloride anions by irradiation of Cl-BODIPY in the presence of DCPD derivatives with diiodo Ru benzylidenes, led to in situ generation of chloride complexes, which quickly produced the corresponding cross-linked polymers. Thus, novel selective pathways that use visible light to guide olefin metathesis based synthetic sequences is presented.

The transradial approach (TRA) for catheter interventions decreases vascular complications and bleeding versus transfemoral approach. Reducing time to hemostasis and preventing radial artery occlusion (RAO) following TRA are important and incompletely realized aspirations.

This first-in-human study sought to evaluate the efficacy of a novel, topically applied compound (hydrophobically modified polysaccharide-chitosan, hm-P) plus minimal required pneumatic compression, to achieve rapid radial arterial hemostasis in post-TRA procedures compared with de facto standards.

About 50 adult patients undergoing 6 French diagnostic TRA procedures were prospectively enrolled. At procedure completion, a topical hm-P impregnated patch was placed over the dermotomy and TR Band (TRB) compression was applied to the access site. This patch was used as part of a novel rapid deflation protocol with a primary outcome of time to hemostasis. Photographic and vascular ultrasound evaluation of the radial artery was performed to evaluate the procedural site.

Time to hemostasis was 40.5 min (IQR 38-50 min) with the majority of patients (n = 39, 78%) not requiring reinflation. Patients with bleeding requiring TRB reinflation were more likely to have low body weight and liver dysfunction, with absence of hypertension and LV dysfunction. The rate of RAO was 0% with predischarge radial artery patency documented in all patients using vascular ultrasound. One superficial hematoma was noted. No late bleeding events or cutaneous reactions were reported in the study follow-up.

Topical application of hm-P in conjunction with pneumatic compression was safe and resulted in rapid and predictable hemostasis at the arterial puncture site.

