Beneficial effects of a strain of Lactobacillus paracasei subsp. paracasei in Staphylococcus aureus-induced intestinal and colonic injury.
The aim of this study was to investigate the in vitro and in vivo anti-staphylococcal activity of a lactic acid bacterial strain and its effect on the intestinal histological damage caused by Staphylococcus aureus infection. Lactobacillus paracasei subsp. paracasei was isolated in our laboratory from breastfed newborn feces and identified phenotypically and genotypically. The strain was analyzed by spot-on-lawn and well diffusion assays for the production of bacteriocins against five antibiotic-resistant S. aureus strains isolated from the feces of hospitalized patients with antibiotic-associated diarrhea. The anti-staphylococcal activity of this strain was evaluated in fermented milk and in vivo using holoxenic rabbits. The strain was able to produce a bacteriocin-like substance active against the staphylococcal strains. A reduction of 2 log in S. aureus cell numbers was registered in co-culture with L. paracasei in fermented milk. Administration of skimmed milk containing S. aureus (10(7) cells/ml) to healthy rabbits induced a persistent diarrheal state 5 days after the challenge. Dissection of the rabbits and consequent histological observations showed damage and an atrophy of the intestinal and colonic mucosae of the diarrheal rabbits; in contrast an arrest of the diarrhea concomitant with recovery of the intestinal villi and the colonic crypts was observed in the rabbits treated with L. paracasei-fermented milk. Furthermore, the diarrheal state persisted in spite of a decrease in the level of S. aureus cells in the feces of the rabbits receiving sterile milk; this was in contrast to the rabbits treated with L. paracasei-fermented milk, in which the decrease in the S. aureus fecal number was associated with the arrest of the diarrhea. L. paracasei could act as a potential barrier to prevent S. aureus- associated injury and might exert its effect on the staphylococcal enterotoxins or their target.


Comparative analysis of pharmacological treatments with N-acetyl-DL-leucine (Tanganil) and its two isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on vestibular compensation: Behavioral investigation in the cat.
Head roll tilt, postural imbalance and spontaneous nystagmus are the main static vestibular deficits observed after an acute unilateral vestibular loss (UVL). In the UVL cat model, these deficits are fully compensated over 6 weeks as the result of central vestibular compensation. N-Acetyl-dl-leucine is a drug prescribed in clinical practice for the symptomatic treatment of acute UVL patients. The present study investigated the effects of N-acetyl-dl-leucine on the behavioral recovery after unilateral vestibular neurectomy (UVN) in the cat, and compared the effects of each of its two isomers N-acetyl-L-leucine and N-acetyl-D-leucine. Efficacy of these three drug treatments has been evaluated with respect to a placebo group (UVN+saline water) on the global sensorimotor activity (observation grids), the posture control (support surface measurement), the locomotor balance (maximum performance at the rotating beam test), and the spontaneous vestibular nystagmus (recorded in the light). Whatever the parameters tested, the behavioral recovery was strongly and significantly accelerated under pharmacological treatments with N-acetyl-dl-leucine and N-acetyl-L-leucine. In contrast, the N-acetyl-D-leucine isomer had no effect at all on the behavioral recovery, and animals of this group showed the same recovery profile as those receiving a placebo. It is concluded that the N-acetyl-L-leucine isomer is the active part of the racemate component since it induces a significant acceleration of the vestibular compensation process similar (and even better) to that observed under treatment with the racemate component only.


Oxygenation of biological membranes by the reticulocyte lipoxygenase. Lack of stoichiometry between oxygen uptake and product formation.
The oxygenation of different types of biological membranes (rat liver mitochondria, rat liver endoplasmic membranes, inside-out erythrocyte ghosts, right side-out erythrocyte ghosts) was studied with respect to products formed during the reaction. In all cases a very similar product pattern was observed with 15S-hydroperoxy-5Z.8Z.11Z.13E-eicosatetraenoic acid (15-HETE) and 13S-hydroperoxy-9Z,11E-octadecadienoic acid, (13-HODE) being the major products. Comparison of the amount of lipoxygenase products formed with the oxygen uptake measured during the reaction indicated an excessive oxygen uptake. With mitochondrial membranes the oxygen consumption was almost one order of magnitude higher than the amount of the products detected. The origin of the excessive oxygen uptake remains unclear. These data, however, indicate that the oxygen consumption with complex substrates is not a reliable measure for the lipoxygenase activity.


Estimation of the accumulation rates and health risks of heavy metals in residential soils of three metropolitan cities in China.
Heavy metal concentrations in urban soils are likely to increase over time because of continuous urbanization and heavy metal emissions. To estimate the accumulation rates of heavy metals in urban soils, we collected soil samples from residential areas with different building ages in the metropolitan cities of Shanghai, Shenzhen, and Beijing, China. Heavy metal concentrations in the soils varied among the cities and were primarily affected by soil parent material and the intensity of anthropogenic sources. Regression analyses revealed that the accumulation rates of Cd and Cu in the soils ranged from 0.0034 to 0.0039 mg/(kg•year) and 0.343 to 0.391 mg/(kg•year), respectively, and were similar across the three cities, while accumulation rates of Zn and Pb in Shanghai were higher than those in Shenzhen and Beijing. The higher accumulation rates of Zn and Pb in Shanghai can be explained by differences in city history and industrial structures among the cities. Residential soils with high health risks posed by the heavy metals were mostly collected from old towns of Shanghai because of high Pb content in the areas. Although recent urbanization resulted in elevated concentrations of Cd, Cu, Zn, and Pb in the residential soils, the effect on the total health risks of residents exposed to the soils was negligible.


Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas.
A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti-vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment. The aim of our study was to determine the expression of VEGF-A and its (co-) receptors by immunohistochemistry and to test the association with patient survival in 350 glioma patients. Additionally, VEGF-A expression was analyzed by in-situ hybridization. In 18 patients, the protein expression was compared with the bevacizumab response according to extended and modified RANO criteria. We found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal-appearing brain tissue (P < .001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1, -2 and neuropilin-1 levels as compared to WHO grade II and III astrocytomas (P < .01) but at lower levels than glioblastomas. The expression of neuropilin-2 was low in all tumors. There was neither a significant correlation between protein expression and patient survival nor between protein levels and bevacizumab response after modified RANO criteria. Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response.


Hypoglycemia in falciparum malaria: is fasting an unrecognized and insufficiently emphasized risk factor?
Hypoglycemia is a frequently encountered complication in falciparum malaria that is usually ascribed to increased glucose use and impaired glucose production caused by the inhibition of gluconeogenesis. Here, in light of recent data showing that glucose production and gluconeogenesis are often increased in falciparum malaria, we review the causes and the risk factors leading to hypoglycemia in malaria. Fasting emerges as an important potential risk factor. Length of fasting should be included in studies on hypoglycemia in malaria. Full recognition of this risk factor for hypoglycemia in malaria could change both advice to the population, especially mothers, and treatment guidelines in the health sector.


Analytical method to improve the decision-making criteria approach in managing digital social channels.
This study explores the decision-making process involved in managing digital communities in the digital social channel ecosystem, specifically in the context of antagonistic digital communication and harmful content dissemination. The rise of digital communities in social media has changed the way people interact with each other, form communities, and participate in social activities. However, these interactions can also lead to conflicts, and the dissemination of harmful content can pose a risk to users' information security. This research proposes a method to mitigate these issues and optimize efficacy while minimizing potential hazards. The proposed method is based on the analysis of the information situation in the management of digital communities under conditions of complete uncertainty, antagonistic behaviour, and partial uncertainty. The study examines the decision-making process involved in antagonistic interaction among users of digital social channels. The methods proposed in this research were implemented to prevent the adverse consequences of community conflicts and the dissemination of potential risks to the security of users' information through prompt and efficacious decision-making. The proposed strategy optimizes efficacy through the implementation of the Wald criteria while minimizing potential hazards by adhering to the Savage criteria. Additionally, the Hurwitz criteria, which presents a balanced approach incorporating both the maximum and minimum criteria, was also employed. The methods were tested within the online community present on the social media platform, Facebook social networks, and the results demonstrate that the suggested technique improves the effectiveness and validity of managers' decisions in digital communities. The study also highlights the use of social networks and the virtual sphere as tools for hybrid warfare on the internet, which can be effective. Effective community management is necessary to mitigate the negative effects of online interactions, and the proposed method offers a valuable tool for managers to make informed decisions and prevent adverse consequences.


An APC/C inhibitor stabilizes cyclin B1 by prematurely terminating ubiquitination.
The anaphase-promoting complex/cyclosome (APC) is a ubiquitin ligase that is required for exit from mitosis. We previously showed that tosyl arginine methyl ester (TAME) inhibits APC-dependent proteolysis by competing with the C-terminal isoleucine-arginine tail of the APC activator cell division cycle 20 (Cdc20) for APC binding. Here we show that in the absence of APC substrates, TAME ejects Cdc20 from the APC by promoting Cdc20 autoubiquitination in its N-terminal region. Cyclin B1 antagonizes TAME's effect by promoting binding of free Cdc20 to the APC and by suppressing Cdc20 autoubiquitination. Nevertheless, TAME stabilizes cyclin B1 in Xenopus extracts by two mechanisms. First, it reduces the k(cat) of the APC-Cdc20-cyclin B1 complex without affecting the K(m), slowing the initial ubiquitination of unmodified cyclin B1. Second, as cyclin B1 becomes ubiquitinated, it loses its ability to promote Cdc20 binding to the APC in the presence of TAME. As a result, cyclin B1 ubiquitination terminates before reaching the threshold necessary for proteolysis.


Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype.
Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT-PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases.


