Pelvic incidence: a fundamental pelvic parameter for three-dimensional regulation of spinal sagittal curves.
This paper proposes an anatomical parameter, the pelvic incidence, as the key factor for managing the spinal balance. Pelvic and spinal sagittal parameters were investigated for normal and scoliotic adult subjects. The relation between pelvic orientation, and spinal sagittal balance was examined by statistical analysis. A close relationship was observed, for both normal and scoliotic subjects, between the anatomical parameter of pelvic incidence and the sacral slope, which strongly determines lumbar lordosis. Taking into account the Cobb angle and the apical vertebral rotation confers a three-dimensional aspect to this chain of relations between pelvis and spine. A predictive equation of lordosis is postulated. The pelvic incidence appears to be the main axis of the sagittal balance of the spine. It controls spinal curves in accordance with the adaptability of the other parameters.


Generation of patient-specific pluripotent induced stem cell line SDUBMSI002-A from a patient with X-linked mental retardation syndrome.
CUL4B gene encodes a scaffold protein that assembles the CRL4B ubiquitin ligase complex, and its mutation can causes X-Linked Mental Retardation (XLMR) emerged with intellectual deficit, delayed puberty, short stature and fine intention tremor. Here we report the generation of SDUBMSi002-A, an induced pluripotent stem cell line derived from patient with c. 1564C→T with CUL4B gene using non-integrative reprogramming technology. The iPSCs line expresses pluripotent markers, has a normal male karyotype and can differentiate into the three germ layers.


A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.


Laboratory aspects of von Willebrand disease: test repertoire and options for activity assays and genetic analysis.
The deficiency or abnormal function of von Willebrand factor (VWF) causes von Willebrand disease (VWD), the most frequent inherited bleeding disorder. The laboratory diagnosis of VWD can be difficult as the disease is heterogeneous and an array of assays is required to describe the phenotype. Basic classification of quantitative (type 1 and 3) and qualitative (type 2) VWD variants requires determination of VWF antigenic (VWF:Ag) levels and assaying of VWF ristocetin cofactor (VWF:RCo) activity, determining the capacity of VWF to interact with the platelet GPIb-receptor. Knowing the VWF:RCo activity is essential for identifying, subtyping and monitoring VWD, but the assay is poorly standardized and many protocols do not fulfil the clinical need in all situations. This has led to the development of novel activity assays, independent of ristocetin, with enhanced assay characteristics. Results from the first independent clinical evaluations are promising, showing that they are reliable and suitable for VWD diagnosis. The qualitative type 2 VWF deficiency can be further divided into four different subtypes (A, B, M and N) using specific assays that explore other activities or the size distribution of VWF multimers. These methods are discussed herein. However, in a number of patients it may be difficult to correctly classify the VWD phenotype and genetic analysis may provide the best option to clarify the disorder, through mutation identification.


Nanocatalytic theranostics with intracellular mutual promotion for ferroptosis and chemo-photothermal therapy.
The reactive oxygen species (ROS) produced through the Fenton reaction, induces lipid peroxide (LPO), causing cellular structural damage and ultimately triggering ferroptosis. However, the generation of ROS in the tumor microenvironment (TME) is limited by the catalytic efficiency of the Fenton reaction. Herein, a novel hollow mesoporous silica nanoparticle (HMSN) combined with multi-metal sulfide-doped mesoporous silica nanocatalyzers (NCs) was developed, namely MxSy-HMSN NCs (M represents Cu Mn and Fe, S denotes sulfur). The MxSy-HMSN can dramatically enhanced the ferroptosis by: (1) facilitating the conversion of H2O2 to ·OH through Fenton or Fenton-like reactions through co-catalysis; (2) weakening ROS scavenging systems by depleting the over expressed glutathione (GSH) in TME; (3) providing exceptional photothermal therapy to augment ferroptosis. The MxSy-HMSN can also act as smart cargos for anticancer drug-doxorubicin (DOX). The release of DOX is responsive to GSH/pH/Near-infrared Light (NIR) irradiation at the tumor lesion, significantly improving therapeutic outcomes while minimizing side effects. Additionally, the MxSy-HMSN has demonstrated excellent magnetic resonance imaging (MRI) potential. This smart MxSy-HMSN offer a synergetic approach combining ferroptosis with chemo-photothermal therapy and magnetic resonance imaging (MRI) diagnose, which could be an informative guideline for the design of future NCs.