Topical application of hm-P in conjunction with pneumatic compression was safe and resulted in rapid and predictable hemostasis at the arterial puncture site.When using quantitative photoacoustic tomography (q-PAT) reconstruction to recover the optical absorption coefficients of tissue, the commonly used diffusion equation has several limitations in the case of the objects that have small geometries and high-absorption or low-scattering areas. Furthermore, the conventional perturbation reconstruction strategy is unsatisfactory when the target tissue containing large heterogeneous features. We herein present a modified q-PAT implementation that employs the higher-order photon migration model achieving the tradeoff between mathematical rigidity and computational efficiency. Besides, a nonlinear iterative method is proposed to obtain the perturbations of optical absorption considering the updating of the sensitivity matrix in calculating the fluence perturbations. Consequently, the distribution of tissue optical properties can be recovered in a robust way even if the targets with high absorption are included. The proposed approach has been validated by simulation, phantom and in vivo experiments, exhibiting promising performances in image fidelity and quantitative feasibility for practical applications.Blood leukocyte counts and respective derived ratios have been described as potential prognostic markers in several tumours in veterinary oncology. This study aimed to evaluate peripheral blood leukocyte subpopulations and neutrophil-to-lymphocyte ratio (NLR) as prognostic factors for feline mammary carcinomas (FMC). Medical records from cats diagnosed with FMC between 2017 to 2019 were reviewed. Cats were included if fully staged, classified as WHO stage I to III, and submitted to mastectomy. Cats were excluded if they had evidence of other diseases. Forty-nine cats were included. The study endpoints were disease-free interval (DFI) and tumour-specific survival (TSS). The median DFI and TSS were 389 days and 528 days respectively. In the univariate analysis, higher values of total white blood cell count (WBC), neutrophil count (NEU) and NLR were identified as significant prognostic factors for both endpoints (P  less then  .05). On the multivariate analysis, NLR remained an independent prognostic factor for TSS (P = .024). In the receiver operating characteristic curve analysis, the estimated cut-off for WBC was 8.49 × 109 /L (DFI and TSS); for NEU was 4.62 × 109 /L (DFI) and 6.65 × 109 /L (TSS) and for NLR was 2.46. These cut-offs were significant prognostic factors for DFI and TSS (P  less then  .05). NLR cut-off remained an independent prognostic factor for both DFI (P = .032) and TSS (P = .043) in the multivariable analysis. Our results suggest that NLR, NEU, and WBC can be important non-invasive presurgical prognostic markers, and that NLR is an independent prognostic marker for FMC. Prospective studies are warranted to validate its clinical use.A novel strategy for the N-arylation of NH-sulfoximines has been developed by merging nickel catalysis and electrochemistry (in an undivided cell), thereby providing a practical method for the construction of sulfoximine derivatives. Paired electrolysis is employed in this protocol, so a sacrificial anode is not required. Owing to the mild reaction conditions, excellent functional group tolerance and yield are achieved. A preliminary mechanistic study indicates that the anodic oxidation of a NiII species is crucial to promote the reductive elimination of a C-N bond from the resulting NiIII species at room temperature.Chiral gold(I)-cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6-enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)-mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio- and stereoselectivities.The spleen is the largest secondary lymphoid organ with major roles in the removal of blood-borne antigens. The Eurasian moorhen is a wild aquatic bird that revealed the adaptation to harsh environmental conditions. Information regarding the structural features of moorhen’s spleen is lacking. The present study aimed to describe the composition of moorhen’s spleen using anatomical dissection, histology, histochemistry, immunohistochemistry, and transmission electron microscopy. The spleen appeared as a brownish red sickle-shaped organ close to the proventriculus and gizzard. The splenic capsule was very thin, and the trabeculae were poorly developed. The white pulp formed of the periarteriolar lymphoid sheath, lymphoid follicles, and periellipsoidal lymphatic sheath. The red pulp composed of sinusoids and cords and contained various types of blood cells. Blood vessels were observed within the splenic capsule and inside the parenchyma. Notably, penicillar capillaries (PCs) appeared branched and surrounded by well-developed ellipsoids. Direct connections were observed between PCs and splenic sinusoids suggesting a closed type of circulation. Ultrastructurally, intercellular spaces and vascular channels were evident in the wall of PCs. Ellipsoid-associated cells, lymphocytes, monocytes, and heterophils were observed within splenic ellipsoids. Ellipsoids were thus suggested as a crucial component of moorhen’s spleen. Numerous MafB-immunoreactive (IR) macrophages were seen within the red pulp. Splenic cords contained the highest number of PHH3-IR cells, while CCASP3-IR cells were exclusive to follicles of the white pulp. In conclusion, the structure of moorhen’s spleen revealed species-specific features. The findings of the present study could help to improve the immunity of domestic birds.An elderly man with cardiogenic shock who was found to have a thrombus burden in the right atrium was described. The thrombus was suctioned via the AngioVac device, with assistance from the Impella CP. This is the first reported case of the use of the AngioVac device in conjunction with left-sided mechanical circulatory devices.The aim of the present study is to investigate the pollen morphology of melliferous plant taxa of Southern Khyber Pakhtunkhwa-Pakistan. Using light microscope (LM) and scanning electron microscope (SEM), the palynological study of 18 species of melliferous plants namely Calendula arvensis, Cenchrus pennisetiformis, Citrullus colocynthis, Cucumis melo subsp. agrestis var. agrestis, Cucurbita maxima, Cymbopogon jwarancusa, Cynodon dectylon, Dactyloctenium aegyptium, Helianthus annus, Lagenaria siceraria, Launaea procumbens, Luffa cylindrica, Pennisetum glaucum, Saccharum spontaneum, Sonchus asper, Verbesina encelioides, Xanthium strumarium, and Zea mays was carried out. Both qualitative and quantitative characteristics of pollen were studied. Variations were observed in pollen morphology. The dominant pollen shape was prolate-spheroidal (11 species). All the pollen units were monad. The highest exine thickness was found in Citrullus colocynthis (8.45 μm). The maximum polar and equatorial diameter (102 and 97.55 μm) was found in Luffa cylindrica. Similarly, the highest P/E ratio was found in Cucurbita maxima (1.46). Most of the species showed tricolpate and monoporate type of pollen. The exine sculpturing, number of spines per pollen and between colpi and the pollen fertility and sterility provided significant results for the documentation of melliferous plants. Thus, the information listed in this article will prove helpful to identify the potential melliferous plants in the area, geographical origin of the honey, and the availability of pure honey in the local and international market.Grading the fecal consistency of carnivores is a frequently used tool for monitoring gut health and overall digestion. Several fecal consistency grading systems are available for mainly felids and canids. No such system exists for the brown bear (Ursus arctos Linnaeus, 1758). We aim at extending current fecal consistency grading systems with a scoring system for brown bears. The system was set up during a diet study with nine individuals fed a variety of diets including beef meat, rabbit, fruit, and grass-fruit-pellet mix in an incomplete crossover design. One additional individual was included opportunistically and was fed the typical zoo diet (vegetable-fruit-meat-pellet diet). All feces from the collection period were photographed, graded by „handling the feces” and visually inspected for dietary components. Based on a total of 446 feces, a six-point scale for uniform fecal consistencies was established. In 11% of all feces, two distinct consistencies could be distinguished, a feature that appears in other carnivore species as well. Hence, an additional grading system for dual consistencies was developed. The fecal consistency of brown bears is heavily dependent on the diet items processed before defecation with the general observation that the more vegetation or whole prey, the firmer the feces, and at certain proportions of the latter, the higher the chance for dual fecal consistencies to occur. The results indicate that in bears, diet may have a strong effect on fecal consistency, hampering animal health assessments without prior knowledge of the diet.Neuroimaging studies have suggested that hMT+ encodes global motion interpretation, but this contradicts the notion that BOLD activity mainly reflects neuronal input. While measuring fMRI responses at 7 Tesla, we used an ambiguous moving stimulus, yielding the perception of two incoherently moving surfaces-component motion-or only one coherently moving surface-pattern motion, to induce perceptual fluctuations and identify perceptual organization size-matched domains in hMT+. Then, moving gratings, exactly matching either the direction of component or pattern motion percepts of the ambiguous stimulus, were shown to the participants to investigate whether response properties reflect the input or decision. If hMT+ responses reflect the input, component motion domains (selective to incoherent percept) should show grating direction stimulus-dependent changes, unlike pattern motion domains (selective to the coherent percept). This hypothesis is based on the known direction-selective nature of inputs in component motion perceptual domains versus non-selectivity in pattern motion perceptual domains. The response amplitude of pattern motion domains did not change with grating direction (consistently with their non-selective input), in contrast to what happened for the component motion domains (consistently with their selective input). However, when we analyzed relative ratio measures they mirrored perceptual interpretation. These findings are consistent with the notion that patterns of BOLD responses reflect both sensory input and perceptual read-out.