Use of anticoagulant rodenticides by pest management professionals in Massachusetts, USA.
Secondary exposure to chemical rodenticides, specifically second-generation anticoagulant rodenticides (SGARs), poses a threat to non-target wildlife including birds of prey. Federal regulations in the United States currently limit homeowner access to SGARs as a way of minimizing this threat. With legal access to SGARs, pest management professionals (PMPs) represent a potential linkage to non-target exposure. There is limited research focused on rodent control practices, chemical rodenticide preferences, level of concern and awareness, or opinions on rodenticide regulations as they relate to PMPs. An online survey was sent to PMP companies across Massachusetts, USA, between October and November 2015. Thirty-five responses were obtained, a 20 % response rate. The preferred rodent control method among responding PMP companies was chemical rodenticides, specifically the SGAR bromadiolone. Respondents varied in their level of concern regarding the impact of chemical rodenticides on non-target species and showed a low level of awareness regarding SGAR potency and half-life. All responding companies reported using integrated pest management (IPM) strategies, with nearly all utilizing chemical rodenticides at some point. Enhanced education focused on SGAR potency, bioaccumulation potential, exposure routes, and negative impacts on non-target wildlife may improve efforts made by PMPs to minimize risk to wildlife and decrease dependence on chemical rodenticide use. Future studies evaluating use of anticoagulant rodenticide (ARs) by PMPs and the association with AR residues found in non-target wildlife is necessary to determine if current EPA regulations need to be modified to effectively reduce the risk of SGARs to non-target wildlife.


[Changes in the peripheral blood, liver and spleen during the long-term experimental administration of modified hemoglobin].
The study of chronic toxicity of polymerized hemoglobin solutions (PHb) has demonstrated the relationship between the dose of the solution administered and the level of functional and morphological changes induced in various organs of experimental animals. Lower doses (1.8 g/kg) of PHb had no effect on the values of protein and carbohydrate metabolism, while the high doses (10-15 g/kg) of PHb resulted in the impairment of protein synthesis, morphological changes in the spleen and lymphatic nodes.


Comparing Outcomes of 45 μm Gelatin Stent Placed ab Externo with Open Conjunctiva to ab Externo with Closed Conjunctiva.
Compare outcomes of a gelatin stent (XEN45 Gel Stent [XGS]) placed either ab externo with open conjunctiva (AEO) or ab externo with closed conjunctiva (AEC) with or without cataract surgery in patients with glaucoma. Retrospective nonrandomized comparative study. A total of 86 eyes from 86 glaucoma patients who received XGS placed either AEO (N = 49) or AEC (N = 37) with or without cataract surgery between May 2019 and April 2022 at Massachusetts Eye and Ear. Reviewed and analyzed 809 visits from patient charts from a level 3 triage center. Intraocular pressure (IOP), medication burden, Kaplan-Meier (KM) success rates, 5-fluorouracil (5-FU) impact, and complications. Baseline demographics were similar between both groups, except for baseline IOP and glaucoma type. Both AEO and AEC procedures resulted in significant patterns of IOP and medication reduction from baseline up to 1 year. The AEO procedure had significantly higher KM qualified success (QS) rates than the AEC procedure, but similar complete success (CS) rates. Under QS, the cumulative probability of survival was 73% in the AEO group and 51% in the AEC group at month 6 and 62% in the AEO group and 20% in the AEC group at year 1. Under CS, the cumulative probability of survival was 41% in the AEO group and 37% in the AEC group at month 6 and 29% in the AEO group and 14% in the AEC group at year 1. The AEO procedure had significantly more IOP reduction than the AEC procedure at all postoperative time points beyond week 2, but similar medication burden reduction. At postoperative year 1 (POY1), the mean IOP was reduced to 10.72 ± 5.71 mmHg on 1.16 ± 1.68 medications after AEO and 17.03 ± 2.37 mmHg on 1.59 ± 1.21 medications after AEC. Phacoemulsification (phaco) was not a significant factor while 5-FU usage trended toward significance. Procedure time was longer for standalone XGS AEO. We demonstrate that both placements reduce medication and IOP from baseline, with AEO placement having more favorable XGS success rates and IOP control at the expense of longer procedure time and greater 5-FU usage. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Conjugated linoleic acid suppresses NF-kappa B activation and IL-12 production in dendritic cells through ERK-mediated IL-10 induction.
Polyunsaturated fatty acids (PUFA) have been shown to modulate immune responses and have therapeutic effects in inflammatory disorders. However, the influence of PUFA on dendritic cells (DC), key cells of the innate immune system in shaping adaptive immune responses, has not yet been defined. In this study, we examine the effects of the cis-9, trans-11 isomer of conjugated linoleic acid (c9, t11-CLA), a dietary PUFA found in meat and dairy products, on murine DC activation. Treatment of DC with c9, t11-CLA suppressed LPS-induced IL-12, enhanced IL-10R expression, and enhanced IL-10 production at the transcriptional and protein level. The suppression of IL-12 by c9, t11-CLA was found to be IL-10 dependent. We investigated the involvement of the MAPK, ERK, and the transcription factor, NF-kappaB, in this IL-10-mediated effect. c9, t11-CLA enhanced ERK activation after LPS stimulation, and inhibition of ERK resulted in abrogation of IL-10 and recovery of IL-12 production. c9, t11-CLA decreased NF-kappaB:DNA binding after LPS stimulation, which was concomitant with delayed translocation of NF-kappaBp65 into the nucleus and an increase in IkappaBalpha. These effects were reversed by addition of a neutralizing anti-IL-10 Ab. Our findings demonstrate that c9, t11-CLA suppresses IL-12 production by LPS-stimulated DC by ERK mediated IL-10-induction. Furthermore, these IL-10-mediated effects are dependent on inhibition of NF-kappaB activation. This is the first study to demonstrate that c9, t11-CLA can enhance transcription and production of the anti-inflammatory cytokine IL-10, while inhibiting the Th1-promoting cytokine IL-12, and may explain certain of its immunosuppressive properties.


The feasibility of laparoscopic management of incarcerated obturator hernia.
Obturator hernia (OH), a rare cause of acute small bowel obstruction, requires immediate surgical intervention to prevent serious complications and mortality. We assessed the safety and efficacy of laparoscopic surgery in patients with incarcerated OH presenting with acute abdomen in an emergency setting. Data pertaining to patients diagnosed with incarcerated OH between 2011 and April 2015 at our hospital were reviewed. Patients' characteristics, operation details and postoperative outcomes were retrospectively analyzed. All ten patients diagnosed with incarcerated obturator hernia during the reference period were females (average age 72.1 ± 11.8 years; average weight 44.1 ± 6.9 kg; average body mass index 17.8 ± 2.1 kg/m2; average operating time 63 ± 15 min; average hospital stay 6.2 ± 6.6 days). Twelve occult hernias, including six contralateral OHs, two ipsilateral femoral hernias and two bilateral femoral hernias were detected in six patients (60 %), which were simultaneously repaired after laparoscopic exploration. Nine patients (90 %) were successfully treated with synthetic mesh by laparoscopic technique. Only one case required intraoperative conversion to open surgery due to strangulated intestine with perforation. Wound infection was reported in one patient who had undergone bowel resection, but with an eventual complete recovery. Postoperative period was uneventful in the other nine patients. No recurrence or complications were reported on follow-up (mean duration of follow-up: 6-54 months). In this study, laparoscopic technique was associated with a reduced duration of hospital stay and fewer complications. In addition to being a safe and minimally invasive strategy, it allowed for simultaneous diagnosis and treatment of occult hernias during the same procedure. The approach may be a better option for the treatment of incarcerated OH and occult hernias in selected patients.


Pharmacokinetic assessment and phytochemical triterpene control from Cecropia angustifolia using plant biotechnology.
Cecropia angustifolia Trécul. is a native Andean plant containing high levels of pentacyclic triterpenes (PTs), including several isobaric molecules that serve as chemical markers. Preclinical studies suggest that PTs positively modulate metabolic and vascular diseases. However, their low oral absorption reduces their bioactive effects. The objective of this study was (1) to improve the absorption of PTs from C. angustifolia and (2) to establish a platform to produce biomass or botanical reference material using a strategy for their accumulation. MALDI-TOF and UPLC-MS were used to characterize and quantify PTs in different matrices. An in vitro platform for PT production was established. Chemical profiles of triterpenes were also evaluated from wild and in vitro herbal material using TLC coupled with mass spectrometry. To overcome the low absorption of PTs, a premier raw material was used, which increased their bioavailability to 9.2%. Active ingredients in herbal material can vary, and there is an urgent need for standardized extracts using pharmacokinetics as an effective tool to reveal the dynamics of active ingredients in vivo. A temporary immersion system was produced as a promising platform with a total PT accumulation exceeding 50% of the content in the dry fraction, indicating it is a feasible mechanism to produce biomass or botanical reference material. Plant tissue culture is a promising eco-friendly technology for phytochemical production and a modern strategy to protect biodiversity in natural assets. Alternative and modern, yet environmentally friendly production methods are needed to meet the large demand for herbal products.


A standardized classification of hypospadias.
Systems for categorizing hypospadias are based on the location of the external meatus. The presented proposal draws on the organogenesis of the urethra and its position against the bone structure of the pelvis. The aim of the study was to examine the position of the corpus spongiosum division relative to pelvic bone structures as an indicator of the true level of hypospadias. The study involved 150 patients aged 6 months to 22.8 years admitted for primary repair. The division of the corpus spongiosum was examined relative to the shaft of the penis and the upper pubis. Hypospadias above the pubis was categorized as penile, while below was proximal, with further subcategorization. The quality of the distal urethral canal was assessed. The external meatus was above the pubis in 94.1% while the division of corpus spongiosum was located above the pubis in 90% (distal penile 38%, mid shaft 25.3%). There was a considerable difference in hypospadias level relative to the indicator used. The distal meatus/urethra was stenotic in 84%, hypoplastic in 86.8% with true chordee in 10.4%. A classification of hypospadias based on organogenesis and in respect to bony structures of the pelvis seems reliable, consistent, and more surgically oriented. The distal urethral canal should be regarded as a fistula.