Dysregulated miR-103 and miR-143 expression in peripheral blood mononuclear cells from induced prediabetes and type 2 diabetes rats.
The progression from normal glucose tolerance (NGT) to type 2 diabetes (T2D) occurs through an intermediate state of glucose intolerance known as pre-diabetes. This transition is usually a gradual phenomenon that occurs over 5-10 years. Among the routinely practiced T2D screening criteria, like, FPG, IFG, IGT or HbA1c, still the issue of a preferable one is debated. The newly emerged microRNAs are created much hope to act as a class of suitable diabetes gene signature detectable at an early stage of the disease development. Although T2D related miRNA fluctuations are reported from the main insulin target organs, sampling of these organs for the sake of screening due to its invasive nature is not practicable. Peripheral blood mononuclear cells (PBMCs) are in constant touch with all body organs hence may exhibit the trace of miRNA changes which take place in insulin target organs. In this study we have evaluated miR-103 and miR-143 expression in three groups of rats namely; normal control, high fat diet (HFD) which is corresponding to prediabetes state, and high fat diet/streptozotocin (STZ) induced T2D. Quantitative real time PCR was used for profiling the selected miRNA expression at various time intervals of the three defined groups of rats. In prediabetes and overt diabetes stages, miR-103 showed significantly elevated expression in PBMC specimens compared to the normal healthy control group. Overexpression pattern of mir-143 was statistically significant in T2D compared to non-diabetic controls. However in HFD (prediabetic) rats also we observed an increasing pattern of miR-143 compared to the normal controls but it was not statistically significant.


Repression of Divergent Noncoding Transcription by a Sequence-Specific Transcription Factor.
Many active eukaryotic gene promoters exhibit divergent noncoding transcription, but the mechanisms restricting expression of these transcripts are not well understood. Here, we demonstrate how a sequence-specific transcription factor represses divergent noncoding transcription at highly expressed genes in yeast. We find that depletion of the transcription factor Rap1 induces noncoding transcription in a large fraction of Rap1-regulated gene promoters. Specifically, Rap1 prevents transcription initiation at cryptic promoters near its binding sites, which is uncoupled from transcription regulation in the protein-coding direction. We further provide evidence that Rap1 acts independently of previously described chromatin-based mechanisms to repress cryptic or divergent transcription. Finally, we show that divergent transcription in the absence of Rap1 is elicited by the RSC chromatin remodeler. We propose that a sequence-specific transcription factor limits access of basal transcription machinery to regulatory elements and adjacent sequences that act as divergent cryptic promoters, thereby providing directionality toward productive transcription.


Aspergillus Species in Lower Respiratory Tract of Hospitalized Patients from Shanghai, China: Species Diversity and Emerging Azole Resistance.
To investigate species diversity and prevalence of antifungal resistance among clinical isolates of Aspergillus spp. in Shanghai, China. In this study, the Aspergillus spp. isolates were analyzed by multilocus sequence typing (MLST) targeting the internal transcribed spacer (ITS) regions, and partial β-tubulin (BenA) and calmodulin (CaM) genes. The susceptibilities of these isolates to nine antifungal agents were determined according to the protocol in document M38-A3 established by the Clinical and Laboratory Standards Institute (CLSI). The most common Aspergillus spp. was A. fumigatus (58.2%), followed by the A. flavus complex (23.5%), and A. niger complex (15.3%). Isolates belonging to A. tamarii and A. effusus of the A. flavus complex and A. tubingensis and A. awamori of the A. niger complex were identified. Moreover, several mutations were found in the azole target cyp51A gene (TR46/Y121F/T289A and F46Y, G89G, M172V, N248T and D255E) in azole-resistant isolates of A. fumigatus. The results of our study revealed a diversity of species in the lower respiratory tract of inpatients in Shanghai and approximately 9% of our isolates were resistant to at least one of the triazole antifungals. Formulation of local treatment strategies to combat emerging azole resistance and species diversity in clinically relevant Aspergillus spp. is needed.


Gait pattern in patients treated with a total hip arthroplasty due to an acute displaced cervical neck fracture: a randomised comparison between 29 cases with a cemented femoral stem and 16 cases with an uncemented femoral stem.
The choice between cemented or uncemented stem fixation in the treatment of a femoral neck fracture may influence patient rehabilitation and the resulting gait pattern, due to potential differences in implant positioning and fixation. We used gait analysis to study temporal gait parameters, hip kinematics and kinetics in patients who, 2 years previously, had been randomised to treatment with a cemented or uncemented stem and due to an acute femoral neck fracture. 45 Patients implanted with a cemented Lubinus SP II (n = 29) and an uncemented (n = 16) Corail stem were studied. Gait analysis was performed using a 16-camera motion capture system and force plates. 28 subjects served as controls. Temporal gait parameters, hip kinematics and kinetics were analysed. The patients had no or minimum pain (median Harris pain score 44, range 40-44) and the majority had no limp (median Harris limp score 11, range 5-11). Temporospatial gait parameters and abduction-adduction motions and moments did not differ between patients with cemented or uncemented stems (p > 0.05). Patients with cemented stems did, however, show more hip flexion and less extension during walking than those with an uncemented stem (p < 0.05). Moreover, the flexion-extension range was less in the cemented group (p < 0.04). Compared with controls, the hip fracture patients walked more slowly, with a shorter stride length and a longer stance phase. Increased hip flexion and reduced extension in patients using the Lubinus SP II cemented stem could be an effect of its anteverted neck, but this question requires further study. Despite acute treatment with THA, hip fracture patients demonstrated a change in gait pattern compared with controls 2 years after the operation. This suggests that these changes are caused by the presence of an implant, or the soft-tissue trauma partly caused by the surgery than by any degenerative disease present in patients undergoing elective surgery.ClinicalTrials.gov Identifier: NCT04791605.