Data on closed loop systems in young children with type 1 diabetes (T1D) are limited. We tested the efficacy and safety of an open-source, do-it-yourself automated insulin delivery system AndroidAPS in preschool and school-aged children.

This retrospective study analyzed diabetes control in 18 preschool (3-7 years) and 18 school-aged children (8-14 years) with T1D who switched from a sensor-augmented pump (SAP) to AndroidAPS. We compared the CGM parameters and HbA1c levels 3 months before and 6 months after the initiation of AndroidAPS therapy and evaluated frequency of severe adverse events during AndroidAPS use, the most frequent reasons for its interruption, and the experience and psychosocial benefits of AndroidAPS use.

General glycemic control was significantly improved after the switch from SAP to AndroidAPS. Time in range (TIR) increased in both preschool (70.8%-78.6%, p = 0.004) and school-aged children (77.2%-82.9%, p < 0.001), whereas HbA1c levels decreased (preschool children 53.8-48.5 mmol/mol, p < 0.001; school-aged children 52.6-45.1 mmol/mol, p = 0.001). Time spent in range of 3.0-3.8 mmol/L increased slightly in school children (2.6%-3.8%, p = 0.040), but not in preschool children (3.0%-3.0%, p = 0.913). Time spent at <3 mmol/L remained unchanged in both preschool (0.95%-0.67%, p = 0.432) and school-aged children (0.8%-0.8%, p = 1.000). No episodes of severe hypoglycemia or DKA and significant improvement of quality of life were reported by AndroidAPS users.

