Biofloc technology improves growth, innate immune responses, oxidative status, and resistance to acute stress in common carp (Cyprinus carpio) under high stocking density.
This study aimed to evaluate the effects of biofloc technology (BFT) on the performance of common carp under high stocking density. Fish (8.41 ± 0.44 g) were stocked into 12 tanks (70 L) in a 2 × 2 factorial design consisting of clear water (CW) and BFT systems at two stocking densities. Fish were divided into four groups according to culture system and stocking density: CW6 (clear water, 6 kg m-3), CW12 (clear water, 12 kg m-3), BFT6 (biofloc, 6 kg m-3), and BFT12 (biofloc, 12 kg m-3). After 49 days, the fish were exposed to acute crowding stress (40 kg m-3) for 7 days to evaluate the fish performance to additional stressors. Total ammonia nitrogen (TAN) concentration was significantly lower in BFT groups at the end of the trial. The growth of fish was significantly higher and the feed conversion ratio was lower in BFT groups. The final density of fish was highest in BFT12 group (25.41 ± 0.48 kg m-3). The amylase and protease activities in BFT groups were significantly higher than the CW12 group. The highest serum catalase, superoxide dismutase, and glutathione peroxidase activities, and malondialdehyde content (3.07 ± 0.16 nmol mg-1 protein) were observed in CW12 group. Serum LDL, cholesterol, triglyceride, total protein, and albumin levels were significantly higher in CW6 and BFT6 groups, followed by BFT12 group, and lowest in CW12 group. Serum globulin level was lowest in CW12 group (0.68 ± 0.06 g dL-1). After 49 days, serum lysozyme, alternative complement (ACH50) and ALP activities were significantly higher and serum cortisol and glucose levels and ALT and AST activities were lower in BFT groups than the CW12 group. After 7 days of acute stress, serum lysozyme activities were significantly lower and ACH50 and ALP activities were higher in BFT groups than the CW12 group. Also, fish in CW12 group were more sensitive to the acute stressor, showing higher cortisol and lower glucose levels. Overall, biofloc had the anti-stress effect, and the culture of common carp in the biofloc system at a stocking density of 12 kg m-3 could be recommended. BFT can also exert beneficial effects on the welfare of fish subjected to acute stress.


Difference between women and men in left ventricular pump function during predischarge exercise test after acute myocardial infarction.
To evaluate the difference in left ventricular (LV) pump function during predischarge exercise testing between postmenopausal women and age-matched men with myocardial infarction, global and regional ejection fraction, LV end-diastolic volume, and the ratio of systolic blood pressure to LV end-systolic volume were investigated using radionuclide angiography in 25 postmenopausal women and 37 age-matched men. There were no significant differences in the resting radionuclide angiographic indexes between women and men. Global and regional ejection fraction of noninfarcted area, and the ratio of systolic blood pressure to LV end-systolic volume decreased at peak exercise in women, but these indexes increased in men. Although there was no significant difference in the amount of change in LV end-diastolic volume during exercise between the 2 groups, the amount of increase in LV end-systolic volume was significantly larger in women than in men. The ratio of systolic blood pressure to LV end-systolic volume had a curvilinear relation with LV end-diastolic volume at rest and peak exercise, but the ratio of systolic blood pressure to LV end-systolic volume was larger at any LV end-diastolic volume in men than in women during exercise. Thus, lower global ejection fraction and the ratio of systolic blood pressure to LV end-systolic volume during exercise in postmenopausal women compared with age-matched men indicate that gender may have played an important role in the LV remodeling process.


Short-term effects of particulate matter during desert and non-desert dust days on mortality in Iran.
Increased atmospheric particulate matter (PM) concentrations are commonly observed during desert dust days in Iran, but there is still no evidence of their effects on human health. We aimed to evaluate the association between daily mortality and exposure to PM10 and PM2.5 during dust and non-dust days in Tehran and Ahvaz, two major Middle Eastern cities with different sources, intensity, and frequency of desert dust days. We identified desert dust days based on exceeding a daily PM10 concentration threshold of 150 µg/m3 between 2014 and 2017, checking for low PM2.5/PM10 ratio typical of dust days. We used a time-stratified case-crossover design to estimate the short-term effects of PM10 and PM2.5 concentrations on daily mortality during dust and non-dust days. Data was analyzed using conditional Poisson regression models. Higher concentrations of PM and frequency of desert dust days were observed in Ahvaz rather than Tehran. In Ahvaz, the effect of PM10 at lag 0 was much higher during dust days, an increment of 10 μg/m3 was associated with 3.28% (95%CI = [2.42, 4.15]) increase of daily mortality, than non-dust days, 1.03% (95%CI = [-0.02, 2.08]), while in Tehran, was slightly higher during non-dust days, 0.72% (95%CI = [0.23, 1.23]), than in dust days, 0.49% (95%CI = [-0.22, 1.20]). No statistically significant associations were observed between PM2.5 and daily mortality in Ahvaz, while in Teheran the effect of PM2.5 increased significantly during non-dust days at lag 2, 1.89% (95%CI = [0.83, 1.2.95] and lag 3, 1.88% (95%CI = [0.83, 1.2.95]). The study provides evidence that exposure to PM during Middle East dust days is an important risk factor to human health in arid regions and areas affected by desert dust events.


HSP90 mediates the connection of multiple programmed cell death in diseases.
Heat shock protein (HSP) 90, an important component of the molecular chaperone network, is closely concerned with cellular signaling pathways and stress response by participating in the process of maturation and activation of client proteins, playing a crucial role both in the normal and abnormal operation of the organism. In functionally defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by HSP90, including apoptosis, autophagy, necroptosis, ferroptosis, and others. Here, we show the complex relationship between HSP90 and different types of PCD in various diseases, and discuss the possibility of HSP90 as the common regulatory nodal in multiple PCD, which would provide a new perspective for the therapeutic approaches in disease.


Pancreatic transection from blunt abdominal trauma: early versus delayed diagnosis and surgical management.
Pancreatic trauma is relatively uncommon, but carries high morbidity and mortality rates, especially when diagnosis is delayed or inappropriate surgery is attempted. The clinical course and surgical management of 14 patients with distal pancreatic transection or severe laceration with or without main pancreatic duct (MPD) injury caused by blunt abdominal trauma were analyzed in a university teaching hospital. The average age of the 14 patients (12 male, 2 female) was 28.9 years (range 5-56). Six patients had isolated pancreatic trauma, and intra-abdominal and extra-abdominal (mean 0.8) injuries associated with pancreatic transection were seen in the other 8 patients. Nine patients were diagnosed and operated on within the first 24 h. Eight of them underwent transection of the gland with MPD injury; distal pancreatectomy with splenectomy was performed in 3 and without splenectomy in 2, distal pancreatogastrostomy in 1, and - due to associated duodenal laceration and/or contusion of the pancreatic head - pylorus-preserving pancreatoduodenectomy in 2. In 1 case (grade II laceration) only external drainage was necessary. All the patients with early, correctly diagnosed parenchymal and ductal injury survived. Only 1 patient required reoperation due to haemorrhage after pancreatoduodenectomy. The other 5 cases were referred elsewhere after initial treatment, and all of them underwent some kind of external drainage. Three had undetected MPD injury, and in the other 2 cases the parenchymal lesions were either underestimated or missed. All of these cases required subsequent resection (1), internal drainage due to fistula (2), or drainage of developed abscess (2). Three of them had severe septic and pulmonary complications; 1 patient with MPD injury was lost to follow-up. Patients requiring delayed surgical intervention after an unsuccessful period of observation or a subsequent operation due to undetected MPD injury demonstrated a higher rate of pancreas-specific mortality and morbidity.


Oestrogen-progestogen oral contraceptives and urinary calcium excretion.
To examine the effects of age and use of oestrogen-progestogen oral contraceptive agents (OCA) on urinary calcium excretion, 24 h urine collections were obtained from 525 women aged 16-69 years during a health survey, and measurements made of the amounts of calcium, creatinine, sodium, potassium and magnesium excreted. Younger women using OCA excreted more potassium and creatinine but less calcium, and less calcium and magnesium relative to creatinine, than corresponding controls using no OCA. Older women excreted less creatine, but significantly greater amounts of calcium, sodium, potassium and magnesium relative to creatinine than younger women. It is postulated that the diminished urinary calcium excretion observed in women using OCA resulted from suppression of bone resorption by oestrogens in OCA.


The St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017: Egyptian view.
The theme of the 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria was about seeking where appropriate to escalate or de-escalate therapies for early breast cancer based on the up-to-date information of loco-regional and systemic therapies. Along with this line, a group of Egyptian experts decided to arrange for a consensus session to elicit the differences and similarities in therapy recommendations for early breast cancer in Egypt compared to the original Saint Gallen voting and recommendations. During the Egyptian National Cancer Institute's Annual Congress held in November 2017, 30 Egyptian scientists and clinicians from different specialties gathered in a special session and voted on the same questions of the original 15th St. Gallen consensus. Therapies were discussed from different aspects including their intensity, duration, and side effects, and were correlated with tumor stage and tumor biology. This report summarizes the voting questions and resulting percentages of answers of the Egyptian scientists. Interestingly the differences were minimal between the Cairo and original Saint Gallen Consensus denoting a more global view of breast cancer management all over the world.


The Role of Inactivated NF-κB in Premature Ovarian Failure.
Premature ovarian failure (POF) is defined as deployment of amenorrhea due to the cessation of ovarian function in a woman younger than 40 years old. The pathologic mechanism of POF is not yet well understood, although genetic aberrations, autoimmune damage, and environmental factors have been identified. The current study demonstrated that NF-κB inactivation is closely associated with the development of POF based on the data from literature and cyclophosphamide (Cytoxan)-induced POF mouse model. In the successfully established NF-κB-inactivated mouse model, the results showed the reduced expression of nuclear p65 and the increased expression of IκBα in ovarian granulosa cells; the reduced numbers of antral follicles; the reduction of Ki-67/proliferating cell nuclear antigen-labeled cell proliferation and enhanced Fas/FasL-dependent apoptosis in granulosa cells; the reduced level of E2 and anti-Müllerian hormone; the decreased expression of follicle-stimulating hormone receptor and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) in granulosa cells, which was reversed in the context of blocking NF-κB signaling with BAY 11-7082; and the decreased expressions of glucose-regulated protein 78 (GRP78), activating transcription factor 6, protein kinase R-like endoplasmic reticulum kinase, and inositol-requiring enzyme 1 in granulosa cells. Dual-luciferase reporter assay demonstrated that p50 stimulated the transcription of GRP78, and NF-κB affected the expression of follicle-stimulating hormone receptor and promoted granulosa cell proliferation through GRP78-mediated endoplasmic reticulum stress. Taken together, these data indicate, for the first time, that the inactivation of NF-κB signaling plays an important role in POF.