A Dynamic Four-Step Data Security Model for Data in Cloud Computing Based on Cryptography and Steganography.
Cloud computing is a rapidly expanding field. It allows users to access computer system resources as needed, particularly data storage and computational power, without managing them directly. This paper aims to create a data security model based on cryptography and steganography for data in cloud computing that seeks to reduce existing security and privacy concerns, such as data loss, data manipulation, and data theft. To identify the problem and determine its core cause, we studied various literature on existing cloud computing security models. This study utilizes design science research methodology. The design science research approach includes problem identification, requirements elicitation, artifact design and development, demonstration, and assessment. Design thinking and the Python programming language are used to build the artifact, and discussion about its working is represented using histograms, tables, and algorithms. This paper's output is a four-step data security model based on Rivest-Shamir-Adleman, Advanced Encryption Standard, and identity-based encryption algorithms alongside Least Significant Bit steganography. The four steps are data protection and security through encryption algorithms, steganography, data backup and recovery, and data sharing. This proposed approach ensures more cloud data redundancy, flexibility, efficiency, and security by protecting data confidentiality, privacy, and integrity from attackers.


Paracetamol: overdose-induced oxidative stress toxicity, metabolism, and protective effects of various compounds in vivo and in vitro.
Paracetamol (APAP) is one of the most widely used and popular over-the-counter analgesic and antipyretic drugs in the world when used at therapeutic doses. APAP overdose can cause severe liver injury, liver necrosis and kidney damage in human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with APAP, and various antioxidants were evaluated to investigate their protective roles against APAP-induced liver and kidney toxicities. To date, almost no review has addressed the APAP toxicity in relation to oxidative stress. This review updates the research conducted over the past decades into the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and oxidative stress as a result of APAP treatments, and ultimately their correlation with the toxicity and metabolism of APAP. The metabolism of APAP involves various CYP450 enzymes, through which oxidative stress might occur, and such metabolic factors are reviewed within. The therapeutics of a variety of compounds against APAP-induced organ damage based on their anti-oxidative effects is also discussed, in order to further understand the role of oxidative stress in APAP-induced toxicity. This review will throw new light on the critical roles of oxidative stress in APAP-induced toxicity, as well as on the contradictions and blind spots that still exist in the understanding of APAP toxicity, the cellular effects in terms of organ injury and cell signaling pathways, and finally strategies to help remedy such against oxidative damage.


Pulmonary capillary embolism caused by cryptococcemia in a hemodialysis patient.
In this report, we describe a patient who contracted fatal cryptococcosis after the induction of hemodialysis. A 76-year-old man was hospitalized to initiate hemodialysis. On admission, clinical findings showed no signs of any infections, and hemodialysis was inducted favorably. On the 6th hospital day he suddenly had a dyspnea and died from acute respiratory failure having a dyspnea for only 6 h. By microscopic examination at autopsy, we detected microemboli in the pulmonary capillary arteries caused by Cryptococcus and that the embolic source was a multiple-abscessed spleen. To the best of our knowledge, this is the first reported case of pulmonary capillary microembolism caused by cryptococcemia.


OCDMA PON supporting ONU inter-networking based on gain-switched Fabry-Pérot lasers with external dual-wavelength injection.
We propose and demonstrate an OCDMA-PON scheme with optical network unit (ONU) internetworking capability, which utilizes low-cost gain-switched Fabry-Pérot (GS-FP) lasers with external dual-wavelength injection as the pulse sources on the ONU side. The injection-generated optical pulses in two wavelengths from the same GS-FP laser are used separately for the PON uplink transmission and ONU internetworking. Experimental results based on a two-user OCDMA system confirm the feasibility of the proposed scheme. With OCDMA technologies, separate ONU-internetworking groups can be established using different optical codes. We also give experiment results to analyze the performance of the ONU-ONU transmission at different power of interference signals when two ONU-internetworking groups are present in the OCDMA-PON.


Brightness and darkness as perceptual dimensions.
A common-sense assumption concerning visual perception states that brightness and darkness cannot coexist at a given spatial location. One corollary of this assumption is that achromatic colors, or perceived grey shades, are contained in a one-dimensional (1-D) space varying from bright to dark. The results of many previous psychophysical studies suggest, by contrast, that achromatic colors are represented as points in a color space composed of two or more perceptual dimensions. The nature of these perceptual dimensions, however, presently remains unclear. Here we provide direct evidence that brightness and darkness form the dimensions of a two-dimensional (2-D) achromatic color space. This color space may play a role in the representation of object surfaces viewed against natural backgrounds, which simultaneously induce both brightness and darkness signals. Our 2-D model generalizes to the chromatic dimensions of color perception, indicating that redness and greenness (blueness and yellowness) also form perceptual dimensions. Collectively, these findings suggest that human color space is composed of six dimensions, rather than the conventional three.


Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation.
CTCF plays an important role in 3D genome organization by adjusting the strength of chromatin insulation at TAD boundaries, where clustered CBS (CTCF-binding site) elements are often arranged in a tandem array with a complex divergent or convergent orientation. Here, using Pcdh and HOXD loci as a paradigm, we look into the clustered CTCF TAD boundaries and find that, counterintuitively, outward-oriented CBS elements are crucial for inward enhancer-promoter interactions as well as for gene regulation. Specifically, by combinatorial deletions of a series of putative enhancer elements in mice in vivo or CBS elements in cultured cells in vitro, in conjunction with chromosome conformation capture and RNA-seq analyses, we show that deletions of outward-oriented CBS elements weaken the strength of long-distance intra-TAD promoter-enhancer interactions and enhancer activation of target genes. Our data highlight the crucial role of outward-oriented CBS elements within the clustered CTCF TAD boundaries in developmental gene regulation and have interesting implications on the organization principles of clustered CTCF sites within TAD boundaries.


Impacts of COVID-19 on aircraft usage and fuel consumption: A case study on four Chinese international airports.
COVID-19 pandemic starting in early 2020 has greatly impacted human and industrial activities. Air transport in China shrank abruptly in February 2020, following a year-long gradual recovery. The airline companies reacted to this unprecedented event by dramatically reducing the flight volume and rearranging the aircraft types. As the first major economy that successfully controls the spread of COVID-19, China can provide a unique opportunity to quantify the medium-long impacts on the air transport industry. To quantify the corresponding changes and to elucidate the effects of COVID-19 in the wake of two major outbreaks centered in Wuhan and Beijing, we analyze twelve flight routes formed by four selected airports, using the Automatic Dependent Surveillance-Broadcast (ADS-B) data in 2019 and 2020. Our results show that the total flight volume in 2020 reduced to 67.8% of 2019 in China. The recovering time of flight volume was about 2-6 months, dependent on the severity. In order to unwind the severe challenge, airlines mainly relied on aircraft B738 and A321 between February and June in 2020 because the fuel consumption per seat of these two aircraft types is the lowest. Besides, fuel consumption and aircraft emissions are calculated according to the Base of Aircraft Data (BADA) and the International Civil Aviation Organization's Engine Emissions Databank (ICAO's EEDB). At the end of 2020, the ratios of daily fuel consumption and aircraft emissions of 2020 to 2019 rebounded to about 0.875, suggesting the domestic commercial flights were nearly fully recovered. Our results may provide practical guidance and meaningful expectation for commercial aircraft management for other countries.


Critical care "normality": individualized versus protocolized care.
Patients with critical illness are heterogeneous, with differing physiologic requirements over time. Goal-directed therapy in the emergency room demonstrates that protocolized care could result in improved outcomes. Subsequent studies have confirmed benefit with such a "bundle-based approach" in the emergency room and in preoperative and postoperative scenarios. However, this cannot be necessarily extrapolated to the medium-term and long-term care pathway of the critically ill patient. It is likely that the development of mitochondrial dysfunction could result in goal-directed types of approaches being detrimental. Equally, arterial pressure aims are likely to be considerably different as the patient's physiology moves toward "hibernation." The agents we utilize as sedative and pressor agents have considerable effects on immune function and the inflammatory profile, and should be considered as part of the total clinical picture. The role of gut failure in driving inflammation is considerable, and the drive to feed enterally, regardless of aspirate volume, may be detrimental in those with degrees of ileus, which is often a difficult diagnosis in the critically ill. The pathogenesis of liver dysfunction may be, at least in part, related to venous engorgement that will contribute toward portal hypertension and gut edema. This, in association with loss of the hepatosplanchnic buffer response, it is likely to contribute to venous pooling in the abdominal cavity, impaired venous return, and decreased central blood volumes. Therapies such as those used in "small-for-size syndrome" may have a role in the chronic stages of septic vascular failure.