AndroidAPS seems effective for T1D control both in preschool and school-age children but further validation by prospective studies is necessary.

AndroidAPS seems effective for T1D control both in preschool and school-age children but further validation by prospective studies is necessary.The morphology of the oral cavity of mammals relates to diet, habitat, and function. The palate is an important region with adaptations for oral somatosensation and mechanical loads due to the pressure of the tongue with food. The research aimed to describe the structural and ultrastructural characteristics of the epithelium and the connective tissue cores of the guinea pig palate using macroscopic, light microscopy, scanning electron microscopy, and transmission electron microscopy analysis. The hard palate had conical and filiform papillae, and the soft palate had open salivary ducts. After the removal of the epithelium, the connective tissue cores revealed thin filaments and laminar projections in the hard palate, and opening ducts were evidenced in the soft palate. The palatine epithelium was keratinized and organized by layers, lamellated corpuscles were found in lamina propria of the hard palate. In contrast, the soft palate had glands clusters associated with nerve fibers, and in both regions were identified telocytes. We concluded that the hard palate presented conical and filiform papillae that differ from other mammals. Besides, it is a new description of the connective tissue cores morphology and the first record of the telocytes in this anatomical region for mammals.Mammary tumours are the first and third most incident neoplasm in women and cats, respectively. Approximately 85% of feline mammary gland tumours are malignant and aggressive, especially the triple-negative and HER-2+ molecular subtypes. Triple-negative basal-like feline mammary carcinomas (FMCs) are considered suitable models due to the clinical and morphological similarities with human basal-like triple-negative breast cancer (TNBC). In women, TNBC has a poor prognosis and is often associated with mutations in the tumour suppressor genes BRCA1 and BRCA2. In light of this, the aim of the present investigation was to screen somatic and germline variants of BRCA1 and BRCA2 in nine female cats bearing FMCs. Matched whole blood and FMC samples were obtained for genetic analysis. Additional tumour samples were obtained for histopathological and immunohistochemical evaluation. Genomic DNA was isolated and 27 exonic regions of BRCA1 and BRCA2 genes were amplified and screened by next-generation sequencing. A somatic variant with high functional impact was found in exon 11 of BRCA2 at a frequency of 4.34% in one FMC-bearing cat. Four germline variants with moderate impact were detected in three of the nine FMC-bearing cats and were restricted to exon 9 of BRCA1. It is concluded that the germline genetic variants found in one-third of FMC-bearing animals might be associated with a higher risk of hereditary mammary carcinogenesis.Recognition of invading pathogens by the innate immune system is essential to initiate antimicrobial responses and trigger adaptive immunity. This is largely mediated by an array of pattern-recognition receptor families that are essential for recognizing conserved molecular motifs characteristic of pathogenic microbes. One such family is the Toll-like receptors (TLRs). Activation of TLRs induces production of pro-inflammatory cytokines and type I interferons the former triggers the synthesis of inflammatory mediators which cause fever, pain and other inflammation, and the latter mediates antiviral responses. Over the past decade, significant progress has been made in structural elucidation of TLRs in higher eukaryotes. The TLR structures with and without agonist and antagonist have been revealed by X-ray crystallography and cryo-electron microscopy studies, demonstrating the activated dimer formation induced by the agonistic ligand and the inhibition mechanism of the antagonistic ligand. Intracellular assembled structures and the TLR-chaperone complex are also reported. As the structural understanding of TLRs becomes better integrated with biochemical and immunological studies, a more comprehensive picture of their architectural and functional properties will emerge. This review summarizes recent advances in structural biological and mechanistic studies on TLRs.The birth of modern organic plastics can be traced back to the mid-1800s with various semi-synthetic plastics derived from cellulose nitrate. Examples of such materials include Parkesine introduced by Alexander Parkes in 1860 and celluloid introduced by John Wesley Hyatt in 1870. The history and development of these early materials is presented, while also attempting to clarify the differences between the related materials collodion, Parkesine, and celluloid.