Silicon nanograss based impedance biosensor for label free detection of rare metastatic cells among primary cancerous colon cells, suitable for more accurate cancer staging.
Detection of rare metastatic cells within a benign tumor is a key challenge to diagnose the cancerous stage of the patients tested by clinical human biopsy or pap smear samples. We have fabricated and tested a nanograssed silicon based bioelectronic device with the ability of detecting a few human colon invasive cancer cells (SW48) in a mixed cell culture of primary cancerous colon cells (HT29) without any biochemical labels. A discernible impedance change was elicited after the presence of 5% metastatic cells in the whole benign sample. The electric field penetration as well as current flow to metastatic cells is different from benign ones due to their different membrane dielectric parameters. Beta dispersion as one of intrinsic bioelectrical properties of the cell membrane in blocking the stimulating current flow in the range of kHz is the specific parameter involved in our diagnosis approach. It can reflect in-depth information about the dielectric properties and the pathological condition of a cell before and after metastatic transformation. Electrically active doped silicon nanograss structures owing to their superior nanocontacts with cell membrane can detect any slight variations in current being originated from the presence of rare metastatic cells on the surface of the sensing electrode. The experimental results revealed that bare doped silicon microelectrodes are incapable of resolving different grades of attached cells.


The anatomy of an antigen molecule: functional subregions of L-tyrosine-p-azobenzenearsonate.
The structural components of antigen molecules that interact with class II major histocompability complex (MHC) molecules on antigen-presenting cells (APCs) (agretopes) and with antigen receptors of T-lymphocytes (epitopes) in class II restricted T-cell responses have not been precisely defined. This issue was addressed here using murine T-cell clones specific for the simple immunogen L-tyrosine-p-azobenzenearsonate (ABA-tyr) and a series of analogs of the homologous antigen. Two experimental approaches were used. First, APCs were pulsed with analogs and used to stimulate T-cell proliferation. The patterns of stimulation segregated the clones into two specificity groups and indicated that the epitope recognized by the T-cell included the arsonate group and elements in the side chain of tyrosine. Furthermore, the clones manifest different sensitivities to antigen. Second, non-stimulatory analogs were used to block the presentation of ABA-tyr in an effort to define the agretope. Compounds containing the azophenyl group blocked presentation of ABA-tyr in a dose-dependent fashion, whereas p-arsanilic acid and L-tyrosine were ineffective. The blocking was specific inasmuch as the compounds had no effect on the antigen-induced proliferative responses of giant keyhole limpet hemocyanin (KLH) or hen egg white lysozyme (HEL)-reactive T-cell clones. The blocking pattern indicated that the feature required for productive association with the APC centered on the planar structure of the azo-linked aromatic rings, with little or no contribution from either the arsonate moiety or the tyrosyl side chain. We propose that this structure forms an agretope for this family of compounds.


Keratinophilic fungi isolated from soils of long-term fold-grazed, degraded pastures in national parks of Slovakia.
A total of 939 isolates of 11 genera representing 15 species of keratinophilic fungi were isolated and identified from the soils of three long-term fold-grazed pastures in national parks of Slovakia (Pod Ploskou, Strungový príslop, and Pod Kečkou) and one non-fold-grazed pasture in sierra Stolicke vrchy (Diel) using the hair-baiting technique. Keratinophilic fungi were present in all soil samples with a prevalence of Trichophyton ajelloi and Paecilomyces lilacinus. These fungi were more abundant in soil from fold-grazed pasture (Strungový príslop) compared to non-fold-grazed pasture (Diel). The occurrence of the other keratinophilic fungi was substantially lower, likely because of low pH in some soils.


A novel method to study the electrodynamic behavior of actin filaments. Evidence for cable-like properties of actin.
Actin, one of the most abundant intracellular proteins, forms long linear polyelectrolytic polymers in solution. A novel technique to handle single actin filaments in solution was developed that allows the study of ionic currents elicited along the surface of electrically stimulated actin filaments. Electrical currents were observed about the polymer's surface under both high (100 mM KCl) and low (1 mM KCl) ionic strength conditions. The data are consistent with a dynamic behavior of the counterionic cloud surrounding the actin filaments that support ionic movements along their longitudinal axis upon electrical stimulation. Counterionic waves were highly nonlinear in nature and remained long after the electrical stimulation of the actin filaments ceased. In this report therefore, we demonstrate that actin filaments can function as biological "electrical wires" and can thus be conceptualized as nonlinear inhomogeneous transmission lines. This ability of actin filaments to conduct electrical signals may have important implications in the coupling of intracellular signals.


Comparison of methods for magnetic resonance-guided [18-F]fluorodeoxyglucose positron emission tomography in human carotid arteries: reproducibility, partial volume correction, and correlation between methods.
Inflammation is a major risk factor for atherosclerotic plaque rupture and clinical events. Previous studies have shown that plaque [(18)F]fluorodeoxyglucose (FDG) uptake correlates with macrophage content. In this study we examined the reproducibility of 3 methods of quantifying plaque FDG uptake in the carotid arteries using positron emission tomography (PET). The correlation between 2 simplified uptake parameters (standardized uptake value [SUV], vessel wall-to-blood ratio [VBR]) and a gold standard technique (influx rate [K(i)]) was also determined. We used MRI to correct carotid plaque FDG uptake for partial volume error. Seven patients with a recent carotid territory transient ischemic attack underwent imaging twice within 8 days using MR and FDG-PET. MR coregistered to PET was used to delineate regions of interest, and to facilitate partial volume correction (PVC). SUV was the most reproducible parameter irrespective of whether it was normalized by body surface area (BSA), lean body mass, or weight (intraclass correlation coefficient=0.85, 0.88, and 0.90, respectively). VBR correlated better to K(i) than SUV (r=0.58 VBR, r=0.46 SUV(BSA)). PVC improved these correlations to r=0.81 VBR and r=0.76 SUV(BSA), and only slightly degraded the reproducibility of SUV (intraclass correlation coefficient=0.83-0.85). MR-guided FDG-PET is a highly reproducible technique in the carotid artery and the excellent anatomic detail provided by MR facilitates PVC. Of the methods examined, SUV(BSA)(PVC) appears to represent the best compromise between reproducible and accurate determination of FDG metabolism in carotid artery vessel wall.


Effect of cannabinoids on spasticity and ataxia in multiple sclerosis.
The chronic motor handicaps of a 30-year-old multiple sclerosis patient acutely improved while he smoked a marihuana cigarette. This effect was quantitatively assessed by means of clinical rating, electromyographic investigation of the leg flexor reflexes and electromagnetic recording of the hand action tremor. It is concluded that cannabinoids may have powerful beneficial effects on both spasticity and ataxia that warrant further evaluation.


Evaluation of tumour markers in patients with burning mouth syndrome.
Burning mouth syndrome (BMS) is an enigmatous condition both for the patient and the clinician, and is diagnosed on the basis of the patient's symptoms when they have on examination an apparently healthy looking oral mucosa. A variety of local and systemic factors are known to contribute to burning mouth syndrome. Some authors reported that underlying malignancy could be a possible cause for BMS. In 23 patients with burning mouth syndrome as well as in 20 age, sex, and race matched healthy controls levels of tumour markers-CEA, CA 19-9, AFP, and CYFRA 21-1-were determined from sera. Immunoradiometric assay (IRMA) for detection of ELSA-CEA, ELSA-CA 19-9, ELSA 2-AFP, ELSA-CYFRA 21-1 (CIS bio international, ORIS group, France) was used. Statistical analysis showed no significant differences in the level of tumour markers CEA, CA 19-9, AFP, CYFRA 21-1 in patients with burning mouth syndrome when compared to the healthy controls. We can conclude that evaluation of tumour markers in patients with burning mouth syndrome is not useful and in terms of cost-benefit this investigation should not be performed in patients with burning mouth syndrome.


An Active In-Home Physician Model of Palliative Care and Its Resulting Performance Indicators Related to Home Deaths, Unplanned Emergency Department Visits and Unplanned Hospital Admissions.
Limited research has characterized team-based models of home palliative care and the outcomes of patients supported by these care teams. A retrospective case series describing care and outcomes of patients managed by the London Home Palliative Care Team between May 1, 2017 and April 1, 2019. The London Home Palliative Care (LHPC) Team care model is based upon 3 pillars: 1) physician visit availability 2) active patient-centered care with strong physician in-home presence and 3) optimal administrative organization. In the 18 month study period, 354 patients received care from the London Home Palliative Care Team. Most significantly, 88.4% (n = 313) died in the community or at a designated palliative care unit after prearranged direct transfer; no comparable provincial data is available. 21.2% (n = 75) patients visited an emergency department and 24.6% (n = 87) were admitted to hospital at least once in their final 30 days of life. 280 (79.1%) died in the community. These values are better than comparable provincial estimates of 62.7%, 61.7%, and 24.0%, respectively. The London Home Palliative Care (LHPC) Team model appears to favorably impact community death rate, ER visits and unplanned hospital admissions, as compared to accepted provincial data. Studies to determine if this model is reproducible could support palliative care teams achieving similar results.