Brain magnetic resonance imaging and histopathology findings in a dog with global brain ischaemia following cardiopulmonary arrest.
Global brain ischaemia following cardiopulmonary arrest is uncommonly reported in veterinary medicine yet neurologic injury after arrest is a known morbidity. An 18-week-old male entire Cavalier King Charles Spaniel-Poodle was referred following 3 days of neurologic abnormalities after cardiopulmonary arrest. After resuscitation, the animal had decerebrate rigidity, a stuporous mentation and intermittent episodes of vocalisation and apnoea. A brain magnetic resonance imaging (MRI) was undertaken 4 days after cardiopulmonary arrest, with standard sequences (T1-weighted, T2-weighted and fluid-attenuated inversion recovery) as well as diffusion-weighted imaging to better discern ischaemic injury and cytotoxic oedema for prognostic reasons. MRI findings were consistent with global brain ischaemia affecting the hippocampus, cerebellum and substantia nigra, the latter two not previously identified in canine cases of global brain ischaemia. The patient was euthanased on day eight post-cardiopulmonary arrest due to a lack of neurological improvement and developing sepsis as a complication. Ante-mortem identification of affected areas of the brain was confirmed on histological examination, with evidence of ischaemic injury seen in the cerebrum, hippocampus, cerebellum, basal nuclei and thalamus. This report describes ante-mortem MRI and postmortem findings in a dog with global brain ischaemia following cardiopulmonary arrest. A multimodal approach to neuroprognostication in patients recovering from cardiopulmonary arrest is recommended.


Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay.
Investigating persistent hyperferritinaemia without apparent iron overload is challenging. Even when inflammation, cirrhosis, Still's disease, fatty liver and malignancy are excluded, there remains a group of patients with unexplained hyperferritinaemia for whom rare forms of haemochromatosis (ferroportin disease) are a consideration. Preliminary results suggest that abnormal percentage glycosylation of serum ferritin is seen in some cases of genetically determined hyperferritinaemia. Serum ferritin is normally 50-81% glycosylated, but low glycosylation (20-42%) prevails in hereditary hyperferritinaemia cataract syndrome. This contrasts with hyperglycosylation (>90%) associated with the benign hyperferritinaemia related to missense L ferritin (p.Thr30Ile) mutation. Here, we describe two novel missense L ferritin variants also associated with hyperglycosylation, p.Gln26Ile and p.Ala27Val. Ferritin glycosylation, a comparatively simple measurement, can identify patients for DNA sequencing as hyperglycosylation (>90%) is associated with benign hyperferritinaemia and mutant L ferritin chain.


Development of long-acting nitrate delivery systems.
In this paper pharmaceutical and biopharmaceutical aspects on the development of long-acting nitrate delivery systems are reviewed. Basic considerations and requirements are also discussed. Recent product development activities are presented, with an emphasis on nitroglycerin in transdermal form and oral isosorbide-5-mononitrate controlled-release formulations.


Rehabilitation for scapholunate injury: Application of scientific and clinical evidence to practice.
In this article, the development of a rehabilitation approach is describe using scapholunate injury as a model. We demonstrate how scientific and clinical evidence is applied to a treatment paradigm and modified based on emerging evidence. Role of the scapholunate interosseous ligament within the pathomechanics of the carpus, along with the progression of pathology, and specific rehabilitation algorithms tailored to the stage of injury. We review the recent and current evidence on the kinematics of wrist motion during functional activity, role of the muscles in providing dynamic stability of the carpus, and basic science of proprioception. Key relevant findings in each of these inter-related areas are highlighted to demonstrate how together they form the basis for current wrist rehabilitation. Finally, we make recommendations for future research to further test the efficacy of these approaches in improving functional outcomes.


Acarine attractants: Chemoreception, bioassay, chemistry and control.
The Acari are of significant economic importance in crop production and human and animal health. Acaricides are essential for the control of these pests, but at the same time, the number of available pesticides is limited, especially for applications in animal production. The Acari consist of two major groups, the mites that demonstrate a wide variety of life strategies, i.e., herbivory, predation and ectoparasitism, and ticks which have evolved obligatory hematophagy. The major sites of chemoreception in the acarines are the chelicerae, palps and tarsi on the forelegs. A unifying name, the "foretarsal sensory organ" (FSO), is proposed for the first time in this review for the sensory site on the forelegs of all acarines. The FSO has multiple sensory functions including olfaction, gustation, and heat detection. Preliminary transcriptomic data in ticks suggest that chemoreception in the FSO is achieved by a different mechanism from insects. There are a variety of laboratory and field bioassay methods that have been developed for the identification and characterization of attractants but minimal techniques for electrophysiology studies. Over the past three to four decades, significant progress has been made in the chemistry and analysis of function for acarine attractants in mites and ticks. In mites, attractants include aggregation, immature female, female sex and alarm pheromones; in ticks, the attraction-aggregation-attachment, assembly and sex pheromones; in mites and ticks host kairomones and plant allomones; and in mites, fungal allomones. There are still large gaps in our knowledge of chemical communication in the acarines compared to insects, especially relative to acarine pheromones, and more so for mites than ticks. However, the use of lure-and-kill and lure-enhanced biocontrol strategies has been investigated for tick and mite control, respectively, with significant environmental advantages which warrant further study.


Glutamine and New Pharmacological Targets to Treat Suicidal Ideation.
Glutamate is the major excitatory neurotransmitter in the central nervous system, and it is linked with the amino acid glutamine through a metabolic relationship of enzymatic compound interconversion and transportation, also known as the glutamate-glutamine cycle.A growing body of evidence suggests involvement of the glutamatergic neurotransmitter system in suicidal behaviours. The initial evidence comes from the pathophysiology of neuropsychiatric disorders, as disruptions in glutamate neurotransmission have been found underlying pathology in multiple suicide-related psychiatric conditions such as major depressive disorder, schizophrenia, post-traumatic stress disorder, and bipolar disorder.Existing data from experimental animal models and human in vivo studies also demonstrate that glutamate plays a key role in suicide-related personality traits including aggression and impulsive aggression.Further studies on glutamate system dysfunction underlying suicidal behaviours have focused on the different steps of the glutamate-glutamine cycle: an inflammation-mediated reduction of glutamine synthetase activity has been found in depressed suicide attempters, phosphate-activated glutaminase genes are reduced in suicide completers, and gene expression abnormalities in NMDA receptors have also been discovered in suicide victims.Evidence of a role of the glutamate-glutamine cycle in suicidal behaviours unveils new targets for anti-suicide interventions. Lithium's mechanism to reduce the risk of suicide in people with mood disorders may be related to its ability to increase glutamine synthetase, whereas novel NMDA antagonists such as ketamine [or its S(+) enantiomer esketamine] have already demonstrated positive results in reducing suicidal ideation.


MR imaging of the thoracic aorta.
MR imaging has been incorporated into the diagnostic algorithm for suspected thoracic aortic pathology, challenging CT and invasive catheter angiography as investigations of choice. Techniques, including spin echo, 3-D steady-state free precession, cardiac cine imaging, phase-contrast flow quantification, and high-resolution contrast-enhanced magnetic resonance angiography, are poised to trump other single competitive modalities. The proliferation of 3-tesla systems has advanced the performance of magnetic resonance, aided by parallel imaging techniques, multiarray surface coils, and powerful gradient coils. This article considers the current status of MR imaging in evaluation of the thoracic aorta, with reference to common clinical indications in clinical practice.


Treatment of neuroblastoma with 131I-metaiodobenzylguanidine: experience of the Münster/Kassel Group.
I-131-metaiodobenzylguanidine was used for treatment of neuroblastoma stage IV in three children after surgery and or chemotherapy had failed to be effective. In two of the children with multilocular lesions, after an impressive improvement of clinical symptoms tumor progression was observed. Because in about 25% of children with relapsing neuroblastoma complete remission may be achieved by combining surgery, chemotherapy, and I-131-MIBG treatment, this therapeutic modality should be included in the therapeutic strategy of stage III and IV neuroblastoma.


A simple, no-cost method for 3D printed model identification.
3D printed models are often very similar in shape and can be inadvertently switched if the related patient is not identified correctly. Here, we present a free and simple method to imprint letters and numbers in a 3D model. CT scan data were used to create an STL file of a patient's mandible. We then used Blender software to modify it with numbers and letters. We chose to imprint a series of four letters and numbers on our 3D models. We chose representative letters and numbers of the Latin alphabet. Six models were printed with an Up plus 2 - easy 120 3D printer with different character sizes and shape to evaluate the readability. All models were printed without any failures. Regarding readability, 2 mistakes were made among ten readers. The favourite extrusion depth was 3 mm, and the largest model was preferred. Identification can be done at different times and by different means, but identifying the 3D model during its creation is safer. Moreover these identified 3D models could be saved in the digital patient medical file. The identification location should take into consideration the future indication of the 3D printed medical model. We recommend that 3D identification should be done using at least 7.5mm high, with a depth of 3mm. Our method allows easy, fast and free 3D text. This 3D text identification printing method may be a first step towards the legal use of 3D printed models made within the hospital.


A Met-enkephalin releaser (kyotorphin)-induced release of plasma membrane-bound Ca2+ from rat brain synaptosomes.
The neuropeptide kyotorphin (Tyr-Arg) released 45Ca2+ from synaptosomal membrane preparations of the rat lower brainstem. This dipeptide also decreased plasma membrane-bound Ca2+ ([Ca2+]m), determined using chlorotetracycline, in the slice and synaptosome of the rat lower brainstem. Taken together with other data indicating that kyotorphin induces an increase in synaptosomal intracellular Ca2+ ([Ca2+]i) in a Ca2+ channel-independent manner, it is suggested that kyotorphin may mobilize the [Ca2+]m and thus increase the [Ca2+]i in the nerve terminals of the rat lower brainstem.