Real-world data on health-related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non-interventional study (NIS; NCT02476942) prospectively collected high-quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice.

To report health-related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors.

Participants were PwHA without FVIII inhibitors age ≥12years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) or Haemophilia-Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo-QoL-SF II). Health status was assessed through EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS).

Ninety-four participants enrolled; median age was 34.0years (range 12-76). Forty-five received episodic treatment and 49 received prophylaxis for a median time of 27.7weeks and 30.4weeks, respectively. Mean (standard deviation) baseline Haem-A-QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ-5D-5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ-VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively).

Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.

Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.

Use of oral opioids does not result in more pain relief than nonopioid alternatives when administered to patients as first-line treatment for acute musculoskeletal pain. This study compared the efficacy of oxycodone/acetaminophen to that of acetaminophen alone as second-line treatment for patients with acute musculoskeletal pain who were administered prescription-strength ibuprofen and reported insufficient relief 1 h later.

A randomized, double-blind study was conducted in two urban emergency departments. Opioid-naïve patients≥18years with an acute musculoskeletal injury were administered ibuprofen 600mg as part of the study protocol. Those who reported insufficient relief 1 h later were randomized (11 ratio) to oxycodone 10mg/acetaminophen 650mg or acetaminophen 650mg. The primary outcome was improvement in 0 to 10 pain scale between randomization and 2 h later. We also assessed medication-associated adverse events. A sample size calculation, built around a minimum clinically important difference of 1.3cation-related adverse events.

Among patients with acute musculoskeletal pain refractory to oral ibuprofen, oxycodone/acetaminophen resulted in slightly greater pain relief than acetaminophen, but this was associated with more medication-related adverse events.Recently, there has been activity at public locations where people have died by suicide, including the erection of suicide prevention messages and memorials (decorations). This research looks at the impact of these decorations and associated media coverage of the decorations on suicidal behaviour at bridges. Incidents (n = 160) of suicidal behaviour on 26 bridges across motorways in England were analysed. Overall, there was no significant difference in the proportion of incidents pre-decoration versus post-decoration (p-value = .55). The incident rates were not significantly different pre- and post-decoration (p = .46). Only one bridge had statistically significantly more incidents post-decoration and media reporting (p = .03). However, following correction for multiple testing there was no significant difference in pre- and post-incident rates at any of the bridges. In total, 58% of bridges had a greater frequency of incidents when decorations were absent; however, this proportion was not statistically significant (p = .41). Further research is required to establish how suicide prevention messages are perceived. There does not appear to be any benefit, but it often generates media coverage which has been shown to increase risk.

Sweat gland function deteriorates with aging, leading to loss of heat tolerance. However, it is unclear whether and how the structure of sweat glands changes during aging, because the 3D structure is complex and inaccessible.

To clarify age-dependent changes in sweat glands, we developed a method for 3D structure analysis of sweat glands by means of X-ray micro-CT observation of human skin specimens followed by 3D digital reconstruction on computer (digital 3D skin).

Comparison of eccrine sweat glands of abdominal skin from young and old subjects showed that the density and volume of sweat glands do not change with aging. In contrast, the depth of the secretory coil from the skin surface is decreased in the aged group. Surprisingly, the secretory ducts appear tortuous or meandering though their length is unchanged. The secretory coils are located at the dermal-adipose layer boundary in both groups, but the thickness of the dermal layer decreases with aging, and the depth of the coils is correlated with the dermal thickness.

Our results suggest that sweat glands twist and rotate with aging to maintain the position of the coil at the dermal-adipose boundary, causing an overall shift toward the skin surface.

Our results suggest that sweat glands twist and rotate with aging to maintain the position of the coil at the dermal-adipose boundary, causing an overall shift toward the skin surface.

This observational study aims to determine individual dental doses in oropharyngeal cancer (OPC) patients managed by intensity modulated radiation treatment (IMRT).