Microsporidial infections due to Encephalitozoon intestinalis in non-HIV-infected patients with chronic diarrhoea.
We determined the prevalence of microsporidia Enterocytozoon (Ent.) bieneusi and Encephalitozoon (E.) intestinalis infection in patients with chronic diarrhoea and hepatocellular carcinoma (HCC). A total of 330 stool samples were examined from 171 (52%) patients with chronic diarrhoea, 18 (5%) with HCC while 141 (43%) were controls. Stool microscopy, polymerase chain reaction (PCR) with species-specific primers for Ent. bieneusi and E. intestinalis and sequencing were carried out. Microsporidia were found by trichrome staining in 11/330 (3%) and E. intestinalis by PCR in 13/330 (4%) while Ent. bieneusi was not detected. PCR for E. intestinalis was positive in 8/171 (5%) stool samples from patients with chronic diarrhoea, 2/141 (1·4%) samples from healthy controls and in 3/18 (17%) samples from patients with HCC. In the chronic diarrhoea group, E. intestinalis was positive in 4/171 (2·3%) (P=0·69) stool samples compared to 2/18 (11%) (P=0·06) in the HCC group and 2/141 (1·4%) from healthy controls. E. intestinalis infection was significantly associated with chronic diarrhoea and HCC in these patients who were negative for HIV. Stool examination with trichrome or species-specific PCR for microsporidia may help establish the cause of chronic diarrhoea.


The gut microbiome and metabolic syndrome.
The metabolic syndrome (MetS) is a constellation of risk factors that, if left untreated, will often progress to greater metabolic defects such as type 2 diabetes and nonalcoholic fatty liver disease. While these risk factors have been established for over 40 years, the definition of MetS warrants reconsideration in light of the substantial data that have emerged from studies of the gut microbiome. In this Review we present the existing recent literature that supports the gut microbiome's potential influence on the various risk factors of MetS. The interplay of the intestinal microbiota with host metabolism has been shown to be mediated by a myriad of factors, including a defective gut barrier, bile acid metabolism, antibiotic use, and the pleiotropic effects of microbially produced metabolites. These data show that events that start in the gut, often in response to external cues such as diet and circadian disruption, have far-reaching effects beyond the gut.


Increased levels of palmitoylethanolamide and other bioactive lipid mediators and enhanced local mast cell proliferation in canine atopic dermatitis.
Despite the precise pathogenesis of atopic dermatitis (AD) is unknown, an immune dysregulation that causes Th2-predominant inflammation and an intrinsic defect in skin barrier function are currently the two major hypotheses, according to the so-called outside-inside-outside model. Mast cells (MCs) are involved in AD both by releasing Th2 polarizing cytokines and generating pruritus symptoms through release of histamine and tryptase. A link between MCs and skin barrier defects was recently uncovered, with histamine being found to profoundly contribute to the skin barrier defects.Palmitoylethanolamide and related lipid mediators are endogenous bioactive compounds, considered to play a protective homeostatic role in many tissues: evidence collected so far shows that the anti-inflammatory effect of palmitoylethanolamide depends on the down-modulation of MC degranulation.Based on this background, the purpose of the present study was twofold: (a) to determine if the endogenous levels of palmitoylethanolamide and other bioactive lipid mediators are changed in the skin of AD dogs compared to healthy animals; (b) to examine if MC number is increased in the skin of AD dogs and, if so, whether it depends on MC in-situ proliferation. The amount of lipid extract expressed as percent of biopsy tissue weight was significantly reduced in AD skin while the levels of all analyzed bioactive lipid mediators were significantly elevated, with palmitoylethanolamide showing the highest increase.In dogs with AD, the number of MCs was significantly increased in both the subepidermal and the perifollicular compartments and their granule content was significantly decreased in the latter. Also, in situ proliferation of MCs was documented. The levels of palmitoylethanolamide and other bioactive lipid mediators were shown to increase in AD skin compared to healthy samples, leading to the hypothesis that they may be part of the body's innate mechanisms to maintain cellular homeostasis when faced with AD-related inflammation. In particular, the increase may be considered a temptative response to down-regulating the observed elevation in the number, functionality and proliferative state of MCs in the skin of AD dogs. Further studies are warranted to confirm the hypothesis.


Poly(ADP-ribose) polymerase-1 affects vasopressin-mediated AQP2 expression in collecting duct cells of the kidney.
Poly(ADP-ribosyl)ation (PARylation), as a post-translational modification mediated by poly(ADP-ribose) polymerases (PARPs) catalyzing the transfer of ADP-ribose from NAD+ molecules to acceptor proteins, involves a number of cellular processes. As mice lacking the poly(ADP-ribose) polymerases 1 (PARP-1) gene (Parp1) produced more urine, we investigated the role of PARP-1, the most prevalent member of the PARP family, in the vasopressin-responsive expression of aquaporin-2 (AQP2). In biotin-conjugated nicotinamide adenine dinucleotide (biotin-NAD+) pulldown and immunoprecipitation assays of poly(ADP)-ribose (PAR) in mpkCCDc14 cells, immunoblots demonstrated that 1-deamino-8-D-arginine vasopressin (dDAVP) induced the PARylation of total proteins, associated with an increase in the cleavage of PARP-1 and cleaved caspase-3 expression. By inhibiting PARP-1 with siRNA, the abundance of dDAVP-induced AQP2 mRNA and protein was significantly diminished. In contrast, despite a substantial decrease in PARylation, the PARP-1 inhibitor (PJ34) had no effect on the dDAVP-induced regulation of AQP2 expression. The findings suggest that PARP-1 protein expression itself, and not PARP-1-mediated PARylation, is necessary for dDAVP-regulated AQP2 expression. Bioinformatic analysis revealed that 408 proteins interact with PARP-1 in the collecting duct (CD) cells of the kidney. Among them, the signaling pathway of the vasopressin V2 receptor (V2R) was identified for 49 proteins. In particular, β-catenin, which is phosphorylated at Ser552 by dDAVP, was identified as the PARP-1-interacting protein. A significant decrease of β-catenin phosphorylation (S552) in response to dDAVP was associated with siRNA-mediated PARP-1 knockdown. Taken together, PARP-1 is likely to play a role in vasopressin-induced AQP2 expression by interacting with β-catenin in renal CD cells.