Topography of mountain belts controlled by rheology and surface processes.
It is widely recognized that collisional mountain belt topography is generated by crustal thickening and lowered by river bedrock erosion, linking climate and tectonics1-4. However, whether surface processes or lithospheric strength control mountain belt height, shape and longevity remains uncertain. Additionally, how to reconcile high erosion rates in some active orogens with long-term survival of mountain belts for hundreds of millions of years remains enigmatic. Here we investigate mountain belt growth and decay using a new coupled surface process5,6 and mantle-scale tectonic model7. End-member models and the new non-dimensional Beaumont number, Bm, quantify how surface processes and tectonics control the topographic evolution of mountain belts, and enable the definition of three end-member types of growing orogens: type 1, non-steady state, strength controlled (Bm > 0.5); type 2, flux steady state8, strength controlled (Bm ≈ 0.4-0.5); and type 3, flux steady state, erosion controlled (Bm < 0.4). Our results indicate that tectonics dominate in Himalaya-Tibet and the Central Andes (both type 1), efficient surface processes balance high convergence rates in Taiwan (probably type 2) and surface processes dominate in the Southern Alps of New Zealand (type 3). Orogenic decay is determined by erosional efficiency and can be subdivided into two phases with variable isostatic rebound characteristics and associated timescales. The results presented here provide a unified framework explaining how surface processes and lithospheric strength control the height, shape, and longevity of mountain belts.


New developments in medical microbiology: computer-assisted diagnosis and automated instruments.
Time and accuracy required for diagnosis are two of the most important factors in medical microbiology. Computer-assisted diagnosis is one tool to overcome these problems. The software of such systems, much more than the hardware, is of utmost importance and both have to fulfill several items. 1) High flexibility and integration within the already existing working schemes of the laboratory. 2) Terminals in every laboratory. 3) High speed of calculation. 4) Online data transfer from automated instruments. 5) External terminals on intensive care units. 6) Epidemiological and etiopathological investigations have to be possible at any time. In the laboratory the burden of simple, repeating tasks is diminished, inquiries can be made in a minute and precise information about the epidemiological situation can be gained within a few hours. Thus, calculated antimicrobial therapy depending on the incidence of certain pathogens in given specimens in different departments is possible. In the case of fast-growing bacteria, preliminary reports, including susceptibility testing available within the first 24 h, are possible and will be of great help to the clinician in monitoring the calculated antimicrobial regimen. External terminals will allow continuous flow of data from the laboratory to wards and vice versa.


Revisiting the role of the complement system in intracerebral hemorrhage and therapeutic prospects.
Intracerebral hemorrhage (ICH) is a stroke subtype characterized by non-traumatic rupture of blood vessels in the brain, resulting in blood pooling in the brain parenchyma. Despite its lower incidence than ischemic stroke, ICH remains a significant contributor to stroke-related mortality, and most survivors experience poor outcomes that significantly impact their quality of life. ICH has been accompanied by various complex pathological damage, including mechanical damage of brain tissue, hematoma mass effect, and then leads to inflammatory response, thrombin activation, erythrocyte lysis, excitatory amino acid toxicity, complement activation, and other pathological changes. Accumulating evidence has demonstrated that activation of complement cascade occurs in the early stage of brain injury, and the excessive complement activation after ICH will affect the occurrence of secondary brain injury (SBI) through multiple complex pathological processes, aggravating brain edema, and pathological brain injury. Therefore, the review summarized the pathological mechanisms of brain injury after ICH, specifically the complement role in ICH, and its related pathological mechanisms, to comprehensively understand the specific mechanism of different complements at different stages after ICH. Furthermore, we systematically reviewed the current state of complement-targeted therapies for ICH, providing a reference and basis for future clinical transformation of complement-targeted therapy for ICH.


Nonpalpable intratesticular masses detected sonographically.
There is controversy concerning the implications of impalpable testicular masses. We examine the sonographic findings and pathology of such tumors. Between 1985 and 1994, 3,019 scrotal ultrasound studies were performed for various indications and 15 impalpable masses were discovered. Pathological study revealed 5 seminomas, 6 nonseminomas, 2 "burned-out" tumors, 1 lipoma and 1 granuloma. Impalpable intratesticular masses are likely to be malignant. Any young man with retroperitoneal or visceral masses should undergo scrotal ultrasound. A testicular mass is likely to be the primary cancer but it may be regressed. Persistent scrotal pain may be a presentation of malignancy and should be evaluated with ultrasound.


Propofol Pretreatment Fails to Provide Neuroprotection Following a Surgically Induced Brain Injury Rat Model.
Neurosurgical procedures are associated with unintentional damage to the brain during surgery, known as surgically induced brain injuries (SBI), which have been implicated in orchestrating structural and neurobehavioral deterioration. Propofol, an established hypnotic anesthetic agent, has been shown to ameliorate neuronal injury when given after injury in a number of experimental brain studies. We tested the hypothesis that propofol pretreatment confers neuroprotection against SBI and will reduce cerebral edema formation and neurobehavioral deficits in our rat population. Sprague-Dawley rats were treated with low- and high-dose propofol 30 min before SBI. At 24 h post injury, brain water content and neurobehavioral assessment was conducted based on previously established models. In vehicle-treated rats, SBI resulted in significant cerebral edema and higher neurological deficit scores compared with sham-operated rats. Low- or high-dose propofol therapy neither reduced cerebral edema nor improved neurologic function. The results suggest that propofol pretreatment fails to provide neuroprotection in SBI rats. However, it is possible that a SBI model with less magnitude of injury or that propofol re-dosing, given the short-acting pharmacokinetic property of propofol, may be needed to provide definitive conclusions.


A chromosome-level genome assembly of Stenchaetothrips biformis and comparative genomic analysis highlights distinct host adaptations among thrips.
Insects have a limited host range due to genomic adaptation. Thysanoptera, commonly known as thrips, occupies distinct feeding habitats, but there is a lack of comparative genomic analyses and limited genomic resources available. In this study, the chromosome-level genome of Stenchaetothrips biformis, an oligophagous pest of rice, is assembled using multiple sequencing technologies, including PacBio, Illumina short-reads, and Hi-C technology. A 338.86 Mb genome is obtained, consisting of 1269 contigs with a contig N50 size of 381 kb and a scaffold N50 size of 18.21 Mb. Thereafter, 17,167 protein-coding genes and 36.25% repetitive elements are annotated. Comparative genomic analyses with two other polyphagous thrips, revealing contracted chemosensory-related and expanded stress response and detoxification gene families in S. biformis, potentially facilitating rice adaptation. In the polyphagous thrips species Frankliniella occidentalis and Thrips palmi, expanded gene families are enriched in metabolism of aromatic and anthocyanin-containing compounds, immunity against viruses, and detoxification enzymes. These expansion gene families play crucial roles not only in adapting to hosts but also in development of pesticide resistance, as evidenced by transcriptome results after insecticides treatment. This study provides a chromosome-level genome assembly and lays the foundation for further studies on thrips evolution and pest management.


Characterisation of a novel peptide, Brevinin-1H, from the skin secretion of Amolops hainanensis and rational design of several analogues.
As drug-resistant bacteria have become a serious health problem and have caused thousands of deaths, finding new antibiotics has become an urgent research priority. A novel antimicrobial peptide, named Brevinin-1H, was identified in the skin secretion of Amolops hainanensis through 'shotgun' cloning. It has broad-spectrum antimicrobial activity against tested micro-organisms and has anticancer cell activity. To improve its bioactivity and decrease its cytotoxicity, two structural analogues-Brevinin-1Ha and Brevinin-1HY-were designed based on the secondary structure of the natural peptide. Brevinin-1HY, in which tyrosine substituted Pro11 , had similar activity to the natural peptide against Gram-negative bacteria and cancer cells, but showed a dramatic increase in haemolytic activity and cytotoxicity at its minimum inhibitory concentration. Brevinin-1Ha, which transferred the Rana-box from the C-terminal to a central position, had significantly decreased haemolytic activity, but also in antimicrobial and anticancer activity. The present data suggest that increasing the proportion of α-helix structure in an AMP can increase its target micro-organism bioactivity to some extent.


Elevated epidermal ornithine decarboxylase activity suppresses contact hypersensitivity.
Previous reports have shown that elevated polyamine biosynthesis is sufficient to promote skin tumorigenesis in susceptible mouse strains. We hypothesized that increased activity of epidermal ornithine decarboxylase (ODC), a key regulatory enzyme in polyamine biosynthesis, may suppress the cutaneous immune response in addition to stimulating proliferation. Using an ODCER transgenic mouse model in which ODC is targeted to the epidermis, we examined the effect of ODC overexpression in keratinocytes on a classic contact hypersensitivity (CHS) response. Compared with normal littermate mice, ODCER transgenic mice showed reduced ear swelling, reduced neutrophil infiltration, and decreased migration of fluorescein isothiocyanate-loaded dendritic cells (DCs) to draining lymph nodes following hapten elicitation of CHS. In addition, elevated epidermal ODC activity suppressed the levels of cytokines keratinocyte-derived chemokine, monocyte chemoattractant protein-1, interleukin-6 (IL-6), and IL-10. Adoptive transfer of lymphocytes from sensitized ODCER transgenic or normal littermate mice to naive ODCER transgenic or wild-type mice indicated that elevated epidermal ODC activity suppresses both the sensitization and elicitation phases of CHS. The specific ODC inhibitor, α-difluoromethylornithine, abrogated all suppressive effects of ODC in CHS reactions. Collectively, these data suggest that the immunosuppression promoted by increased epidermal ODC is mediated by a reduction in cytokine levels, which suppresses DC migration and reduces immune cell infiltration to the site of hapten application.


Pathways for nicotinic receptor desensitization.
Nicotinic acetylcholine receptors (AChRs) are ligand-gated ion channels that generate transient currents by binding agonists and switching rapidly between closed- and open-channel conformations. Upon sustained exposure to ACh, the cell response diminishes slowly because of desensitization, a process that shuts the channel even with agonists still bound. In liganded receptors, the main desensitization pathway is from the open-channel conformation, but after agonists dissociate the main recovery pathway is to the closed-channel conformation. In this Viewpoint, I discuss two mechanisms that can explain the selection of different pathways, a question that has puzzled the community for 60 yr. The first is based on a discrete-state model (the "prism"), in which closed, open, and desensitized conformational states interconnect directly. This model predicts that 5% of unliganded AChRs are desensitized. Different pathways are taken with versus without agonists because ligands have different energy properties (φ values) at the transition states of the desensitization and recovery reactions. The second is a potential energy surface model (the "monkey saddle"), in which the states connect indirectly at a shared transition state region. Different pathways are taken because agonists shift the position of the gating transition state relative to the point where gating and desensitization conformational trajectories intersect. Understanding desensitization pathways appears to be a problem of kinetics rather than of thermodynamics. Other aspects of the two mechanisms are considered, as are experiments that may someday distinguish them.