OPC patients treated with IMRT had each tooth individually contoured on post-IMRT CT scans. The mean, maximum and minimum doses were calculated per tooth-based upon patient and tumor demographics (tumor size and nodal status).

A total of 160 patients were included in this study. Escalating tumor size and nodal status led to an observed increase in Dmean doses to the dentition on the contralateral tumor side. A significant region in both jaws received>30Gy in this tumor group.

Tumor demographics were observed to influence RT doses to the dentition and need to be considered when providing a pre-RT dental assessment. The observed dose of>30Gy in large spans of the dentition and jaws highlights future risk of dental deterioration and ORN with long term survival.

30 Gy in large spans of the dentition and jaws highlights future risk of dental deterioration and ORN with long term survival.The jail-based competency treatment (JBCT) model has become an established forensic practice across the country. From the perspective of implementation science and the three core elements of the Promoting Action on Research Implementation in Health Service (PARiHS) framework, the JBCT model is a remarkable example of how context (an unrelenting and overwhelmingly strong demand for forensic beds) has driven multiple state governments to facilitate implementation of a methodology in the absence of empirical evidence supporting its efficacy. This 7-year study of outcomes from four JBCT program sites provides this much-needed evidence by showing that JBCT restored 56% of 1553 male and 336 female patients over an average of 48.7 days. At the same time, the study highlights how variations in JBCT models, methods, and preadmission stabilization time present challenges to planned and effective implementation of evidence-based practice at the statewide system level. By identifying differential responsiveness to JBCT treatment by diagnosis and other factors, the study suggests preliminary implementation ideas for what types of patients are well served by the JBCT model as part of a continuum of restoration options that includes inpatient, outpatient and diversion. Significant findings showed that JBCT patients were restored at a higher rate and in a shorter time if they were female, less then 20 years old (highest restoration rate; those less then 60 years old also significantly better rates), free of co-occurring intellectual and cognitive deficits, and malingering. Of the major diagnoses, schizoaffective disorder required a significantly longer length of JBCT treatment for restoration, and lower restoration rates than schizophrenia and bipolar disorder, although this was moderated by a significant interaction with abuse of amphetamines.Non-small cell lung cancer (NSCLC) incited by epidermal growth factor receptor (EGFR) mutation makes up ∼85% of lung cancer diagnosed and death cases worldwide. The presented study introduced an alternative approach in detecting EGFR mutation using nano-silica integrated with polydimethylsiloxane (PDMS) polymer on interdigitated electrode (IDE) sensor. A 400 μm gap-sized aluminum IDE was modified with nano-polymer layer, which was made up of silica nanoparticles and PDMS polymer. IDE and PDMS-coated IDE (PDMS/IDE) were imaged using electron microscopes that reveals its smooth and ideal sensor morphology. The nano-silica-integrated PDMS/IDE surface was immobilized with EGFR probe and target to specify the lung cancer detection. The sensor specificity was justified through the insignificant current readouts with one-base mismatch and noncomplementary targets. The sensitivity of nano-silica-integrated PDMS/IDE was examined with mutant target spiked in human serum, where the resulting current affirms the detection of EGFR mutation. Based on the slope of the calibration curve, the sensitivity of nano-silica-integrated PDMS/IDE was 2.24E-9 A M-1 . The sensor recognizes EGFR mutation lowest at 1 aM complementary mutant target; however, the detection limit obtained based on 3σ calculation is 10 aM with regression value of 0.97.

Anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) is known as a useful application for improving depressive symptoms or cognitive performance. Antidepressive effects by anodal tDCS over the left DLPFC are expected, but the neural mechanisms of these effects are still unclear. Further, in depression, reduced performance and left prefrontal hypofunction during the verbal fluency task (VFT) are generally known. However, few studies have examined the effect of tDCS on the language-related cerebral network. We aimed to investigate whether anodal tDCS at the left DLPFC affects cognitive performance and the neural basis of verbal fluency.