Structure-Function and Therapeutic Potential of Spider Venom-Derived Cysteine Knot Peptides Targeting Sodium Channels.
Spider venom-derived cysteine knot peptides are a mega-diverse class of molecules that exhibit unique pharmacological properties to modulate key membrane protein targets. Voltage-gated sodium channels (NaV) are often targeted by these peptides to allosterically promote opening or closing of the channel by binding to structural domains outside the channel pore. These effects can result in modified pain responses, muscle paralysis, cardiac arrest, priapism, and numbness. Although such effects are often deleterious, subtype selective spider venom peptides are showing potential to treat a range of neurological disorders, including chronic pain and epilepsy. This review examines the structure-activity relationships of cysteine knot peptides from spider venoms that modulate NaV and discusses their potential as leads to novel therapies for neurological disorders.


Modulation of cyclic AMP-dependent protein kinase by vasopressin and calcitonin in cultured porcine renal LLC-PK1 cells.
We have previously demonstrated that a cultured porcine kidney cell, LLC-PK(1), maintains the characteristics of a polar renal epithelial cell in culture, and responds to salmon calcitonin and [arginine]vasopressin by increasing cyclic AMP content. To demonstrate the usefulness of this cell line as a model for the study of the biochemical events distal to cyclic AMP production, the activation of cyclic AMP-dependent protein kinase was examined. Intact cells in monolayer demonstrated progressive increases in cyclic AMP content and activation of protein kinase in response to [arginine]vasopressin (2-200nm) and salmon calcitonin (0.03-30nm) with both hormones fully activating the enzyme at a cell cyclic AMP content of 35pmol/mg of protein. Of the total cyclic AMP-dependent protein kinase activity, 80% was found in the 27000g supernatant fraction of sonicated cell material, and this soluble protein kinase could be fully activated by hormone. Conversely, the 27000g pellet contained a significant proportion of cyclic AMP-independent protein kinase and only 20% of total cell cyclic AMP-dependent protein kinase; the latter showed little response to hormone. On the basis of DEAE-cellulose chromatography, type II protein kinase was the predominant isoenzyme in both soluble and particulate fractions of the LLC-PK(1) cells and the soluble fractions of rat and guinea-pig renal medulla. Thus, the LLC-PK(1) cell line can serve as a model for hormonal modulation of protein kinase and as a potential source for defining the endogenous substrates for these enzymes.


Medical records in family practice. A review.
The organisation of general practice in England is outlined and the independent contractor basis of the family practioner emphasised. Data from family practice, like data from hospital practice, may be used for clinical management, practice management, or research. Examples of applications in each of these fields are given. The basic records used in family practice--the medical record envelope, the prescription form and the claim for sickness benefit--are described. Some practices record morbidity (E Book or Diagnostic Index), some record systematically details of their activities (L Book or Activities Ledger) and some maintain age and sex registers and other registers of their patients; all these developments are outlined. Attention is drawn to the introduction of problem orientated records and to the use of computers in family practice, but these innovations are not discussed. Outstanding issues are the same as those in hospital record systems--accuracy, definitions, coverage, confidentiality, clerical support and costs, and the use made of the information.


Reverse Cheese-Wire Septotomy to Create a Distal Landing Zone for Thoracic Endovascular Aortic Repair.
The objective of this study is to describe a novel method for creating a distal landing zone for thoracic endovascular aortic repair (TEVAR) in chronic aortic dissection. The technique is described in a patient with prior total arch and descending aortic replacement, with false lumen expansion. A cheese-wire endovascular septotomy was desired to create a single lumen above the celiac axis. To avoid dividing the septum caudally across the visceral segment, we performed a modified septotomy in a cephalad direction. Stiff wires were passed into the prior surgical graft, through true lumen on the right and false lumen on the left. An additional wire was passed across an existing fenestration at the level of the celiac axis, and snared and externalized. 7F Ansel sheaths were advanced and positioned tip-to-tip at the fenestration. Using the stiff wires as tracks, the through-wire was pushed cephalad to endovascularly cut the septum. Angiogram demonstrated successful septotomy, and TEVAR was performed to just above the celiac with successful aneurysm exclusion and no endoleak or retrograde false lumen perfusion. Follow-up computed tomography angiogram (CTA) showed continued exclusion without false lumen perfusion. This novel modification in a reverse direction provides an alternative method for endovascular septotomy, when traditional septotomy may threaten the visceral vessels.