Tetracycline antibiotics: Potential anticancer drugs.
In recent years, research on tetracycline antibiotics has gradually shifted from their antibacterial effects to anticancer effects. Doxycycline, minocycline, and tigecycline as the US Food and Drug Administration (FDA) approved tetracycline antibiotics have been the main subjects of studies. Evidence indicated that they have anticancer properties and are able to control cancer progression through different mechanisms, such as anti-proliferation, anti-metastasis, and promotion of autophagy or apoptosis. In addition, studies have shown that these three tetracycline antibiotics can be utilized in conjunction with chemotherapeutic and targeted drugs to inhibit cancer progression and improve the quality of patient survival. Therefore, doxycycline, minocycline, and tigecycline are taken as examples in this work. Their mechanisms of action in different cancers and related combination therapies are introduced. Their current roles in alleviating the suffering of patients undergoing chemotherapy when used as adjuvant drugs in clinical treatment are also described. Finally, the research gaps and potential research directions at this stage are briefly summarized.


Inhibin secretion during the rat estrous cycle: relationships to FSH secretion and FSH beta subunit mRNA concentrations.
Serum inhibin and FSH and FSH beta subunit mRNA levels were measured at 3h intervals throughout the 4 day estrous cycle in female rats and hourly between 1000 and 2400 h of proestrus. On proestrus, serum inhibin concentrations fell during the late morning-early afternoon, then increased transiently during the late afternoon gonadotropin surges. Inhibin levels decreased during the late evening of proestrus, coincident with the FSH surge-related rise in FSH beta mRNA levels. Serum inhibin remained relatively stable during estrus and early metestrus, but rose during the late evening of metestrus and remained elevated until early diestrus. FSH beta mRNA levels were elevated on late estrus and early metestrus and declined during the evening of metestrus as serum inhibin levels increased. These data show that concentrations of serum inhibin change during the estrous cycle and that a general inverse relationship exists between serum inhibin and FSH levels and FSH beta mRNA concentrations in the pituitary. This suggests that inhibin may inhibit FSH beta gene expression and FSH secretion during the 4 day cycle in female rats.


Association between smoking and postoperative delirium in surgical patients with pulmonary hypertension: a secondary analysis of a cohort study.
Previous studies have declared that smoking was a risk factor for postoperative delirium (POD), but others have inconsistent results. Up till now, the association between smoking and POD has not been verified. This study investigates the relationship between smoking and POD in patients with pulmonary hypertension (PHTN) in the United States. Patients with PHTN who underwent non-cardiac, non-obstetric surgery were enrolled in the original research completed by Aalap C. et al. We further excluded the patients undergoing intracranial surgery and the patients with sepsis and perioperative stroke to avoid interference with POD assessment. The generalized linear model and generalized additive model were used to explore the relationship between smoking and POD. The propensity score adjustment was used for sensitivity analyses. Five hundred thirty-nine patients were included in this study. The overall incidence of POD was 3.0% (16/539). After adjusting the potential confounders (age, systemic hypertension, coronary artery disease, COPD, length of surgery, intrathoracic surgery, vascular surgery), a positive relationship was found between smoking status and POD (OR = 4.53, 95% CI: 1.22 to 16.86, P = 0.0243). In addition, the curvilinear relationship between smoking burden (pack-years) and POD is close to a linear relationship. Smoking probably shows a positive correlation with POD in patients with PHTN.


Integrative review of school integration support following pediatric cancer.
This study aims to understand parents' experiences of school integration support for their child's transition to K-12 schooling during or after cancer treatment. This integrative literature review used PubMed, CINAHL, PsycINFO, and Embase databases and included articles from January 2000 to July 2022 describing parent experiences with support from healthcare providers, school faculty/systems, and school integration programs. This review was guided by an adapted School Re-Entry Model and used constant comparison to identify common themes and guide synthesis. The Johns Hopkins Evidence and Quality Guide was used to appraise article quality and level of evidence. Thirty-five articles were included in the final review: seventeen qualitative, fourteen quantitative, and four mixed or multi-method designs. Parents reported experiences receiving support from healthcare providers, school faculty/systems, school integration programs, and "other" sources. Parents reported both facilitators and barriers to communication, knowledge, and the process of receiving school integration support. Parents found neuro/psychologists highly supportive but reported limited support from other healthcare providers. Most parents reported mixed experiences with school faculty and reported many barriers to school system support. Parents reported positive experiences with school integration programs; however, limited programs were available. Future programs and research should focus on addressing identified barriers and facilitators of school integration support. Further work is also needed to understand a wider range of parent experiences during school integration.


A comparison of opioid prescription trends in England and the United States from 2008 to 2020.
The prescription opioid epidemic in the United States (US) is well documented, and recent measures have reduced prescribing rates in that country. Evidence suggests opioid prescriptions have been rising recently in other countries too. The current paper aimed to compare trends in opioid prescribing in England and the US. Trends in rates of prescriptions per 100 members of the population were calculated for England and the US using publicly available government data on prescriptions and population statistics. Rates of prescribing are converging. At the peak of the US epidemic in 2012, there were 81.3 prescriptions per 100 people, but this had fallen to 43.3 by 2020. Prescribing peaked in England in 2016 at 43.2 prescriptions per 100 people, but has fallen only slightly, so that in 2020 there were 40.9 prescriptions per 100 people. The data indicate that levels of opioid prescribing in England are now similar to those in the US. They remain high in both countries, despite recent falls. This suggests the need for further measures to prevent over-prescribing and to support people who would benefit from withdrawing from these drugs.


Noise-tolerant similarity search in temporal medical data.
Temporal medical data are increasingly integrated into the development of data-driven methods to deliver better healthcare. Searching such data for patterns can improve the detection of disease cases and facilitate the design of preemptive interventions. For example, specific temporal patterns could be used to recognize low-prevalence diseases, which are often under-diagnosed. However, searching these patterns in temporal medical data is challenging, as the data are often noisy, complex, and large in scale. In this work, we propose an effective and efficient solution to search for patients who exhibit conditions that resemble the input query. In our solution, we propose a similarity notion based on the Longest Common Subsequence (LCSS), which is used to measure the similarity between the query and the patient's temporal medical data and to ensure robustness against noise in the data. Our solution adopts locality sensitive hashing techniques to address the high dimensionality of medical data, by embedding the recorded clinical events (e.g., medications and diagnosis codes) into compact signatures. To perform pattern search in large EHR datasets, we propose a filtering approach based on tandem patterns, which effectively identifies candidate matches while discarding irrelevant data. The evaluations conducted using a real-world dataset demonstrate that our solution is highly accurate while significantly accelerating the similarity search.


DNA methylation changes in prostate cancer.
Epigenetic alterations contribute significantly to the development and progression of prostate cancer, the most prevalent malignant tumor in males of Western industrialized countries. Here, we review recent research on DNA methylation alterations in this cancer type. Hypermethylation of several genes including GSTP1 is well known to occur in a consistent and apparently coordinate fashion during the transition from intraepithelial neoplasia to frank carcinoma. These hypermethylation events have shown promise as biomarkers for detection of prostate carcinoma. Many other individual genes have been shown to undergo hypermethylation, which is typically associated with diminished expression. These investigations indicate additional candidates for biomarkers; in particular, hypermethylation events associated with progression can be employed to identify more aggressive cases. In addition, some of genes silenced by aberrant methylation in prostate have been shown to exhibit properties of tumor suppressors, revealing insights into mechanisms of carcinogenesis. Whereas most studies in the past have used candidate gene approaches, new techniques allowing genome-wide screening for altered methylation are increasingly employed in prostate cancer research and have already yielded encouraging results.


On-line sources of toxicological information in Canada.
This paper will provide an overview of the on-line resources available in toxicology in Canada. It will describe a brief history of The Society of Toxicology of Canada, with reference to other societies and also provide information on education, research and other resources related to toxicology. Toxicology in Canada emerged as a distinct and vibrant discipline following the thalidomide tragedy of the 1960s. In the pharmaceutical industry and government, toxicology was readily established as an essential component of drug development and safety, and as the need for toxicologists expanded, training programs were established, usually in collaboration with departments of pharmacology. In the last two to three decades other disciplines, environmental biology, analytical chemistry and epidemiology joined the ranks of toxicology. The on-line sources of toxicology information are rapidly expanding. This article describes those sources considered by the authors to be important from a national and international perspective. The majority of these sources are professional organizations and government agencies.


Responding to Domestic and Family Violence: A Qualitative Study on the Changing Perceptions of Frontline Police Officers.
Police officers gave accounts of how their perceptions toward Domestic and Family Violence have changed over repeated exposure to these types of incidents as first responders. Interviews were conducted with 16 police officers in an Australian state. Officers expressed a desire to help people and reported personal growth through increased interpersonal skills and open-mindedness but many also became disillusioned. Officers highlighted futility, paperwork, and scrutiny of their actions as factors that inhibited their ability to cope. The findings imply that although officers' competence may increase, their well-being and capacity to do their job effectively and compassionately may become impaired.


Non-immunological recognition and killing of xenogeneic cells by macrophages. III. Destruction of fish cells by murine macrophages.
Non-immune non-activated murine peritoneal macrophage killed in vitro fish (Cyprinus carpio) PHA-induced lymphoblasts. Addition of PHA and WGA to effector-target cell cultures did not potentiate the killing. This killing (xenolysis) was expressed by non-elicited and thioglycollate-elicited macrophages as well as by macrophages depleted of lymphocytes. It is suggested that mammalian macrophages have a xenolytic potential towards phylogenetically distant species which is analogous to the capacity of invertebrate phagocytes to destroy xenografts.