Nineteen healthy volunteers participated in this study. The effects of tDCS on cognitive behavior and cerebral function were evaluated by (i) performance and accuracy of implicit/explicit motor learning task (serial reaction time task/sequential finger-tapping task), and (ii) cerebral activation while the subjects were performing the VFT by using a functional MRI protocol of a randomized sham-controlled, within-subjects crossover design.

Reaction times of the implicit motor learning task were significantly faster with tDCS in comparison with the sham. Further, language-related left prefrontal-parahippocampal-parietal activation was significantly less with tDCS compared with the sham. Significant correlation was observed between shortened response time in serial reaction time task and decreased cerebral activation during VFT with tDCS.

Anodal tDCS over the left DLPFC could improve cognitive behavior of implicit motor learning by improving brain function of the frontoparietal-parahippocampal region related to motor learning, as well as language-related regions.

Anodal tDCS over the left DLPFC could improve cognitive behavior of implicit motor learning by improving brain function of the frontoparietal-parahippocampal region related to motor learning, as well as language-related regions.

Pneumonia caused by the 2019 novel Coronavirus (COVID-2019) shares overlapping signs and symptoms, laboratory findings, imaging features with influenza A pneumonia. We aimed to identify their clinical characteristics to help early diagnosis.

We retrospectively retrieved data for laboratory-confirmed patients admitted with COVID-19-induced or influenza A-induced pneumonia from electronic medical records in Ningbo First Hospital, China. We recorded patients’ epidemiological and clinical features, as well as radiologic and laboratory findings.

The median age of influenza A cohort was higher and it exhibited higher temperature and higher proportion of pleural effusion. COVID-19 cohort exhibited higher proportions of fatigue, diarrhea and ground-glass opacity and higher levels of lymphocyte percentage, absolute lymphocyte count, red-cell count, hemoglobin and albumin and presented lower levels of monocytes, c-reactive protein, aspartate aminotransferase, alkaline phosphatase, serum creatinine. Multivariate logistic regression analyses showed that fatigue, ground-glass opacity, and higher level of albumin were independent risk factors for COVID-19 pneumonia, while older age, higher temperature, and higher level of monocyte count were independent risk factors for influenza A pneumonia.

In terms of COVID-19 pneumonia and influenza A pneumonia, fatigue, ground-glass opacity, and higher level of albumin tend to be helpful for diagnosis of COVID-19 pneumonia, while older age, higher temperature, and higher level of monocyte count tend to be helpful for the diagnosis of influenza A pneumonia.

In terms of COVID-19 pneumonia and influenza A pneumonia, fatigue, ground-glass opacity, and higher level of albumin tend to be helpful for diagnosis of COVID-19 pneumonia, while older age, higher temperature, and higher level of monocyte count tend to be helpful for the diagnosis of influenza A pneumonia.

To determine whether deuterated water (HDO) generated from the metabolism of [

H

]glucose is a sensitive biomarker of cerebral glycolysis and oxidative flux.

A bolus of [

H

]glucose was injected through the tail vein at 1.95 g/kg into Sprague-Dawley rats. A

H surface coil was placed on top of the head to record

H spectra of the brain every 1.3 minutes to measure glucose uptake and metabolism to HDO, lactate, and glutamate/glutamine. A two-point Dixon method based on a gradient-echo sequence was used to reconstruct deuterated glucose and water (HDO) images selectively.

The background HDO signal could be detected and imaged before glucose injection. The

H NMR spectra showed arrival of [

H

]glucose and its metabolism in a time-dependent manner. A ratio of the HDO to glutamate/glutamine resonances demonstrates a pseudo-steady state following injection, in which cerebral metabolism dominates wash-in of HDO generated by peripheral metabolism. Brain spectroscopy reveals that HDO generation is linear with lactate and glutamate/glutamine appearance in the appropriate pseudo-steady state window. Selective imaging of HDO and glucose is easily accomplished using a gradient-echo method.

Metabolic imaging of HDO, as a marker of glucose, lactate, and glutamate/glutamine metabolism, has been shown here for the first time. Cerebral glucose metabolism can be assessed efficiently using a standard gradient-echo sequence that provides superior in-plane resolution compared with CSI-based techniques.