How does increasing mast seeding frequency affect population dynamics of seed consumers? Wild boar as a case study.
Mast seeding in temperate oak populations shapes the dynamics of seed consumers and numerous communities. Mast seeding responds positively to warm spring temperatures and is therefore expected to increase under global warming. We investigated the potential effects of changes in oak mast seeding on wild boar population dynamics, a widespread and abundant consumer species. Using long-term monitoring data, we showed that abundant acorn production enhances the proportion of breeding females. With a body-mass-structured population model and a fixed hunting rate of 0.424, we showed that high acorn production over time would lead to an average wild boar population growth rate of 1.197 whereas non-acorn production would lead to a stable population. Finally, using climate projections and a mechanistic model linking weather data to oak reproduction, we predicted that mast seeding frequency might increase over the next century, which would lead to increase in both wild boar population size and the magnitude of its temporal variation. Our study provides rare evidence that some species could greatly benefit from global warming thanks to higher food availability and therefore highlights the importance of investigating the cascading effects of changing weather conditions on the dynamics of wild animal populations to reliably assess the effects of climate change.


[Detection of antituberculosis antibodies and antigens by enzyme immunoassay in young and preschool children suffering from tuberculosis].
Antituberculosis antibodies and mycobacterial antigens were detected in 74 young and preschool children suffering from tuberculosis by using enzyme immunoassay (EIA). They were found in 75.7% and 68.9% of children, respectively. The highest levels of antibodies were significantly greater in patients with active disseminated processes than in those with active restrictive processes. There were no great differences in the levels of antigens between the patients having different activities of a tuberculosis process. Follow-up indicated that there was a reduction in the levels of antibodies and antigens at 6-month treatment. The use of enzyme EIA in children ill with tuberculosis may serve an additional criterion for diagnosis of tuberculosis, evaluation of its activity and course.


Selected conservation management strategies enhance maize yield stability in the sub-humid tropical agro-ecozone of Upper Eastern Kenya.
Conservation management strategies have been recommended to enhance soil fertility, moisture retention, crop yield, and yield stability in rainfed agriculture. However, there is limited research on yield stability. We evaluated the effect of integrating soil inputs in conservation tillage on yield and yield stability in Meru South, Upper Eastern Kenya, for eleven consecutive cropping seasons. The trial treatments included conservation tillage without soil inputs (Mt), conservation tillage with soil inputs: sole inorganic fertilizer (F), residue + inorganic fertilizer (RF), residue + inorganic fertilizer + manure (RFM), residue + manure + legume Dolichos Lablab L. (RML), residue + Tithonia + manure (RTM), residue + Tithonia + phosphate rock (RTP) and conventional tillage (Control). Conservation tillage with RFM was the best-fit strategy for enhancing yields. There was heterogeneity in yield residual variance. A larger residual variance implied lesser yield stability. Mt treatment had the least yield residual variance of 0.12 Mg ha-2, followed by Ct and RML, 0.15 Mg ha-2, while RTM had the highest yield residual variance of 0.62 Mg ha-2. Contrarily, the most stable treatments had the least average yields. The study indicated a positive influence of incorporating soil inputs in conservation tillage on yield and suggests longer-term research for yield stability.


Clinico-pathological impact of fibroplasia in melanocytic nevi: a critical revision of 209 cases.
Fibroplasia is a peculiar stromal reaction at the base of melanocytic lesions, particularly observed in so-called dysplastic nevi. This study evaluates a series of clinico-pathological features in nevi with fibroplasia, their frequence in comparison to usual nevi, and the association of fibroplasia with the risk for the development of melanoma. A total of 209 consecutive nevi showing fibroplasia, belonging to 203 patients, was reviewed. Nevi with fibroplasia were more frequent in men, about half of the lesions belonged to patients aged 11-40 years, and the highest number (52%) were located on the posterior trunk. Lesions 6 mm or greater were 152 (72.73%). Junctional and compound nevi were 52 (24.8%), and 157 (75.2%), respectively. Inflammatory infiltrate was present in 67.8% of cases, melanophages in 56.4%, a lentiginous pattern in 31.1%, focal pagetoid infiltration in three lesions. Nevi with fibroplasia constituted 4.27% of all junctional and compound nevi diagnosed in the same period. A total of 23 patients (11.3%) had a personal history of melanoma. The total number of nevi excised from the 203 patients ranged between 1 and 21, and significantly correlated with the patient's personal history of melanoma (p < 0.001). Fibroplasia is relatively infrequent in melanocytic nevi, it does not appear related to a process of senescence of the lesion, and does not represent a particularly strong predictor of risk of melanoma.