Excretion time courses of lambda-cyhalothrin metabolites in the urine of strawberry farmworkers and effect of coexposure with captan.
There are limited literature data on the impact of coexposure on the toxicokinetics of pesticides in agricultural workers. Using the largely employed pyrethroid lambda-cyhalothrin (LCT) and fungicide captan as sentinel pesticides, we compared individual temporal profiles of biomarkers of exposure to LCT in strawberry field workers following an application episode of LCT alone or in coexposure with captan. Participants provided all urine voided over a 3-day period after an application of a pesticide formulation containing LCT alone (E1) or LCT mixed with captan (E2), and in some cases following re-entry in treated field (E3). Pyrethroid metabolites were measured in all urine samples, in particular 3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethyl-cyclopropanecarboxylic acid (CFMP), 3-phenoxybenzoic acid (3-PBA), and 4-hydroxy-3-phenoxybenzoic acid (4-OH3PBA). There were no obvious differences in individual concentration-time profiles and cumulative excretion of metabolites (CFMP, 3-PBA, 4-OH3BPA) after exposure to LCT alone or in combination with captan. For most workers and exposure scenarios, CFMP was the main metabolite excreted, but time courses of CFMP in urine did not always follow that of 3-PBA and 4-OH3BPA. Given that the latter metabolites are common to other pyrethroids, this suggests that some workers were coexposed to pyrethroids other than LCT. For several workers and exposure scenarios E1 and E2, values of CFMP increased in the hours following spraying. However, for many pesticide operators, other peaks of CFMP were observed at later times, indicating that tasks other than spraying of LCT-containing formulations contributed to this increased exposure. These tasks were mainly handling/cleaning of equipment used for spraying (tractor or sprayer) or work/inspection in LCT-treated field according to questionnaire responses. Overall, this study provided novel excretion time course data for LCT metabolites valuable for interpretation of biomonitoring data in workers, but also showed that coexposure was not a major determinant of variability in exposure biomarker levels. Our analysis also pointed out the importance of measuring specific metabolites.


Evaluation of the sensitivity of Aedes aegypti and Anopheles gambiae complex mosquitoes to two insect repellents: DEET and KBR 3023.
We conducted laboratory tests to assess the sensitivity to the insect repellent 1-piperidinecarboxylic acid, 2-(2-hydroxyethyl)-, 1-methylpropylester (known as KBR 3023 or Picaridin, trade name Bayrepel) of West African strains of the yellow fever mosquito Aedes aegypti and of malaria vectors of the Anopheles gambiae complex, in comparison with the standard repellent N,N-diethyl-3-methyl-benzamide (DEET). Test mosquitoes were exposed according to a 'separate arms' protocol to logarithmic dose increments applied on one arm of human subjects to evaluate the relative potency, and the median effective dosages (ED50 and ED90). According to a logistic regression model fitted to the experimental data, the dose-response relationship for the two repellents was the same within each species, thus pooled ED values were assessed for each mosquito separately. The median ED of KBR 3023 and DEET was estimated at 0.78 (95% confidence limits (CI): 0.57-1.04) and at 0.018 microg/cm2 (0.004-0.052) for mosquitoes of the An. gambiae complex and Ae. aegypti, respectively. ED90 values were 125.6 (81.4-201.3) and 24.0 microg/cm2 (5.7-208.5) for An. gambiae s.l. and Ae. aegypti, respectively. The relative potency of KBR 3023 was not significantly different from that of DEET for An. gambiae s.l. (95% confidence limits 0.7-1.0), whereas in the case of Ae. aegypti it was with 95% probability 1.1-2.0 times more potent than DEET. On the basis of available evidence, KBR 3023 represents a promising alternative to DEET for personal protection against bites of these important vectors of disease in the Afrotropical region.


Mutation spectrum leading to an attenuated phenotype in dystrophinopathies.
Although Becker muscular dystrophy (BMD; MIM 300376) is mainly caused by gross deletions of the dystrophin gene, the nature of the mutations involved in the remaining cases is of importance because of the milder clinical course of Becker. We have extensively characterized the mRNA changes associated with five novel point mutations giving rise to a Becker phenotype, which confirm that Becker arises largely due to alterations in splicing. In two cases the milder phenotype arises because of exon skipping, leading to an in-frame deletion (c.1603-2A>C and c.4250T>A). In further two cases intronic mutations (c.4519-5C>G and c.961-5925A>C) result in complex splicing changes, but with some residual normal transcripts. The last case, c.10412T>A (p.Leu3471X), results in a truncated transcript missing only part of the COOH terminal of the protein, suggesting that this region is not crucial for dystrophin function. The detection of a low amount of dystrophin in this patient could be attributable to a reduced efficiency of nonsense-mediated decay. The results emphasize that mRNA analysis is important in defining Becker mutations and will be of value in assessing various gene therapy strategies.


Oliver-McFarlane syndrome in a chinese boy: retinitis pigmentosa, trichomegaly, hair anomalies and mental retardation.
We report a male patient with retinitis pigmentosa, growth failure, long eyelashes, and sparse hair, which are typical signs of Oliver-McFarlane syndrome. The patient was born to healthy parents and developed night blindness at 2 years of age. Retinitis pigmentosa was diagnosed when he was 5 years old. To date, only 11 cases of Oliver-McFarlane syndrome have been documented, with the present case being the 12th overall and the first in China. Thus, the existence of typical Oliver-McFarlane syndrome in Asians was verified.


Synthesis, characterization and fabrication of sodium carboxymethyl-okra-gum-grafted-polymethacrylamide into sustained release tablet matrix.
The objective of the present study was to modify okra gum (Abelmoschus esculentus) by carboxymethylation and subsequent graft-copolymerization, characterize and fabricate into sustained-release tablet matrix. Firstly, okra gum was carboxymethylated using sodium hydroxide and monochloroacetic acid followed by grafting with polymethacrylamide employing synergistic combination of free-radical-initiator and microwave-irradiation. The FTIR, NMR, elemental analysis and viscosity study corroborate the formation of sodium-carboxymethyl-okra gum-grafted-polymethacrylamide copolymer (SCMOG-g-PMA). The maximum degree of carboxymethyl-substitution (DCS) and % grafting (%G) were found to be 0.604 ± 0.011 and 644.1, respectively. Water-uptake-capacity was found to increase by 3.5 fold. The tablet formulation of diclofenac sodium with SCMOG-g-PMA (DCS 0.604 and 423.4% G) showed to exhibit excellent sustained-release capacity with 90% drug-release at 11.7 h and similarity-factor of 72.0. The toxicity and biodegradability study also exhibited the bio-compatible and biodegradable nature of the copolymer, which might make the copolymer suitable for sustained-release drug delivery systems as smart semi-synthetic biopolymer.


Response of lumbar spinocervical tract cells to natural and electrical stimulation of the hindlimb footpads in cats.
Extracellular and intracellular recordings were made from antidromically identified spinocervical tract (SCT) cells in the medial part of the lumbosacral dorsal horn in anesthetized cats. The low threshold mechanoreceptive fields (RFs) of 18 cells were mapped during extracellular recording, and for 15 the RF included an area of glabrous skin. Intracellular recordings were made from 6 of these during electrical microstimulation of glabrous skin and all showed excitatory postsynaptic potentials at latencies consistent with conduction over group II primary afferent fibers. The distance from the medial border of the dorsal horn of the recording loci of 12 cells, 4 of which were injected with horseradish peroxidase, was measured. It is concluded that some medially situated SCT cells receive excitatory input from low threshold group II primary afferent fibers from glabrous skin.


Is high potassium solution necessary for reinfusions in "multidose" cold cardioplegia? A randomized prospective study using computerized Holter system.
Multidose potassium cardioplegia is a common method of myocardial preservation. Although initial potassium arrest conserves high-energy phosphates, there is conflicting evidence that repeat high potassium boluses augment this protection. Fifty-six patients were prospectively randomized to receive multidose cold high potassium cardioplegia (27 mEq of KCl/L) both in the initial and subsequent infusions (Group 1) or an initial cold high potassium (27 mEq/L) cardioplegia followed by boluses of cold low potassium (7 mEq, of KCl/L) solution (Group 2). The two groups were compared in terms of postoperative myocardial electrical stability and hemodynamic performance. Electrocardiograms were recorded by continuous Holter monitor, and the data were analyzed by computer. The duration of aortic cross-clamping and cardiopulmonary bypass did not differ between groups. Group 1, who received more total KCl than Group 2 (p less than .005), experienced more high-grade ventricular ectopia during both reperfusion (p less than .001) and the immediate postoperative period (p less than .001), and required more lidocaine hydrochloride (p less than .001) for arrhythmias. There was no significant difference in hemodynamic performance between the two groups. This study fails to show an advantage to multidose "high potassium" cardioplegia and found a significant increase in ventricular ectopia associated with its use. We advocate using low potassium solutions after initial cold high potassium arrest.


Five myofibrillar lesion types in eccentrically challenged, unloaded rat adductor longus muscle--a test model.
Sarcomere disruptions are observed in the adductor longus (AL) muscles following voluntary reloading of spaceflown and hindlimb suspension unloaded (HSU) rat, which resemble lesions in eccentrically challenged muscle. We devised and tested an eccentric contraction (ECCON) test system for the 14-day HSU rat AL. Six to 7 hours following ECCON, ALs were fixed to allow immunostaining and electron microscopy (EM). Toluidine blue-stained histology semithin sections were screened for lesion density (#/mm2). Serial semithin sections from the ECCON group were characterized for myosin immunointensity of lesions. Five myofibrillar lesion types were identified in histological semithin sections: focal contractions; wide A-bands; opaque areas; missing A-bands; and hyperstretched sarcomeres. Lesion density by type was greater for ECCON than NonECCON ALs (P< or =0.05; focal contractions and opaque regions). Lesion density (#-of-all-five-types/mm2) was significantly different (ECCON: 23.91+/-10.58 vs. NonECCON: 5.48+/-1.28, P< or =0.05; ECCON vs. SHAM: 0.00+/-0.00; P< or = 0.025). PostECCON optimal tension decreased (Poi-drop, 17.84+/-4.22%) and was correlated to lesion density (R2=0.596), but prestretch tension demonstrated the highest correlation with lesion density (R2=0.994). In lesions, the darkly staining A-band lost the normally organized thick filament alignment to differing degrees across the different lesion types. Ranking the five lesion types by a measure of lesion length deformation (hypercontracted to hyperstretched) at the light microscopy level, related to the severity of thick filament registry loss across the lesion types at the electron microscopic level. This ranking suggested that the five lesion types seen in semithin sections at the light level represented a lesion progression sequence and paralleled myosin immunostaining loss as the distorted A-band filaments spread across the hyperlengthening lesion types. Lesion ultrastructure indicated damage involved calcium homeostasis loss (focal contraction lesions) and "thick-filament-centering" failure of titin (wide A-band lesions) in the early stages of lesion development.