Electrospun scaffolds for tissue engineering of vascular grafts.
There is a growing demand for off-the-shelf tissue engineered vascular grafts (TEVGs) for the replacement or bypass of damaged arteries in various cardiovascular diseases. Scaffolds from the decellularized tissue skeletons to biopolymers and biodegradable synthetic polymers have been used for fabricating TEVGs. However, several issues have not yet been resolved, which include the inability to mimic the mechanical properties of native tissues, and the ability for long-term patency and growth required for in vivo function. Electrospinning is a popular technique for the production of scaffolds that has the potential to address these issues. However, its application to human TEVGs has not yet been achieved. This review provides an overview of tubular scaffolds that have been prepared by electrospinning with potential for TEVG applications.


A practice test and selection of a core set of outcome-based quality indicators in Dutch primary care physical therapy for patients with COPD: a cohort study.
To estimate the comparability and discriminability of outcome-based quality indicators by performing a practice test in Dutch physical therapy primary care, and to select a core set of outcome-based quality indicators that are well accepted by physical therapists based on their perceived added value as a quality improvement tool. First, a list of potential quality indicators was defined, followed by determination of the comparability (case-mix adjusted multilevel analysis) and discriminability (intraclass correlation coefficient (ICC)). Second, focus group meetings were conducted with stakeholders (physical therapists and senior researchers) to select a core set of quality indicators. Overall, 229 physical therapists from 137 practices provided 2651 treatment episodes. Comparability: in 10 of the 11 case-mix adjusted models, the ICC increased compared with the intercept-only model. Discriminability: the ICC ranged between 0.01 and 0.34, with five of the 11 ICCs being >0.10. The majority of physical therapists in each focus group preferred the inclusion of seven quality indicators in the core set, including three process and four outcome indicators based upon the 6-min walk test (6MWT), the Clinical COPD Questionnaire (CCQ), and the determination of quadriceps strength using a hand-held dynamometer. This is the first study to describe the comparability and discriminability of the outcome-based quality indicators selected for patients with COPD treated in primary care physical therapy practices. Future research should focus on increasing data collection in daily practice and on the development of tangible methods to use as the core set of a quality improvement tool.


Volatile fatty acids recovery and antibiotic degradation from erythromycin fermentation residues by combined thermal pretreatment and anaerobic fermentation: Insights into microbial communities and metabolic pathways.
High resistance of erythromycin has been the key factor restricting the disposal of erythromycin fermentation residues (EFR). Considering the high sensitivity of erythromycin to acidic conditions, anaerobic fermentation may be a good approach for EFR treatment, through which pH decreases along with the volatile fatty acids (VFA) accumulation. This study firstly explored the EFR treatment by combined thermal pretreatment and anaerobic fermentation. Results showed that thermal pretreatment and anaerobic fermentation exhibited a synergistic effect on erythromycin removal. Erythromycin concentration decreased to 20.0 mg/L with the maximum removal rate of 60.0%, which was 140% and 71.4% higher than erythromycin removal by sole thermal pretreatment and anaerobic fermentation. Thermal pretreatment induced the increased VFA production by 22.3% with the highest VFA concentration of 5325.4 mg/L. Microbial analysis shows that thermal pretreatment stimulated erythromycin degradation and VFA production by increasing the microbial diversity and enriching the functional enzymes involved in acetate-producing pathways.


Preparative isolation, quantification and antioxidant activity of dihydrochalcones from Sweet Tea (Lithocarpus polystachyus Rehd.).
Dihydrochalcones are the main active components of Lithocarpus polystachyus Rehd. (Sweet Tea), they are directly related to the sweet tonic beverage and traditional herb. In this work, two runs of preparative high-speed counter-current chromatography (HSCCC) with a two-phase solvent system composed of n-hexane/ethyl acetate/ethanol/water (1:4:3:4, v/v) were employed to separate three dihydrochalcones (phloridzin, trilobatin and phloretin) from Sweet Tea. About 6.4mg of phloridzin, 48.4mg of trilobatin, and 4.7mg of phloretin with purities of 96.7%, 98.4% and 98.1% were obtained from 130mg of the crude Sweet Tea extract. Phloridzin, trilobatin, and phloretin had effective radical scavenging activities, with IC50 values of 866.80, 20.16 and 179.47μg/mL, respectively, in a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical method. The contents of phloridzin, trilobatin and phloretin in dried old leaves and tender leaves of tea were in the range of 10.1-18.0, 113.7-128.8, 3.6-4.3mg/g and 9.3-9.8, 82.9-103.1, 1.9-2.5mg/g, respectively. The results indicated that the HPLC had good precision, accuracy and repeatability for the determination of three dihydrochalcones in samples.


Long-acting therapeutic delivery systems for the treatment of gliomas.
Despite the emergence of cutting-edge therapeutic strategies and tremendous progress in research, a complete cure of glioma remains elusive. The heterogenous nature of tumor, immunosuppressive state and presence of blood brain barrier are few of the major obstacles in this regard. Long-acting depot formulations such as injectables and implantables are gaining attention for drug delivery to brain owing to their ease in administration and ability to elute drug locally for extended durations in a controlled manner with minimal toxicity. Hybrid matrices fabricated by incorporating nanoparticulates within such systems help to enhance pharmaceutical advantages. Utilization of long-acting depots as monotherapy or in conjunction with existing strategies rendered significant survival benefits in many preclinical studies and some clinical trials. The discovery of novel targets, immunotherapeutic strategies and alternative drug administration routes are now coupled with several long-acting systems with an ultimate aim to enhance patient survival and prevent glioma recurrences.


KDR-LacZ-expressing cells are involved in ovarian and testis-specific vascular development, suggesting a role for VEGFA in the regulation of this vasculature.
Our objectives were to evaluate kinase insert domain protein receptor (KDR)-β-galactosidase (LacZ) expression as a marker for vascular development during gonadal morphogenesis and to determine whether any novel non-angiogenic KDR-LacZ expression was present in mouse testes or ovaries. Gonads were collected from mice expressing LacZ driven by the Kdr promoter (KDR-LacZ) from embryonic day 11 (E11) through postnatal day 60 (P60). At E11.5, mesonephric cells expressing KDR-LacZ seemed to migrate into the developing testis and surrounded developing seminiferous cords. Cells expressing KDR-LacZ appeared in the ovary with no apparent migration from the adjacent mesonephros, suggesting a different origin of endothelial cells. Testis organ cultures from E11 mice were treated with 8 μM VEGFR-TKI, a vascular endothelial growth factor A signal transduction inhibitor; subsequently, the amount of KDR-LacZ staining was reduced by 66%-99% (P<0.002), and the ability of KDR-expressing cells to form a densely organized vascular network was inhibited. Novel non-angiogenic KDR-LacZ staining was detected in the testis on specific subsets of germ cells at E16, E17, P4, P20, P30, and P60. In ovaries, staining was present on oocytes within oocyte cysts at E17 and within late secondary follicles of postnatal mice. Thus, KDR is an excellent marker for analyzing vascular development in the gonads. Inhibition of VEGFA signal transduction prevents the development of testis-specific vasculature. Furthermore, non-vascular KDR-LacZ staining suggests that KDR directly affects both spermatogenesis and somatic-oocyte interactions during gametogenesis.


Acrylamide Induces Neurotoxicity in SH-SY5Y Cells via NLRP3-mediated Pyroptosis.
Acrylamide (ACR), a soft electrophile, is a typical environmental and food contaminant that presents potential health hazards and, consequently, is attracting increasing attention in the quest for its control. ACR neurotoxicity has been widely reported in experimental animals and attributed to neuroinflammation; however, the mechanisms involved therein require clarification. In this study, we used a neuron cell model to investigate the mechanisms of ACR-induced neuroinflammation and pyroptosis. The results showed that ACR treatment induced lytic cell death morphologically under both the canonical pyroptotic pathway (NOD-like receptor protein 3 (NLRP3)-apoptosis-associated speck-like protein containing CARD (ASC)-cysteinyl aspartate specific proteinase 1 (caspase-1)-gasdermin D (GSDMD)-interleukin-1β (IL-1β)/interleukin-18 (IL-18)) and an alternative pyroptotic pathway (cysteinyl aspartate specific proteinase 3 (caspase-3)-gasdermin E (GSDME)-IL-1β/IL-18) in SH-SY5Y cells. Moreover, the lactate dehydrogenase (LDH) production, cytokines release, and lytic cell death induced by ACR were diminished by caspase-1 and -3 inhibitors. Furthermore, the knockdown of caspase-1 by small interfering RNA attenuated ACR-induced lytic cell death, suggesting that canonical pyroptosis (the NLRP3-caspase 1-GSDMD-IL-1β signaling axis) played a primary role in the ACR-induced pyroptosis. Of the two pyroptotic-related pathways, the NLRP3 inflammasome cascade was activated first within the 6-h period of ACR exposure, while the activation of the alternative pyroptotic pathway was delayed. Collectively, these results indicate that ACR mainly induces NLRP3-related neuroinflammation and pyroptosis in SH-SY5Y cells, which is, thus, suggestive of an alternative mechanism for ACR-induced neurotoxicity.


Structural basis for the activation of the lipid scramblase TMEM16F.
TMEM16F, a member of the conserved TMEM16 family, plays a central role in the initiation of blood coagulation and the fusion of trophoblasts. The protein mediates passive ion and lipid transport in response to an increase in intracellular Ca2+. However, the mechanism of how the protein facilitates both processes has remained elusive. Here we investigate the basis for TMEM16F activation. In a screen of residues lining the proposed site of conduction, we identify mutants with strongly activating phenotype. Structures of these mutants determined herein by cryo-electron microscopy show major rearrangements leading to the exposure of hydrophilic patches to the membrane, whose distortion facilitates lipid diffusion. The concomitant opening of a pore promotes ion conduction in the same protein conformation. Our work has revealed a mechanism that is distinct for this branch of the family and that will aid the development of a specific pharmacology for a promising drug target.