Metabolic imaging of HDO, as a marker of glucose, lactate, and glutamate/glutamine metabolism, has been shown here for the first time. Cerebral glucose metabolism can be assessed efficiently using a standard gradient-echo sequence that provides superior in-plane resolution compared with CSI-based techniques.The influence of asthma on physical activity (PA) in youth remains equivocal. This review synthesizes the evidence regarding the influence of asthma on PA and sedentary time and evaluates the role of key moderators for this relationship. In accordance with PRISMA guidelines, six electronic databases and gray literature were searched. Primary studies in English were included if they reported device-assessed PA in youth with and without asthma. Random effects meta-analyses examined the effect of asthma on PA and, separately, sedentary time. Mixed-effect meta-regression analyses were conducted using age and sex as moderators, with sub-group comparisons for study quality and asthma diagnosis criteria. Overall, of 3944 citations retrieved, 2850 were screened after the removal of supplication and 2743 citations excluded. Of the 107 full-text publications reviewed, 16 were included in data extraction and analysis, with 15 and five studies included in the PA and sedentary time meta-analyses, respectively. The robust effect size estimate for the influence of asthma on PA and sedentary time was -0.04 [95% CI = -0.11, 0.03] and -0.09 [95% CI = -0.12, -0.06], indicating a non-significant and significant trivial effect, respectively. The effect of asthma on PA levels or sedentary time was not associated with age or sex. Youth with controlled asthma are equally physically (in)active as their healthy peers, with asthma associated with less sedentary time. However, methodological limitations and a paucity of clear methodological reporting temper these conclusions. More rigorous device-based assessments, with a particular focus on sedentary time, and more robust diagnoses of asthma, especially with regard to severity, are needed.Peptides and proteins self-assemble into β-sheet-rich fibrils, amyloid, which extends its structure by incorporating peptide/protein molecules from solution. At the elongation edge, the peptide/protein molecule binds to the edge of the amyloid β-sheet. Such processes are transient and elusive when observing molecular details by experimental methods. We used a model protein system, peptide self-assembly mimic (PSAM), which mimics an amyloid-like structure within a globular protein by capping both edges of single-layer β sheet (SLB) with certain domains. We constructed a PSAM variant that lacks the capping domain on the C-terminal side to observe the structure of the β-sheet edge of the peptide self-assembly. This variant, which we termed PSAM-edge, proved to be soluble with a monomeric form. Urea-induced unfolding experiments revealed that PSAM-edge displayed two-state cooperative unfolding, indicating the N-terminal capping domain and extended SLB folded as one unit. The crystal structure showed that SLB was almost completely structured except for a few terminal residues. A molecular dynamics simulation results revealed that the SLB structure was retained while the C-terminal four residues fluctuated, which was consistent with the crystal structure. Our findings indicate that SLB is stable even when one side of the β-sheet edge is exposed to a solvent. This stability may prevent the dissociation of the attached peptide from the peptide self-assembly. Because of the scarcity of SLB proteins with exposed β-sheet edges in nature, successful construction of the PSAM-edge expands our understanding of protein folding and design.Para-hydroxybenzoic acid (PHBA) has great potential in biological applications due to its putative antiviral activity against SARS-CoV-2 and its antimicrobial activity in the face of the radically increasing number of multidrug-resistant pathogens. This is in addition to its antimutagenic, anti-inflammatory, antioxidant, hypoglycemic, antiestrogenic, and antiplatelet aggregating activities. In this study, an approximate sixfold increase in the production of PHBA was achieved via biotransformation of caffeic acid by Candida albicans. The improvement was performed in two steps first, through mutation by gamma irradiation (5 KGy dose), resulting in the recovery of a mutant (CI-24), which produced approximately triple the amount of PHBA produced by the wild-type isolate. Then, biotransformation by this mutant was further optimized via response surface methodology model-based optimization. The maximum PHBA production (7.47 mg/mL) was obtained in a fermentation medium composed of 1% w/v yeast extract as a nitrogen source, with an initial pH of 6.