The role of the membrane-bound iron-sulphur centres A and B in the photosystem I reaction centre of spinach chloroplasts.
Photosystem I particles prepared from spinach chloroplast using Triton X-100 were frozen in the dark with the bound iron-sulphur Centre A reduced. Illumination at cryogenic temperatures of such samples demonstrated the photoreduction of the second bound iron-sulphur Centre B. Due to electron spin-electron spin interaction between these two bound iron-sulphur centres, it was not possible to quantify amounts of Centre B relative to the other components of the Photosystem I reaction centre by simulating the line-shape of its EPR spectrum. However, by deleting the free radical signal I from the EPR spectra of reduced Centre A alone or both Centres A plus B reduced, it was possible to double integrate these spectra to demonstrate that Centre B is present in the Photosystem I reaction centre in amounts comparable to those of Centre A and thus also signal I (P-700) and X. Oxidation-reduction potential titrations confirmed that Centre A had Em congruent to -550 mV, Centre B had Em congruent to -585 mV. These results, and those presented for the photoreduction of Centre B, place Centre B before Centre A in the sequence of electron transport in Photosystem I particles at cryogenic temperatures. When both A and B are reduced, P-700 photooxidation is reversible at low temperature and coupled to the reduction of the component X. The change from irreversible to reversible P-700 photooxidation and the photoreduction of X showed the same potential dependence as the reduction of Centre B with Em congruent to -585 mV, substantiating the identification of X as the primary electron acceptor of Photosystem I.


Bioinspired copper single-atom nanozyme as a superoxide dismutase-like antioxidant for sepsis treatment.
Sepsis is a systemic inflammatory response syndrome with high morbidity and mortality mediated by infection-caused oxidative stress. Early antioxidant intervention by removing excessively produced reactive oxygen and nitrogen species (RONS) is beneficial to the prevention and treatment of sepsis. However, traditional antioxidants have failed to improve patient outcomes due to insufficient activity and sustainability. Herein, by mimicking the electronic and structural characteristics of natural Cu-only superoxide dismutase (SOD5), a single-atom nanozyme (SAzyme) featuring coordinately unsaturated and atomically dispersed Cu-N4 site was synthesized for effective sepsis treatment. The de novo-designed Cu-SAzyme exhibits a superior SOD-like activity to efficiently eliminate O2 •-, which is the source of multiple RONS, thus blocking the free radical chain reaction and subsequent inflammatory response in the early stage of sepsis. Moreover, the Cu-SAzyme effectively harnessed systemic inflammation and multi-organ injuries in sepsis animal models. These findings indicate that the developed Cu-SAzyme possesses great potential as therapeutic nanomedicines for the treatment of sepsis.


An Epidermal-Specific Role for Arginase1 during Cutaneous Wound Repair.
Nonhealing wounds are a major area of unmet clinical need remaining problematic to treat. Improved understanding of prohealing mechanisms is invaluable. The enzyme arginase1 (ARG1) is involved in prohealing responses, with its role in macrophages best characterized. ARG1 is also expressed by keratinocytes; however, ARG1 function in these critical wound repair cells is not understood. We characterized ARG1 expression in keratinocytes during normal cutaneous repair and reveal de novo temporal and spatial expression at the epidermal wound edge. Interestingly, epidermal ARG1 expression was decreased in both human and murine delayed healing wounds. We therefore generated a keratinocyte-specific ARG1-null mouse model (K14-cre;Arg1fl/fl) to explore arginase function. Wound repair, linked to changes in keratinocyte proliferation, migration, and differentiation, was significantly delayed in K14-cre;Arg1fl/fl mice. Similarly, using the arginase inhibitor N(omega)-hydroxy-nor-L-arginine, human in vitro and ex vivo models further confirmed this finding, revealing the importance of the downstream polyamine pathway in repair. Indeed, restoring the balance in ARG1 activity through the addition of putrescine proved beneficial in wound closure. In summary, we show that epidermal ARG1 plays, to our knowledge, a previously unreported intrinsic role in cutaneous healing, highlighting epidermal ARG1 and the downstream mediators as potential targets for the therapeutic modulation of wound repair.


Undescribed abietane-type diterpenoids and oleanane-type triterpenoids from the stem and branch of Tripterygium wilfordii.
Six undescribed abietane-type diterpenoids (tripterydinoids A-F) and five undescribed oleanane-type triterpenoids (tripterytrinoids A-E) were obtained and determined from the stem and branch of Tripterygium wilfordii Hook. f. (Celastraceae). Tripterydinoids A-C possessed the abietane-type diterpenoid skeleton with rare 8, 9-epoxy ring. The structures of undescribed compounds were established by extensive spectroscopic studies [HRESIMS, 1D/2D-NMR and electronic circular dichroism (ECD) calculation]. The absolute configurations of tripterydinoids A, B, E and tripterytrinoid A were defined by X-ray crystallographic analyses. Bioactivity screening indicated that tripterydinoids A-C exhibited potent inhibitory effects against NO release in LPS-activated RAW 264.7 macrophages with IC50 values of 6.93, 4.46 and 2.98 μM, respectively. Meanwhile, tripterydinoids A-D and tripterytrinoids B, C showed moderate and selective cytotoxicities against five human tumor cell lines (A375, Huh7, MCF-7, HCT-116 and NCI-H460).


Mutations suppressing the effects of a deletion of the phosphoglucose isomerase gene PGI1 in Saccharomyces cerevisiae.
A mutant with a deletion covering the phosphoglucose isomerase gene PGI1, allele pgil delta, can only grow on a medium containing fructose and low concentrations of glucose whereas growth is completely inhibited by glucose concentrations higher than 0.4%. This was used to select suppressor mutants restoring growth on synthetic media with 2% glucose as the sole carbon source. One complementation group, SPG1, was defined by recessive mutations. The ability to grow on glucose media was strictly dependent on functional mitochondria. The generation time of the selected mutants on YEP glucose was 6-8 h. No ethanol was formed from glucose and the levels of respiration were very high. These phenotypes were also observed in single pgil delta mutants when growing on fructose media supplemented with 0.4% glucose. The other glycolytic enzymes, the enzymes of the glucose-6-phosphate oxidation pathway as well as catabolite repression were normal in suppressed pgil delta mutants. The suppressor mutation alone caused no abnormal phenotype. The results suggest that the spg1 suppressor mutations allow S. cerevisiae pgil delta mutant strains to grow on glucose by using the Pentose-P cycle in combination with unusual strong respiration.


Inhibition of experimental autoimmune uveoretinitis in rats by S-antigen-specific monoclonal antibodies.
Mouse monoclonal antibodies (mAb), of either IgG2a or IgG2b isotypes, specific for the retinal S-autoantigen (S-Ag) or a pool of rat anti-S-Ag sera prevented experimental autoimmune uveoretinitis in Lewis rats when injected i.p. at the time of immunization. Control mAb of the same isotypes, irrelevant to S-Ag, had no inhibitory effect. The humoral response to S-Ag, as studied by enzyme-linked immunosorbent assay using a mouse mAb specific for rat kappa chain, was moderately but significantly reduced in suppressed animals. The rapid disappearance of the injected mAb from rat sera, as measured using a rat mAb specific for mouse kappa chain, could be explained by its complexing with either autologous antigen released from the retina at the site of inflammation, or anti-idiotypic antibodies.


Aorto-right atrial fistula following transseptal catheterization and catheter ablation for atrial fibrillation.
Aorto-cameral fistula, either congenital or acquired, is an abnormal connection between the ascending aortic root and one of the cardiac chambers. We report a case of a 61-year-old male with history of atrial fibrillation and 2 radiofrequency ablation procedures, referred to us for surgical Cox Maze procedure. Preoperative cardiac computerized tomography revealed a fistulous connection between the aortic root and the right atrium. Later, the patient underwent successful surgical closure of the fistula during the Cox Maze procedure. In this paper, we also discuss the clinical presentation, natural history, anatomy of the interatrial septum, and management of aorto-cameral fistula.


Clinical and laboratory findings in childhood mixed connective tissue disease: presence of antibody to ribonucleoprotein containing the small nuclear ribonucleic acid U1.
Seven children and adolescents are described with mixed connective tissue disease. The patients had varying clinical features, commonly characterized by Raynaud phenomenon, arthritis, abnormal pulmonary function, and esophageal dysmotility. All patients had speckled antinuclear antibodies and high titers (greater than 1:100,000) of antibodies to ribonuclease-sensitive extractable nuclear antigen. We prepared extractable nuclear material from radioactively labeled HeLa cells, analogous to classic extractable nuclear antigen. Sera from all seven patients precipitated ribonucleoprotein containing the small nuclear ribonucleic acid species U1 from the HeLa cell extract. Antibody to U1 ribonucleoprotein was not found in sera from 51 of 53 children and adults having a variety of autoimmune and other diseases, nor in sera from nine normal individuals. The U1 ribonucleoprotein appears to be the component of extractable nuclear antigen characteristically reacting with sera from patients with mixed connective tissue disease. The finding of a distinct molecular marker in all children studied with mixed connective tissue disease indicates that this is a distinct disease entity and not a heterogeneous population of immune disorders.