What induces capture in motion capture?
The phenomenon of "motion capture" has been demonstrated by presenting, one after the other, two identical Kanizsa squares spatially separated and superimposed on a regular matrix of dots. For appropriate temporal intervals, one illusory square is seen to jump from one location to the other and the dots in it appear to move with it even though they are physically stationary. The standard explanation of the effect is that motion signals from the subjective figure are spontaneously attributed to the static elements laying on it. We have found, however, that if alternative removal of right-angle sectors (required to obtain apparent motion of the illusory square) is not accompanied by alternative appearance and disappearance of a few dots, motion capture does not occur. This suggests that the basic mechanism underlying capture is not the motion of the subjective figure per se, but the spreading of motion signals arising from those texture elements that alternately go on and off between frames. On the other hand, subjective contours do play a role by confining the spreading of motion signals to the texture elements located on the figure.


A comparison of the effect of 1.5% glycine and 5% glucose irrigants on plasma serum physiology and the incidence of transurethral resection syndrome during prostate resection.
To examine changes in the pathophysiology and frequency of the transurethral resection (TUR) syndrome with two irrigation fluids, as variable amounts of irrigation fluid are absorbed during TUR of the prostate (TURP), and although polar solutes are required to prevent an effect on diathermy, the solutes may have effects when absorbed. Between December 2001 and March 2003, 250 patients were included in a prospective randomized trial comparing glycine 1.5% with 5% glucose irrigation fluids. We measured blood loss, fluid absorption, temperature change, biochemistry including a glycine assay, and peri-operative symptoms. Blood samples were taken immediately before and immediately, 5 and 24 h after TURP. Irrigating fluid absorption during TURP was measured with 1% ethanol as a marker and breath ethanol measurements. Operative details were recorded, including the type of anaesthesia (with or with no sedation), resection time and weight of resected tissue. Peri-operative symptoms were documented prospectively. TUR syndrome was defined as a serum sodium level of < or = 125 mmol/L with two or more associated symptoms or signs of TUR syndrome. Five (2%) patients had TUR syndrome; all five were irrigated with glycine, although this difference was not statistically significant (P = 0.06). Of the five men, three had hypotension, four were tired, one was nauseous, two had parasthesia, two had 'uneasiness', one had blurred vision and two were confused; none had chest pain. There was a large variation between the groups in the level of glycine assayed immediately after TURP; a high glycine level was associated with the TUR syndrome (P = 0.01). There was no difference between the groups in levels of sodium, potassium, urea, creatinine, osmolality, calcium, haematocrit, albumin serum levels or peri-operative blood loss (defined as a change from before to after TURP in haemoglobin level, accounting for transfusions). An increase in serum glycine was associated with TUR syndrome; there were large variations in the amounts of glycine absorbed, reaching levels many times the upper limit of normal. In other studies, glycine was reportedly toxic, and that the levels recorded were many times the upper limit of normal may have both immediate and long-term effects.


Contact lenses in the treatment of patients with overcorrected radial keratotomy.
Thirty-two eyes of 28 patients who underwent radial keratotomy had a hyperopic overcorrection after the surgical procedure. Anisometropia, with associated aniseikonia and depth perception problems were present in many of these patients. The patients were subsequently fit with contact lenses. Conventional methods of fitting contact lenses in these patients were unsuccessful. A trial lens technique is used with the initial lens having a base curve equal to the preoperative keratometry measurements and the power equal to the preoperative spherical equivalent. Superficial neovascularization developed within the radial incisions in 33% of the eyes fitted with soft contact lenses. Gas permeable contact lenses offered patients the best-corrected visual acuity as well as minimal complications. In addition, the anisometropia was minimized, and fluctuating vision was eliminated in cases in which it was a problem.


LC-MS/MS method for the determination of several drugs used in combined cardiovascular therapy in human plasma.
A simple, fast and validated method is reported for the simultaneous analysis, in human plasma, of several drugs usually combined in cardiovascular therapy (atenolol, bisoprolol, hydrochlorothiazide, chlorthalidone, salicylic acid, enalapril and its active metabolite enalaprilat, valsartan and fluvastatin) using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) with electrospray ionization (ESI), working in multiple reaction monitoring mode (MRM). Separation of analytes and internal standard (pravastatin) was performed on a Luna C18(2) (150mm×4.6mm, 3μm) column using a gradient elution mode with a run time of 15min. The mobile phase consisted of a mixture of acetonitrile and water containing 0.01% formic acid and 10mM ammonium formate at pH 4.1. Sample treatment consisted of a simple protein precipitation with acetonitrile, enabling a fast analysis. The method showed good linearity, precision (RSD% values between 0.7% and 12.7%) and accuracy (relative error values between 0.9% and 14.0%). Recoveries were within 68-106% range and the ion-suppression was not higher than 22% for any analyte. The method was successfully applied to plasma samples obtained from patients under combined cardiovascular treatment.


Foundations of Rural Resiliency: America during the COVID-19 Pandemic.
In recent decades, a culture of hopelessness has emerged among rural Americans, visible in epidemic levels of suicide, overdose, and other addiction-related illnesses. While the arrival of a novel coronavirus aggravated existing strains in rural economies, it also enabled positive transformations in some rural cities and towns. This research explores how businesses in rural America experienced and adapted to economic shocks caused by the Covid-19 pandemic and, in the process, changed the economic and social landscape. Applying a qualitative research methodology, the present research offers Pennsylvania's Central Susquehanna Valley as a case study, using data from 60 semi-structured interviews. The analyses demonstrate rural businesses' resiliency and adaptive responses, bolstered by embedded rural capitals and the unique characteristics of rural businesses themselves. Furthermore, the pandemic forced drastic changes for businesses in the rural landscape. On the one hand, Covid-19's losses and miseries take much material, human, and social resources from the rural community. On the other hand, changing relationships between businessowners and workers, and among partners in the supply chain could be long-lasting, creating extra rural capitals and better working relationships at the factory and beyond. Finally, adoption of new technologies and automation; new business directions, such as e-commerce and higher value-added production; and increases in mergers and acquisitions across industries were prevalent during 2020-2021. In many ways, the Covid-19 impacts could make rural America more dynamic and competitive. This research offers conceptual and empirical pathways to supporting economic and social development in rural America.


Identification of a unique three-component sex pheromone produced by the tea black tussock moth, Dasychira baibarana (Lepidoptera: Erebidae: Lymantriinae).
The tea black tussock moth Dasychira baibarana Matsumura is a devastating pest in tea plantations that causes substantial economic losses. Presently, there is no effective method to control this pest other than pesticide application. The identified sex pheromone of D. baibarana could be used for detecting and monitoring this pest. Gas chromatography-electroantennogram detection showed that D. baibarana male moth antennae responded strongly to three components in the female sex pheromone gland, which were identified as: (3Z,6Z)-cis-9,10-epoxyhenicosa-3,6-diene (Z3,Z6,epo9-21:H) (I), (3Z,6Z,11E)-cis-9,10-epoxyhenicosa-3,6,11-triene (Z3,Z6,epo9,E11-21:H) (II) and (3Z,6Z)-henicosa-3,6-dien-11-one (Z3,Z6-21:11-one) (III). Dasychira baibarana uses a unique composition of an epoxydiene, epoxytriene, and dienone with the same 3,6-dienyl motif as its sex pheromone. The epoxytriene and dienone were not previously characterized as insect pheromone components. Electroantennogram analysis showed that each synthetic compound strongly stimulated male antennae, and compounds II and III elicited stronger responses than compound I. A wind tunnel bioassay and field trapping experiments proved that, ternary blends of compounds I-III attracted D. baibarana. Efficient attraction was achieved with a rubber septum baited with 500 μg of a mixture of compounds I-III at the ratio 25:20:55. The three identified compounds elicited an electroantennogram response in D. baibarana male moth antennae, and a mixture of the three components at the ratio 25:20:55 attracted D. baibarana male moths in a wind tunnel assay and field trapping experiments. This blend could be used for integrated management of D. baibarana in tea plantations. © 2022 Society of Chemical Industry.


Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage.
The c-Jun N-terminal kinases (JNKs), which are essential regulators of physiological and pathological processes, are involved in several diseases including diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. Inhibition of JNKs suppresses pathological features of these diseases but the many physiological functions of these enzymes argue against the use of sustained, systemic, nonspecific inhibition in the treatment of these diseases. For example, deletion of the gene that encodes JNK1 prevents insulin resistance but disrupts neuronal cytoarchitecture and initiates the pathology of Alzheimer's disease. Thus, it is not sufficient to inhibit selectively either JNKs or individual isoforms of JNK. Instead, the aim is to inhibit the damaging actions of JNK. This can be achieved using peptides that selectively block molecular domains of individual JNK signaling complexes (exclusively) that form under pathological conditions. To date, peptide inhibitors of JNK have been successful in protecting against ischemia-induced brain damage and insulin resistance following obesity. In this review, we discuss novel pharmacological strategies to inhibit JNK and the limitations of these strategies.


Current Insights into the Joint Genetic Basis of Type 2 Diabetes and Coronary Heart Disease.
The large-scale genome-wide association studies conducted so far identified numerous allelic variants associated with type 2 diabetes (T2D), coronary heart disease (CHD) and related cardiometabolic traits. Many T2D- and some CHD-risk loci are also linked with metabolic traits that are hallmarks of insulin resistance (lipid profile, abdominal adiposity). Chromosome 9p21.3 and 2q36.3 are the most consistently replicated loci appearing to share genetic risk for both T2D and CHD. Although many glucose- or insulin-related trait variants are also linked with T2D risk, none of them is associated with CHD. Hence, while T2D and CHD are strongly clinically linked together, further ongoing analyses are needed to clarify the existence of a shared underlying genetic signature of these complex traits. The present review summarizes an updated picture of T2D-CHD genetics as of 2013, aiming to provide a platform for targeted studies dissecting the contribution of genetics to the phenotypic heterogeneity of T2D and CHD.


Calcium oxalate crystal interaction with renal tubular epithelium, mechanism of crystal adhesion and its impact on stone development.
The interaction between renal epithelial cells and calcium oxalate (CaOx) crystals and/or oxalate ions plays a critical role in the formation of urinary stones. Epithelial cells respond to hyperoxaluria and the presence of CaOx crystals in the kidneys by increased enzymuria and internalization of the crystals. Crystal cell interaction results in movement of crystals from the luminal to the basolateral side between the cells and the basement membrane. Once beneath the epithelium, crystals adhere to the basement membrane and become anchored inside the kidneys. Crystals anchored to basement membrane of the peripheral collecting duct aggregate with other crystals and move through an eroding epithelium to the papillary surface, furnishing an encrustation platform or a nidus for future development of a kidney stone. Thus interaction between renal epithelial cells and CaOx crystals and/or oxalate ions is an essential element in the development of urinary stone disease.


Characterization of focal liver lesions by ADC measurements using a respiratory triggered diffusion-weighted single-shot echo-planar MR imaging technique.
The aim of this study was to determine apparent diffusion coefficients (ADCs) of focal liver lesions on the basis of a respiratory triggered diffusion-weighted single-shot echo-planar MR imaging sequence (DW-SS-EPI) and to evaluate whether ADC measurements can be used to characterize lesions. One hundred and two patients with focal liver lesions [11 hepatocellular carcinomas (HCC), 82 metastases, 4 focal nodular hyperplasias (FNH), 56 hemangiomas and 51 cysts; mean size, 16.6 mm; range 5-92 mm] were examined on a 1.5-T system using respiratory triggered DW-SS-EPI (b-values: 50, 300, 600 s/mm2). Results were correlated with histopathologic data and follow-up imaging. The ADCs of different lesion types were compared, and lesion discrimination using optimal thresholds for ADCs was evaluated. Mean ADCs (x10(-3)mm2/s) were 1.24 and 1.04 for normal and cirrhotic liver parenchyma and 1.05, 1.22, 1.40, 1.92 and 3.02 for HCCs, metastases, FNHs, hemangiomas and cysts, respectively. Mean ADCs differed significantly for all lesion types except for comparison of metastases with HCCs and FNHs. Overall, 88% of lesions were correctly classified as benign or malignant using a threshold value of 1.63 x 10(-3)mm2/s. Measurements of the ADCs of focal liver lesions on the basis of a respiratory triggered DW-SS-EPI sequence may constitute a useful supplementary method for lesion characterization.


Tucatinib's journey from clinical development to clinical practice: New horizons for HER2-positive metastatic disease and promising prospects for brain metastatic spread.
Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice.


Spinal cord repair: from experimental models to human application.
Axon regeneration fails in the CNS because the glial environment is inhibitory, and because the regenerative response of CNS is poor. Regeneration can therefore be induced by removing the inhibitory effect of CNS glial molecules, by increasing the regenerative in animal models of spinal cord injury has recently been achieved by several strategies that apply these principles. The successful techniques have been to block inhibitory molecules made by astrocytes, to implant peripheral nerve grafts embedded in a bFGF-containing fibrin gel, to implant olfactory ensheathing cells, to graft embryonic spinal cord tissue, and to implant trophic factor-secreting fibroblasts. The next challenge is to prepare to apply these types of treatment to human patients with spinal cord injuries.


Development and Validation of a Novel Survival Model for Cutaneous Melanoma Based on Necroptosis-Related Genes.
Necroptosis is crucial for organismal development and pathogenesis. To date, the role of necroptosis in skin cutaneous melanoma (SKCM) is yet unveiled. In addition, the part of melanin pigmentation was largely neglected in the bioinformatic analysis. In this study, we aimed to construct a novel prognostic model based on necroptosis-related genes and analysis the pigmentation phenotype of patients to provide clinically actionable information for SKCM patients. We downloaded the SKCM data from the TCGA and GEO databases in this study and identified the differently expressed and prognostic necroptosis-related genes. Patients' pigmentation phenotype was evaluated by the GSVA method. Then, using Lasso and Cox regression analysis, a novel prognostic model was constructed based on the intersected genes. The risk score was calculated and the patients were divided into two groups. The survival differences between the two groups were compared using Kaplan-Meier analysis. The ROC analysis was performed and the area under curves was calculated to evaluate the prediction performances of the model. Then, the GO, KEGG and GSEA analyses were performed to elucidate the underlying mechanisms. Differences in the tumor microenvironment, patients' response to immune checkpoint inhibitors (ICIs) and pigmentation phenotype were analyzed. In order to validate the mRNA expression levels of the selected genes, quantitative real-time PCR (qRT-PCR) was performed. Altogether, a novel prognostic model based on four genes (BOK, CD14, CYLD and FASLG) was constructed, and patients were classified into high and low-risk groups based on the median risk score. Low-risk group patients showed better survival status. The model showed high accuracy in the training and the validation cohort. Pathway and functional enrichment analysis indicated that immune-related pathways were differently activated in the two groups. In addition, immune cells infiltration patterns and sensitivity of ICIs showed a significant difference between patients from two risk groups. The pigmentation score was positively related to the risk score in pigmentation phenotype analysis. In conclusion, this study established a novel prognostic model based on necroptosis-related genes and revealed the possible connections between necroptosis and melanin pigmentation. It is expected to provide a reference for clinical treatment.


Effect of levamisole and methisoprinol on in vitro lymphocyte reactivity in chronically irradiated subjects and patients affected by neoplasias.
The data of this experiment show that Levamisole moderately stimulates T-lymphocyte proliferation and efficiency in vitro and methisoprinol markedly does so when both drugs act in combination with PHA in subjects with severely impaired cell-mediated responsiveness, whereas they do not exert any effect on lymphocytes in normal subjects. B-lymphocyte in vitro responsiveness does not appear to be affected by the immunomodulators, except for some cases of cancer of the stomach wherein B-lymphocyte responsiveness is stimulated in vitro by Levamisole and more evidently by Methisoprinol. These data support the use of Methisoprinol or Levamisole in therapy, and further investigations regarding the mechanisms whereby they might act and the dose-effect relationship which might show to be important for the type of desired immunomodulation would appear appropriate.


Photoinitiated anti-Hydropentafluorosulfanylation of Terminal Alkynes.
A photoinitiated anti-hydropentafluorosulfanylation of terminal alkynes using SF5 Cl and (TMS)3 SiH as the hydrogen atom donor is reported. This transformation generates selectively (Z)-(1-alken-1-yl)pentafluoro-λ6 -sulfanes (Z:E : >85:15), thus allowing the preparation of this previously unknown geometrical isomer. DFT calculations highlight that the selectivity is due to the intrinsic preference of SF5 -substituted vinylic radicals to adopt a cis geometry, and to increased steric contacts during the transition structures leading to the minor (E)-products.


Characterization of substance P and somatostatin receptors on adrenal chromaffin cells using structural analogues.
Substance P (SP) and somatostatin (SRIF) are known to inhibit the nicotine-induced release of catecholamines (CAs) from isolated adrenal chromaffin cells in culture22,24. In order to characterize the receptors mediating this action, we have tested several SP and SRIF analogues for their effects on release of [3H]L-norepinephrine ([3H]NE) from chromaffin cell cultures. SP-free acid and a series of 11 SP analogues, in which each amino acid of SP is replaced in turn by L-alanine, all inhibited the nicotine-induced release of [3H]NE from these cultures. The rank order of potency of the analogues for this action was similar to their reported order of potency in other SP-responsive tissues. The least potent were SP-free acid, [Ala7]-SP, [Ala10]-SP, [Ala8]-SP and [Ala11]-SP, while the potencies of the Ala 1 to 6 analogues and [Ala9]-SP were closer to that of SP. [Leu7]- and [Leu7,8]-SP had potencies similar to that of SP. SP itself had no effect on basal [3H]NE release and only the highest concentrations of some of the analogues tested had an effect (enhancement) on basal [3H]NE release. The results suggest that adrenal chromaffin cells possess a specific SP receptor mediating inhibition of agonist-induced CA release and that the binding site of this receptor shares similar structural requirements with the binding site of the SP receptor on other tissues. Several SRIF analogues, which have been previously shown to be more potent than native SRIF at selective SRIF receptors2,3,31, 35, were compared to SRIF for effects on [3H]NE release from chromaffin cell cultures. These analogues were found to be active but less potent than SRIF in inhibiting nicotine-induced [3H]NE release from these cultures, suggesting that the site mediating this action differs in its structural requirements from the SRIF receptor found in some other tissues.


Aneuploidy in Drosophila, I. Genetic test systems in the female Drosophila melanogaster for the rapid detection of chemically induced chromosome gain and chromosome loss.
An account is provided of two genetic schemes in the Drosophila melanogaster female designed as rapid detectors of chemically induced aneuploidy, including both chromosome gain and chromosome loss. One scheme is referred to as FIX, in which the female carried free (heterozygously) inverted X (chromosomes) and the other, ZESTE, where females do not carry inversions and the X-linked sexually dimorphic zeste mutation plays the key role in the detection of aneuploid offspring. The principle attribute of the FIX system is that all euploid offspring are wild-type for body and eye color whereas aneuploid females have a yellow body and aneuploid males white eyes; int he ZESTE system all euploid individuals are wild-type for eye color, aneuploid females possess zeste-colored eyes and aneuploid males white eyes. In addition induced polyploidies (2X:2A gametes) appear as yellow and zeste male intersexes in the FIX and ZESTE systems, respectively. In this way all aneuploids are recognized immediately. Consequently, detection of compounds with weak effects requiring large sample sizes may be made in a fraction of the time associated with more traditional schemes for aneuploidy detection in Drosophila.