Comprehensive characterisation of hypertensive heart disease left ventricular phenotypes.
Myocardial intracellular/extracellular structure and aortic function were assessed among hypertensive left ventricular (LV) phenotypes using cardiovascular magnetic resonance (CMR). An observational study from consecutive tertiary hypertension clinic patients referred for CMR (1.5 T) was performed. Four LV phenotypes were defined: (1) normal with normal indexed LV mass (LVM) and LVM to volume ratio (M/V), (2) concentric remodelling with normal LVM but elevated M/V, (3) concentric LV hypertrophy (LVH) with elevated LVM but normal indexed end-diastolic volume (EDV) or (4) eccentric LVH with elevated LVM and EDV. Extracellular volume fraction was measured using T1-mapping. Circumferential strain was calculated by voxel-tracking. Aortic distensibility was derived from high-resolution aortic cines and contemporaneous blood pressure measurements. 88 hypertensive patients (49±14 years, 57% men, systolic blood pressure (SBP): 167±30 mm Hg, diastolic blood pressure (DBP): 96±14 mm Hg) were compared with 29 age-matched/sex-matched controls (47±14 years, 59% men, SBP: 128±12 mm Hg, DBP: 79±10 mm Hg). LVH resulted from increased myocardial cell volume (eccentric LVH: 78±19 mL/m(2) vs concentric LVH: 73±15 mL/m(2) vs concentric remodelling: 55±9 mL/m(2), p<0.05, respectively) and interstitial fibrosis (eccentric LVH: 33±10 mL/m(2) vs concentric LVH: 30±10 mL/m(2) vs concentricremodelling: 19±2 mL/m(2), p<0.05, respectively). LVH had worst circumferential impairment (eccentric LVH: -12.8±4.6% vs concentric LVH: -15.5±3.1% vs concentric remodelling: -17.1±3.2%, p<0.05, respectively). Concentric remodelling was associated with reduced aortic distensibility, but not with large intracellular/interstitial expansion or myocardial dysfunction versus controls. Myocardial interstitial fibrosis varies across hypertensive LV phenotypes with functional consequences. Eccentric LVH has the most fibrosis and systolic impairment. Concentric remodelling is only associated with abnormal aortic function. Understanding these differences may help tailor future antihypertensive treatments.


Outcome of fetal talipes following in utero sonographic diagnosis.
To examine the association between fetal talipes and other defects, and outcome in relation to postnatal surgery. All cases of talipes presenting to the fetal medicine unit between 1993 and 1998 and cases of isolated talipes presenting to the ultrasound department between 1991 and 1998 were examined. The infants were followed-up to determine the number of cases that had structural or positional talipes and the number of cases requiring surgery. There were 76 cases, 59 of which attended the fetal medicine unit and 17 the ultrasound department. Postnatal follow-up details were available in 31 of the 40 live births. There were three neonates with unilateral talipes at birth who were thought to have bilateral talipes on prenatal ultrasound and one neonate had bilateral talipes at birth who had been thought to have unilateral talipes prenatally. In two (6.4%) neonates in whom talipes was not confirmed at birth the abnormality was diagnosed prenatally. Of the 29 neonates with confirmed talipes at birth, the defect was structural in 26 (90%) cases and positional in three. Surgery was necessary in 21 (72%) of the 29 cases and 18 (86%) of those undergoing surgery required only one operation. When live births with associated anomalies were excluded, there were 24 cases with confirmed isolated talipes and 18 (75%) required surgery. This study provides long-term outcome data which can be used to complement current prenatal counseling and shows that in cases of fetal talipes diagnosed prenatally, 90% have a structural rather than a positional deformity. For isolated talipes three quarters of children will require surgery and in the majority of cases only one operation on the foot is necessary. Parents should be made aware of the small possibility of a false-positive diagnosis and discrepancy between the ultrasound and postnatal diagnoses of laterality.


Job insecurity and incident coronary heart disease: the Whitehall II prospective cohort study.
This study uses a prospective design to examine the association between self-reported job insecurity and incident coronary heart disease; an association which has been little investigated previously. Participants were 4174 British civil servants (1236 women and 2938 men), aged 42 to 56 with self-reported data on job insecurity and free from coronary heart disease at baseline (1995-6). These participants were followed until 2002-4, an average of 8.6 years, for incident fatal coronary heart disease, clinically verified incident non-fatal myocardial infarction, or definite angina (a total of 168 events). Cox proportional hazard models adjusted for socio-demographic characteristics showed job insecurity to be associated with a 1.42-fold (95% CI, 1.05-1.93) risk of incident coronary heart disease compared with secure employment. Adjustment for physiological and behavioral cardiovascular risk factors had little effect on this estimate; 1.38 (1.01-1.88). This study suggests that job insecurity may adversely affect coronary health.


Mitochondrial diseases.
Mitochondrial disorders represent a major challenge in medicine. Most of the mitochondrial proteins are encoded by the nuclear DNA (nDNA), whereas a very small fraction is encoded by the mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction. The disease usually affects multiple organs in varying locations and severity; however, there are some forms which affect a single organ. The diagnosis of mitochondrial disorders is based on clinical examination, biochemical and histopathologic examinations, functional studies, and molecular genetic testing. Neuropathologic alterations of the muscle are variable and can range from striking abnormalities, such as cytochrome oxidase-negative and ragged red fibers, to nonspecific or minimal changes. Neuropathologic alterations in the brain show common features in disorders with different genetic background. These are characterized by various degrees of vacuolation in the white and gray matter, regional neurodegeneration with reactive astrogliosis, loss of oligodendrocytes, presence of macrophages and microgliosis, capillary proliferation, and mineralization of vessel walls. The advent of molecular genetics, the discovery of biomarkers and new sequencing platforms to perform targeted exome and whole-genome sequencing have changed traditional approaches to diagnose mitochondrial diseases.


Optimization of cyclodextrin glucanotransferase production from Bacillus clausii E16 in submerged fermentation using response surface methodology.
Cyclodextrin glucanotransferase production from Bacillus clausii E16, a new bacteria isolated from Brazilian soil samples was optimized in shake-flask cultures. A 2(4) full-factorial central composite design was performed to optimize the culture conditions, using a response surface methodology. The combined effect among the soluble starch concentration, the peptone concentration, the yeast extract concentration, and the initial pH value of the culture medium was investigated. The optimum concentrations of the components, determined by a 2(4) full-factorial central composite design, were 13.4 g/L soluble starch, 4.9 g/L peptone, 5.9 g/L yeast extract, and initial pH 10.1. Under these optimized conditions, the maximum cyclodextrin glucanotransferase activity was 5.9 U/mL after a 48-h fermentation. This yield was 68% higher than that obtained when the microorganism was cultivated in basal culture medium.


Association of Participation in the American Board of Physical Medicine and Rehabilitation Maintenance of Certification Program and Physician Disciplinary Actions.
The study analyzed the relationship between participation in the American Board of Physical Medicine and Rehabilitation maintenance of certification program and the incidence of disciplinary actions by state medical boards over a physician's career. The hypothesis is that physicians who do not maintain their board certification have a higher likelihood of state medical board disciplinary actions. This retrospective cohort study analyzed American Board of Physical Medicine and Rehabilitation maintenance of certification data from all board-certified physiatrists who were enrolled in the American Board of Physical Medicine and Rehabilitation maintenance of certification program from 1993 to 2007. Matching examination and license data were available for 4794 physicians, who received a total of 212 disciplinary action reports through the Federation of State Medical Boards. The results showed that physicians who have a lapse in completing the American Board of Physical Medicine and Rehabilitation maintenance of certification program have a 2.5-fold higher incidence of receiving a disciplinary action report through the Federation of State Medical Boards (95% confidence interval = 1.76-3.63) and had higher severity violations (χ = 7.14, P < 0.05) than physicians whose certificate never lapsed. For physicians in physical medicine and rehabilitation, loss of board certification through failure to fulfill the maintenance of certification program requirements is associated with an increased risk of disciplinary action from a state medical licensing board.


Secondary use of data extracted from a clinical information system to assess the adherence of tidal volume and its impact on outcomes.
To extract data from clinical information systems to automatically calculate high-resolution quality indicators to assess adherence to recommendations for low tidal volume. We devised two indicators: the percentage of time under mechanical ventilation with excessive tidal volume (>8mL/kg predicted body weight) and the percentage of patients who received appropriate tidal volume (≤8mL/kg PBW) at least 80% of the time under mechanical ventilation. We developed an algorithm to automatically calculate these indicators from clinical information system data and analyzed associations between them and patients' characteristics and outcomes. This study has been carried out in our 30-bed polyvalent intensive care unit between January 1, 2014 and November 30, 2019. All patients admitted to intensive care unit ventilated >72h were included. Use data collected automatically from the clinical information systems to assess adherence to tidal volume recommendations and its outcomes. Mechanical ventilation days, ICU length of stay and mortality. Of all admitted patients, 340 met the inclusion criteria. Median percentage of time under mechanical ventilation with excessive tidal volume was 70% (23%-93%); only 22.3% of patients received appropriate tidal volume at least 80% of the time. Receiving appropriate tidal volume was associated with shorter duration of mechanical ventilation and intensive care unit stay. Patients receiving appropriate tidal volume were mostly male, younger, taller, and less severely ill. Adjusted intensive care unit mortality did not differ according to percentage of time with excessive tidal volume or to receiving appropriate tidal volume at least 80% of the time. Automatic calculation of process-of-care indicators from clinical information systems high-resolution data can provide an accurate and continuous measure of adherence to recommendations. Adherence to tidal volume recommendations was associated with shorter duration of mechanical ventilation and intensive care unit stay.


Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma.
High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology.


A new amino acid substitution (Ala-205-Phe) in acetolactate synthase (ALS) confers broad spectrum resistance to ALS-inhibiting herbicides.
This is a first report of an Ala-205-Phe substitution in acetolactate synthase conferring resistance to imidazolinone, sulfonylurea, triazolopyrimidines, sulfonylamino-carbonyl-triazolinones, and pyrimidinyl (thio) benzoate herbicides. Resistance to acetolactate synthase (ALS) and photosystem II inhibiting herbicides was confirmed in a population of allotetraploid annual bluegrass (Poa annua L.; POAAN-R3) selected from golf course turf in Tennessee. Genetic sequencing revealed that seven of eight POAAN-R3 plants had a point mutation in the psbA gene resulting in a known Ser-264-Gly substitution on the D1 protein. Whole plant testing confirmed that this substitution conferred resistance to simazine in POAAN-R3. Two homeologous forms of the ALS gene (ALSa and ALSb) were detected and expressed in all POAAN-R3 plants sequenced. The seven plants possessing the Ser-264-Gly mutation conferring resistance to simazine also had a homozygous Ala-205-Phe substitution on ALSb, caused by two nucleic acid substitutions in one codon. In vitro ALS activity assays with recombinant protein and whole plant testing confirmed that this Ala-205-Phe substitution conferred resistance to imidazolinone, sulfonylurea, triazolopyrimidines, sulfonylamino-carbonyl- triazolinones, and pyrimidinyl (thio) benzoate herbicides. This is the first report of Ala-205-Phe mutation conferring wide spectrum resistance to ALS inhibiting herbicides.