Is unicompartmental knee arthroplasty truly contraindicated in an obese patient? A meta-analysis.
Obesity has long been considered a relative contraindication to unicompartmental knee arthroplasty (UKA). However, with improved implants and techniques, the criteria for UKAs have been challenged. This paper aims to assess the impact of body mass index (BMI) on revision rates and functional outcomes in UKAs. Databases of Pubmed, EMBASE, MEDLINE, CINHL and the Cochrane registries were systematically searched following the PROSPERO protocol. Studies comparing implant survival and functional outcome scores between obese and non-obese patients after a UKA were included. Twenty-five articles reported revision rates or functional outcomes in 42,434 UKA surgeries. There was a trend to higher revision rates in patients with BMI > 30 kg/m2 (odds ratio [OR] 0.91 [0.79-1.05]), BMI >35 kg/m2 (OR 0.70 [0.48, 1.01]) or BMI >40 kg/m2 (OR 0.66 [0.41, 1.07]), although the difference was not significant. There was a significant larger improvement in Oxford Knee Scores in obese patients after a UKA (OR 2.68 [1.79, 3.57], p < 0.00001), but no difference in Knee Society Scores or Visual Analogue Scale scores. With no significant increase in revision rates after a UKA, a significantly greater improvement in Oxford Knee Scores and no differences Knee Society Scores or Visual Analogue Scales, obesity should no longer be viewed as a relative contraindication when performing unicompartmental knee replacements.


Prognostic and proliferative evaluation of ameloblastoma based on radiographic boundary.
Ameloblastoma is a benign odontogenic tumor with an aggressive biological behavior, and the surgical treatment frequently results in failure for the postoperative recurrence. The aim of this article was to investigate whether the proliferative ability and prognosis of ameloblastoma could be evaluated by the radiographic boundary. The ameloblastoma cases treated by the conservative therapy in our hospital between 1981 and 2001 were divided into three groups based on the nature of the radiographic borders of the lesions. The biologic behavior was evaluated by Ki-67 antibody immunohistochemically. Comparisons of prognosis and Ki-67 expression were carried out by statistic methods. There were 24 cases of well-defined edge with sclerosis (group I), 41 cases of well-defined edge without sclerosis (group II) and 32 cases of ill-defined edge (group III). The recurrent rates were 29.2% in group I, 43.9% in group II and 62.5% in group III (P<0.05). The cells in group III expressed the highest Ki-67 level (P<0.05). The radiographic boundary could be used as one of indicators in evaluating the proliferative ability of ameloblastoma and the patient's prognosis, which was consistent with Ki-67 expression.


Activation of stress signaling pathways by oxidized and nitrated lipids.
Oxygen and nitric oxide-derived reactive species at high concentrations can mediate the oxidation of macromolecules such as lipids, thereby contributing to disease pathology. At lower rates of generation, the oxidation and nitration of free or phospholipid-esterified unsaturated fatty acids also mediate more subtle, specific and highly-evolved cell signaling reactions. Notably, electrophilic products of unsaturated fatty acid oxidation and nitration can elicit cytoprotective responses such as those regulated by the Keap1-Nrf2-ARE pathway. The molecular characteristics of lipid-derived signaling mediators that define their ability to trigger stress signaling responses is constrained by their protein targets within the signaling pathways. Recent findings on the Nrf2-activating properties of nitrated fatty acids will be presented, with special reference to interactions with the endothelin signaling system. The functionally significant interactions of Keap1-Nrf2-ARE-mediated signaling with other stress signaling pathways, interrogated utilizing novel genome-wide deep sequencing methods, is also discussed in the context of electrophilic fatty acid signaling. Interrogating the stress signaling pathways elicited by electrophilic lipid mediators will yield important insights into their signaling functions, which ultimately leads to better understanding of the pathogenesis of cardiovascular diseases and the potential for lipid-derived electrophiles as therapeutic agents.


Insulin-like growth factor 1 receptors in human breast tumour: localisation and quantification by histo-autoradiographic analysis.
To assess the precise role of IGF1 in benign and malignant breast diseases, we analysed the tissular localisation, characterised, and quantified specific insulin-like growth factor 1 (IGF1) binding sites in these heterogenous tissues, using histo-autoradiographic analysis (HAA). The 125I-IGF1 binding was performed on frozen tissue sections and analysed using 3H Ultrofilm autoradiography coupled to computerised image analysis. Competitive binding experiments using unlabelled IGF1, IGF2 and insulin showed that the tissues exhibited typical type I IGF binding sites. This specificity was confirmed by the use of alpha IR-3 monoclonal antibody, as inhibitor of 125I-IGF1 binding. IGF1 binding sites were detected in 18 human primary breast cancers, 12 benign breast tumours and two normal breast tissues. Using HAA we found that the human breast carcinomas studied exhibit a specific and high binding capacity for 125I-IGF1 exclusively localised on the proliferative epithelial component. The 125I-IGF1 binding activity of benign breast tumours or normal breast tissue was significantly lower than in cancerous tissues. There was a significant correlation between IGF1-R concentrations detected with HAA and those detected with a classical biochemical method. Moreover, HAA could be useful in further detailing whether a tumour is IGF1-R positive or negative HAA appears to be a useful method for the detection of growth factor receptors, specially in small biopsy specimens.


Influence of filler on the difference between the transmitted and reflected colors of experimental resin composites.
This study sought to determine the influence of filler size and amount on the difference between the transmitted and reflected colors and the translucency of experimental resin composites. The color of experimental resin composites (38 mm in diameter and 1 mm in thickness) was measured in the transmittance and reflectance modes. Opalescence parameter (OP) was calculated as the difference in blue-yellow and red-green coordinates between the transmitted and reflected colors. Translucency parameter (TP) was calculated as the color difference between the reflected colors over a white and a black background. The range of OP was between 1.0 and 5.7, which was varied by the size and amount of filler. TP decreased as the amount of filler increased when the filler size was the same. Controls on the proper filler size and amount should be studied further to modify the opalescence and translucency of resin composites, considering also the effect of filler on mechanical properties.


Anopheles gambiae and A. melas at Brefet, The Gambia, and their role in malaria transmission.
Anopheles melas and A. gambiae were studied at the village of Brefet, The Gambia. The population density of A. gambiae varied according to the rainfall. However, this was not so with A. melas, the highest densities of which occurred after the cessation of the rains. The sporozoite rate averaged 3.5% in A. gambiae but only 0.35% in A. melas. Possible causes of these differences are discussed.


Phenothiazine-Based Donor-Acceptor Polymers as Multifunctional Materials for Charge Storage and Solar Energy Conversion.
The increasing energy demand for diverse applications requires new types of devices and materials. Multifunctional materials that can fulfill different roles are of high interest as they can allow fabricating devices that can both convert and store energy. Herein, organic donor-acceptor redox polymers that can function as charge storage materials in batteries and as donor materials in bulk heterojunction (BHJ) photovoltaic devices are investigated. Based on its reversible redox chemistry, phenothiazine is used as the main building block in the conjugated copolymer design and combined with diketopyrrolopyrrol and benzothiadiazole as electron-poor comonomers to shift the optical absorption into the visible region. The resulting polymers show excellent cycling stability as positive electrode materials in lithium-organic batteries at discharge potentials of 3.6-3.7 V versus Li/Li+ as well as good performances in BHJ solar cells with up to 1.9% power conversion efficiency. This study shows that the design of such multifunctional materials is possible, however, that it also faces challenges, as essential properties for good device function can lead to diametrically opposite requirements in materials design.


Behavioral, physiological and biochemical responses and differential gene expression in Mytilus galloprovincialis exposed to 17 alpha-ethinylestradiol and sodium lauryl sulfate.
Mixture of contaminants often determine biological responses of marine species, making difficult the interpretation of toxicological data. The pharmaceutical 17 alpha-ethinylestradiol (EE2) and the surfactant Sodium Lauryl Sulfate (SLS) commonly co-occur in the marine environment. This study evaluated the effects of EE2 (125.0 ng/L) and SLS (4 mg/L), acting individually and combined, in the mussel Mytilus galloprovincialis. Contaminated mussels closed their valves for longer periods than control ones, especially in the presence of both contaminants, with longer closure periods immediately after spiking compared to values obtained one day after spiking. Nevertheless, males and females increased their metabolism when in the presence of both contaminants (males) and SLS (females), and independently on the treatment males and females were able to activate their antioxidant and biotransformation defences. Although enhancing defences mussels still presented cellular damage and loss of redox balance, especially noticed in the presence of EE2 for males and SLS for females. Histopathological damage was found at mussel's gills in single and mixture exposure, and qPCR analysis revealed a clear estrogen receptor expression with no additive effect due to combined stressors. The results obtained highlight the harmful capacity of both contaminants but further research on this matter is needed, namely considering different climate change scenarios.


Increased heparin binding in cystic fibrosis: a reflection of altered glycoprotein biosynthesis?
Some of the serum proteins which bind to heparin and contribute to the pH 5.57 "heparin binding capacity" of human serum are glycoproteins; those from cystic fibrosis serum were found to be 27% higher in fucose (methylpentose) content, 27% lower in sialic acid content, and 31% lower in hexose content when compared to heparin-precipitated serum glycoproteins from normal control subjects. Hexosamine content of the heparin-precipitated serum glycoproteins was the same. Results of this preliminary investigation indicate that altered carbohydrate composition in serum glycoproteins may affect significantly their heparin binding capacity.


Analysis of antipyretics by semimicro liquid chromatography.
Using semimicro columns (150 X 1 mm I.D.) of octadecyl silica and styrene-divinylbenzene porous polymer, antipyretic drugs were analyzed by means of high-performance liquid chromatography. The antipyretics studied were sulpyrin, caffeine, guaiacol glycerol ether, acetaminophen, 3-hydroxy-p-butyrophenetidine, methyl p-hydroxybenzoate, phenacetin, mefenamic acid, aspirin, salicylamide, salicylic acid, o-ethoxybenzamide, theobromine, theophylline and their preparations. The semimicro columns are economical in solvents in chromatographic analysis.


Low density receptor-related protein 1 (LRP1) promotes anti-inflammatory phenotype in murine macrophages.
We have previously reported that apolipoprotein E (apoE), a protein component of very-low-density lipoproteins (VLDL) and high-density lipoproteins and a potent plasma-borne atheroprotective factor, exerts anti-inflammatory activity in macrophages by switching the activation profile from M1 ("classic") to M2 ("alternative") in a process involving signaling via low-density lipoprotein receptor (LDLR) family members including the VLDL receptor (VLDLR) or apoE receptor-2 (apoER2). The present study was undertaken to investigate whether LDLR-related protein 1 (LRP-1), another member of the LDLR family and a ubiquitously expressed multifunctional cell surface receptor, modulates M1→M2 conversion in murine macrophages. We investigate bone marrow or peritoneal macrophages isolated from wild-type C57/Bl6 mice or mice with conditional inactivation of the LRP-1 gene in the myeloid lineage for the expression of polarization markers. Our results suggest that the deficiency of LRP-1 down-regulates M2 marker expression in macrophages, while enhancing the macrophage response to M1 stimuli. To our knowledge, this is the first demonstration that LRP-1 affects macrophage polarization and promotes the development of an anti-inflammatory M2 functional phenotype.


A novel approach to the synthesis of cytotoxic C2-C3 unsaturated pyrrolo[2,1-c]benzodiazepines (PBDs) with conjugated acrylyl C2-substituents.
A concise synthesis of three novel C2-C3 unsaturated pyrrolo[2,1-c][1,4]benzodiazepine analogues (18-20) containing conjugated acrylyl C2-substituents is reported that utilises Heck coupling to install the C2-acrylyl side chains. These analogues possess significant cytotoxicity according to the NCI 60-cell line screen with 18 surpassing anthramycin (1) in potency.


MITAgating viral infection.
Two recent papers, one in this issue of Immunity (Zhong et al., 2008), report the identification of a membrane protein, termed MITA or STING, that activates the transcription factor IRF3 to induce type-I interferons to mitigate viral infection.


Comparative proteomics elucidates the potential mechanism of heritable carapace color of three strains Chinese mitten crab Eriocheir sinensis.
The carapace coloration is important for the environmental adaptation and reproductive behaviors of crustaceans. We selected red, green and white three carapace color strains of Chinese mitten crab (Eriocheir sinensis) strains. These three carapace colors have stable heritability, but the mechanism for their coloration remains unclear.Through histological observations, we have found significant differences in the composition of pigment cells and pigments within the inner membrane of the three color strains, which may be one of the reasons for the color variation. The levels of various carotenoids in both the shell and inner membrane tissues of red and green strains were significantly higher than those of the white strain, while there was no significant difference between the red and green strains. Proteomics studies have identified 2, 034 and 947 different proteins in the shell and inner membrane, respectively. In the shell, there were 18, 13 and 43 differential proteins between red and white strains, green and white strains and green and red strains, respectively. In the inner membrane, there were 44, 24 and 16 differential proteins between red and white strains, green and white strains and green and red strains, respectively. It is clear that the deposited quantity of carotenoids affects the shell formation of three color strains. Some members of the hemocyanin family showed significant variation among different strains. The study yielded two crustacyanin proteins, which were extracted from both the shell and membrane. Of the two proteins, only Crustacyanin-A1 expression showed a difference between the red and green shells strains. In conclusion, these results indicated that the carapace color formation of E. sinensis may be accomplished through pigment binding proteins (PBPs) and pigment cells, which enhance the understanding of color formation mechanism for crustacean.


Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.
Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.


Analysis of Phenolic Components and Related Biological Activities of 35 Apple (Malus pumila Mill.) Cultivars.
Apple (Malus pumila Mill.) is a popular fruit with high economic values and various biological activities that are beneficial to human health. In this study, 35 apple cultivars were collected and were evaluated for their basic quality indexes, phenolic compositions, antioxidant activity, anti-tumour, and anti-diabetic activities. The compositions of phenolics were detected by using high-performance liquid chromatography (HPLC) and high-resolution mass spectroscopy (HRMS) assays. The antioxidant activities of peel and pulp extracts from 35 apple cultivars were evaluated by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay and ferric reducing antioxidant power (FRAP) assay. Results showed that the contents of phenolic acids and proanthocyanidins showed significant correlations with the antioxidant activities. Phenolic-rich extracts significantly inhibited HepG2 cell proliferation, with the inhibition activity varied significantly between cultivars. 'Gold Delicious' pulp extract, 'Xiboliyabaidian' peel and pulp extracts showed protective effects on H2O2-induced injury of human umbilical vein endothelial cells (HUVEC). 'Red Fuji' peel extract, 'Xiboliyabaidian' peel and pulp extracts, as well as 'Gold Delicious' peel extract, significantly increased glucose consumption of HepG2 cells, in a dose-dependent manner. This research may provide theoretical guidance for further nutritional investigation of the apple resources.


Caesarean scar ectopic pregnancy: Evolution from medical to surgical management.
Caesarean scar ectopic pregnancy (CSP) is defined as blastocyst implantation occurring in a uterine scar. The incidence of CSP continues to rise with increasing caesarean section rates; prevalence is estimated to be 1:1800 to 1:2226 of all pregnancies. To date, over 30 treatment regimens have been published. The Royal College of Obstetricians and Gynaecologists guidelines (2016) state there is insufficient evidence to support one specific intervention over another. To review outcomes of medical and surgical management of CSP cases at a single tertiary centre over a nine-year period, in order to establish the safest and most effective management approach. An audit was undertaken of patients treated for CSP between January 2009 and March 2017 at King Edward Memorial Hospital, Western Australia. Patient demographic and treatment outcome data were extracted from medical records. Fifty-one patients were identified as having CSP diagnosed during this time period, of which five were excluded due to lack of data, leaving a total of 46 cases. The majority of patients (52%, n = 24) elected for initial surgical management, while 41% (n = 19) trialled medical management. Seven percent (n = 3) opted for conservative management. Success rates of surgical, medical and conservative management were 100%, 53% and 0% respectively (P < 0.001). Medical management was associated with prolonged follow-up; there was no difference in complication rates between surgical and medical managements. In this audit, surgical management was the most effective way to manage CSP. There was no significant difference in complication rates between the two groups.


Chloracetamide-N-metholol: an example of an in vitro and in vivo clastogen which is non-mutagenic to Salmonella.
The industrial biocide chloracetamide-N-metholol (CAM) has been shown to be non-mutagenic to 6 strains of Salmonella using both the plate-incorporation and a pre-incubation test protocol. Its biocidal activity is unlikely to have influenced these results since Kathon 886, a more potent biocide, was concomitantly detected as mutagenic to strain TA100. In contrast, CAM was weakly clastogenic to human lymphocytes cultured in vitro and elicited a positive response in the mouse bone marrow micronucleus test when assayed using the intraperitoneal, but not the oral route of administration. A positive response was concomitantly observed for the rodent carcinogen and formaldehyde-releasing agent hexamethylphosphoramide (HMPA) in these 2 clastogenicity assays. Data are presented showing the slow hydrolysis of CAM to formaldehyde in vitro, and both [carbonyl-14C]CAM and [metholol-14C]CAM have been shown to interact covalently with calf-thymus DNA in vitro. It is concluded that CAM may be a direct-acting carcinogen to rodents, but that both the qualitative and quantitative outcome of its bioassay for carcinogenicity will be influenced critically by the bioassay protocol adopted; in particular, by the route of administration selected. These findings emphasize the need to complement the Salmonella gene-mutation assay with an in vitro assay for the induction of chromosomal aberrations if in vivo genotoxins are to be detected efficiently in vitro.


Functional characteristics of a series of N4-substituted 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazines as 5-HT1A receptor ligands. Structure-activity relationships.
The agonistic/antagonistic profile of a series of 10 N4-substituted 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazines is evaluated in the in vitro adenylyl cyclase assay. The profile is severely affected by the characteristics of the N4-substituents ranging from full agonism (benzamidoethyl derivative 1), mixed agonism/antagonism (phthalimidobutyl derivative 7) to predominantly antagonism (saccharinbutyl derivate 9). A novel full antagonist 10, as potent as WAY 100635, is obtained by substitution of Cl at C-7 of the benzodioxinyl moiety in 9.


PagMYB151 facilitates proline accumulation to enhance salt tolerance of poplar.
Poplar is one of the main urban and rural greening and shade tree species in the northern hemisphere, but its growth and development is always restricted by salt stress. R2R3-MYB transcription factor family is commonly involved in many biological processes during plant growth and stress endurance. In this study, PagMYB151 (Potri.014G035100) one of R2R3-MYB members related to salt stress and expressed in both nucleus and cell membrane was cloned from Populus alba × P. glandulosa to perfect the salt tolerance mechanism. Morphological and physiological indexes regulated by PagMYB151 were detected using the PagMYB151 overexpression (OX) and RNA interference (RNAi) transgenic poplar lines. Under salt stress conditions, compared with RNAi and the non-transgenic wild-type (WT) plants, the plant height, both aboveground and underground part fresh weight of OX was significantly increased. In addition, OX has a longer and finer root structure and a larger root surface area. The root activity of OX was also enhanced, which was significantly different from RNAi but not from WT under salt treatment. Under normal conditions, the stomatal aperture of OX was larger than WT, whereas this phenotype was not obvious after salt stress treatment. In terms of physiological indices, OX enhanced the accumulation of proline but reduced the toxicity of malondialdehyde to plants under salt stress. Combing with the transcriptome sequencing data, 6 transcription factors induced by salt stress and co-expressed with PagMYB151 were identified that may cooperate with PagMYB151 to function in salt stress responding process. This study provides a basis for further exploring the molecular mechanism of poplar PagMYB151 transcription factor under abiotic stress.