Extracellular matrix composition alters endothelial force transmission.
Extracellular matrix (ECM) composition is important in a host of pathophysiological processes such as angiogenesis, atherosclerosis, and diabetes, and during each of these processes ECM composition has been reported to change over time. However, the impact ECM composition has on the ability of endothelium to respond mechanically is currently unknown. Therefore, in this study, we seeded human umbilical vein endothelial cells (HUVECs) onto soft hydrogels coated with an ECM concentration of 0.1 mg/mL at the following collagen I (Col-I) and fibronectin (FN) ratios: 100% Col-I, 75% Col-I-25% FN, 50% Col-I-50% FN, 25% Col-I-75% FN, and 100% FN. We subsequently measured tractions, intercellular stresses, strain energy, cell morphology, and cell velocity. Our results revealed that tractions and strain energy are maximal at 50% Col-I-50% FN and minimal at 100% Col-I and 100% FN. Intercellular stress response was maximal on 50% Col-I-50% FN and minimal on 25% Col-I-75% FN. Cell area and cell circularity displayed a divergent relationship for different Col-I and FN ratios. We believe that these results will be of great importance to the cardiovascular field, biomedical field, and cell mechanics.NEW & NOTEWORTHY The endothelium constitutes the innermost layer of all blood vessels and plays an important role in vascular physiology and pathology. During certain vascular diseases, the extracellular matrix has been suggested to transition from a collagen-rich matrix to a fibronectin-rich matrix. In this study, we demonstrate the impact various collagen and fibronectin ratios have on endothelial biomechanical and morphological response.


Fast food restaurant lighting and music can reduce calorie intake and increase satisfaction.
Recent research shows that environmental cues such as lighting and music strongly bias the eating behavior of diners in laboratory situations. This study examines whether changing the atmosphere of a fast food restaurant would change how much patrons ate. The results indicated that softening the lighting and music led people to eat less, to rate the food as more enjoyable, and to spend just as much. In contrast to hypothesized U-shaped curves (people who spend longer eat more), this suggests a more relaxed environment increases satisfaction and decreases consumption.


First Report on the Versatile Secretome of an Environmental Isolate Acinetobacter pittii S-30.
Acinetobacter species is currently ranked as high-priority pathogen for their extraordinary ability to become resistant to almost all existing antibiotics. The diverse range of effectors secreted by Acinetobacter spp. constitutes a significant proportion of the virulence arsenal. Therefore, our study aims to characterize the secretome of Acinetobacter pittii S-30. Analysis of extracellular secreted proteins of A. pittii S-30 revealed the presence of transporter proteins, outer membrane proteins, molecular chaperones, porins, and several proteins of unknown function. Additionally, proteins related to metabolism, as well as those involved in gene expression and protein translation, type VI secretion system (T6SS) proteins, and stress response-related proteins were also identified in the secretome. The comprehensive analysis of secretome revealed putative protein antigens which could elicit substantial immune response. The limited availability of effective antibiotics and the worldwide growth of secretome data make this approach appealing in the development of effective vaccines against Acinetobacter and other bacterial pathogens.


Experimental autoimmune encephalomyelitis mediated by T-cell line. II. Specific requirements and the role of pertussis vaccine for the in vitro activation of the cells and induction of disease.
Murine T-cell lines derived from (SJL/J X BALB/c)F1 mice were established which are specifically proliferating in response to myelin basic protein (BP) and are also functional in mediating experimental autoimmune encephalomyelitis (EAE) in normal recipients. Partial characterization of the cells, the requirements of their selection and in vitro activation, and the role of pertussis vaccine for mediation of EAE were studied. The EAE-effector line cells were characterized as Lyt 1+2- cells, suggesting delayed-type hypersensitivity mechanism as a major EAE-effector mechanism in mice. Activation in vitro of EAE-effector line cells by stimulation with BP or concanavalin A in the presence of irradiated syngeneic accessory cells was required to facilitate their capacity to mediate EAE in normal recipients. (SJL/J X BALB/c)F1 EAE-effector line cells recognize BP presented by F1-specific accessory cells to facilitate adequate specific proliferation of the cells. Pertussis vaccine was found nonessential for mediation of EAE by BP-specific effector line cells, but was found essential for uncovering T cells responding to BP. Thus, the pertussis vaccine may play a more crucial role at the sensitization phase, by enhancing a T-cell response to BP, rather than by altering the blood-brain barrier at the effector phase of EAE.


Monosynaptic nigral inputs to the pedunculopontine tegmental nucleus neurons which send their axons to the medial reticular formation in the medulla oblongata. An electron microscopic study in the cat.
An electron microscopic study in the cat has suggested that neurons in the substantia nigra pars reticulata (SNr) project to the medial reticular formation of the medulla oblongata (MRF) via the pedunculopontine tegmental nucleus (PPN): PPN neurons, which were labeled with a retrograde tracer (WGA-HRP; horseradish peroxidase conjugated to wheat germ agglutinin) injected into the MRF, were found to be in synaptic contact with axon terminals which were degenerated with neurotoxic agents applied into the SNr.


NMNATs, evolutionarily conserved neuronal maintenance factors.
Proper brain function requires neuronal homeostasis over a range of environmental challenges. Neuronal activity, injury, and aging stress the nervous system, and lead to neuronal dysfunction and degeneration. Nevertheless, most organisms maintain healthy neurons throughout life, implying the existence of active maintenance mechanisms. Recent studies have revealed a key neuronal maintenance and protective function for nicotinamide mononucleotide adenylyl transferases (NMNATs). We review evidence that NMNATs protect neurons through multiple mechanisms in different contexts, and highlight functions that either require or are independent of NMNAT catalytic activity. We then summarize data supporting a role for NMNATs in neuronal maintenance and raise intriguing questions on how NMNATs preserve neuronal integrity and facilitate proper neural function throughout life.


NMR indicates the N-termini of PSGL1 and CCR7 bind competitively to the chemokine CCL21.
Chemokines are from a family of secreted cytokines that direct the trafficking of immune cells to coordinate immune responses. Chemokines are involved in numerous disease states, including responding to infections, autoimmune disorders, and cancer metastasis. Ther are chemokines, like CCL21, that signal for cellular migration through the activation of G protein-coupled receptors, like CCR7, through interaction with the receptor's extracellular N-terminus, loops, and core of the receptor. CCL21 is involved in routine immune surveillance but can also attract metastasizing cancer cells to lymph nodes. P-selectin glycoprotein ligand 1 (PSGL1) has a role in cellular adhesion during chemotaxis and is a transmembrane signaling molecule. PSGL1 expression enhances chemotactic responses of T cells to CCL21. Here NMR studies indicate the binding sites on CCL21 for the N-termini or PSGL1 and CCR7 overlap, and binding of the N-termini of PSGL1 and CCR7 is competitive.


Engineering Corynebacterium glutamicum for de novo production of 2-phenylethanol from lignocellulosic biomass hydrolysate.
2-Phenylethanol is a specific aromatic alcohol with a rose-like smell, which has been widely used in the cosmetic and food industries. At present, 2-phenylethanol is mainly produced by chemical synthesis. The preference of consumers for "natural" products and the demand for environmental-friendly processes have promoted biotechnological processes for 2-phenylethanol production. Yet, high 2-phenylethanol cytotoxicity remains an issue during the bioproduction process. Corynebacterium glutamicum with inherent tolerance to aromatic compounds was modified for the production of 2-phenylethanol from glucose and xylose. The sensitivity of C. glutamicum to 2-phenylethanol toxicity revealed that this host was more tolerant than Escherichia coli. Introduction of a heterologous Ehrlich pathway into the evolved phenylalanine-producing C. glutamicum CALE1 achieved 2-phenylethanol production, while combined expression of the aro10. Encoding 2-ketoisovalerate decarboxylase originating from Saccharomyces cerevisiae and the yahK encoding alcohol dehydrogenase originating from E. coli was shown to be the most efficient. Furthermore, overexpression of key genes (aroGfbr, pheAfbr, aroA, ppsA and tkt) involved in the phenylpyruvate pathway increased 2-phenylethanol titer to 3.23 g/L with a yield of 0.05 g/g glucose. After introducing a xylose assimilation pathway from Xanthomonas campestris and a xylose transporter from E. coli, 3.55 g/L 2-phenylethanol was produced by the engineered strain CGPE15 with a yield of 0.06 g/g xylose, which was 10% higher than that with glucose. This engineered strain CGPE15 also accumulated 3.28 g/L 2-phenylethanol from stalk hydrolysate. In this study, we established and validated an efficient C. glutamicum strain for the de novo production of 2-phenylethanol from corn stalk hydrolysate. This work supplied a promising route for commodity 2-phenylethanol bioproduction from nonfood lignocellulosic feedstock.


Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone.
Tumor necrosis factor-alpha (TNF) is an extremely potent cytokine which is involved in the pathogenesis of a number of diseases. Interruption of its synthesis can result in a reduction of inflammation and subsequent pathology. A new experimental drug pirfenidone (5-methyl-L-phenyl-2-(1H)-pyridone, trade name: Deskar) has been reported to have beneficial effects for the treatment of certain fibrotic diseases. The present study describes the inhibition of TNF in vitro as well as the inhibition of circulating TNF in vivo by pirfenidone. Isolated, thioglycollate-induced peritoneal macrophages (Mphi) from C57BL/6 mice were exposed to either lipopolysaccharide (LPS) or mannosylated bovine serum albumin then incubated with 0.1-0.9 mg/ml of pirfenidone. This substance inhibited the production of TNF in a dose-dependent manner as measured by ELISA. One i.p. injection of either 100 or 200 mg/kg pirfenidone inhibited the induction of circulating TNF following a single i.v. injection of LPS. Endotoxin shock was induced in mice using an i.p. injection of galactosamine and LPS. The higher dose of pirfenidone (200 mg/kg) completely inhibited shock and subsequent mortality. Lower doses of pirfenidone or administration either prior to or post challenge only partially inhibited symptoms. These results indicate that pirfenidone is able to inhibit both TNF induction and subsequent endotoxin shock. Additional studies are warranted to establish this drug as a potential treatment for diseases where TNF plays a major role.