Characterisation of the promoter for the LexA regulated sulA gene of Escherichia coli.
The sulA gene of Escherichia coli, which encodes an inducible inhibitor of cell division, plays a role in the SOS response. Its expression, like that of other SOS genes, is repressed by the LexA protein. This paper reports the identification and characterisation of the promoter for the cloned sulA gene. The promoter bears good resemblance to the consensus promoter sequence and directs the synthesis of two major RNA species both in vitro and in vivo. Comparison of the sequence around the sulA promoter with the operator sequences of other SOS genes revealed the presence of an SOS box, the LexA protein binding site. This overlaps the -10 region of the promoter and covers the transcriptional initiation sites. LexA protein bound to this SOS box, would, therefore, effectively block transcription.


Antioxidant Response Activating nanoParticles (ARAPas) localize to atherosclerotic plaque and locally activate the Nrf2 pathway.
Atherosclerotic disease is the leading cause of death world-wide with few novel therapies available despite the ongoing health burden. Redox dysfunction is a well-established driver of atherosclerotic progression; however, the clinical translation of redox-based therapies is lacking. One of the challenges facing redox-based therapies is their targeted delivery to cellular domains of redox dysregulation. In the current study, we sought to develop Antioxidant Response Activating nanoParticles (ARAPas), encapsulating redox-based interventions, that exploit macrophage biology and the dysfunctional endothelium in order to selectively accumulate in atherosclerotic plaque. We employed flash nanoprecipitation (FNP) to synthesize bio-compatible polymeric nanoparticles encapsulating the hydrophobic Nrf2 activator drug, CDDO-Methyl (CDDOMe-ARAPas). Nuclear factor erythroid 2-related factor 2 (Nrf2)-activators are a promising class of redox-active drug molecules whereby activation of Nrf2 results in the expression of several antioxidant and cyto-protective enzymes that can be athero-protective. In this study, we characterize the physicochemical properties of CDDOMe-ARAPas as well as confirm their in vitro internalization by murine macrophages. Drug release of CDDOMe was determined by Nrf2-driven GFP fluorescence. Moreover, we show that these CDDOMe-ARAPas exert anti-inflammatory effects in classically activated macrophages. Finally, we show that CDDOMe-ARAPas selectively accumulate in atherosclerotic plaque of two widely-used murine models of atherosclerosis: ApoE-/- and LDLr-/- mice, and are capable of increasing gene expression of Nrf2-transcriptional targets in the atherosclerotic aortic arch. Future work will assess the therapeutic efficacy of intra-plaque Nrf2 activation with CDDOMe-ARAPas to inhibit atherosclerotic plaque progression. Overall, our present studies underline that targeting of atherosclerotic plaque is an effective means to enhance delivery of redox-based interventions.


Altered antigenicity and immunogenicity of human papillomavirus virus-like particles in the presence of thimerosal.
Thimerosal has been widely used as a preservative in human vaccines for decades. Thimerosal, a thiol capping agent with ethyl mercury being the active degradant, could have impacts on the vaccine potency due to potential thiol modification. The effects on the antigenicity and immunogenicity of human papillomavirus (HPV) virus-like particles (VLPs) in the presence of thimerosal was studied. In general, reduced binding activity was observed between HPV antigens and monoclonal antibodies (mAbs) upon thimerosal treatment, accompanied by reduced protein conformational stability. The immunogenicity of a pentavalent vaccine formulation (HPV6, HPV11, HPV16, HPV18 and hepatitis E virus) with or without thimerosal was studied in mice. The functional antibody titres, as well as the binding titres, were determined, showing a substantial decrease for vaccine formulations containing thimerosal for HPV16/18. Similarly, epitope-specific competition assays using specific and functional mAbs as tracers also showed a significant reduction in immunogenicity for HPV16/18 in the presence of thimerosal. Structural alterations in the capsid protein for HPV18 were observed with cryo-electron microscopy and 3-dimensional reconstruction in the comparative structural analysis. The results should alert scientists in formulation development field on the choice for vaccine preservatives, in particular for thiol-containing antigens.


Evidence for positive selection acting on microcystin synthetase adenylation domains in three cyanobacterial genera.
Cyanobacteria produce a wealth of secondary metabolites, including the group of small cyclic heptapeptide hepatotoxins that constitutes the microcystin family. The enzyme complex that directs the biosynthesis of microcystin is encoded in a single large gene cluster (mcy). mcy genes have a widespread distribution among cyanobacteria and are likely to have an ancient origin. The notable diversity within some of the Mcy modules is generated through various recombination events including horizontal gene transfer. A comparative analysis of the adenylation domains from the first module of McyB (McyB1) and McyC in the microcystin synthetase complex was performed on a large number of microcystin-producing strains from the Anabaena, Microcystis and Planktothrix genera. We found no decisive evidence for recombination between strains from different genera. However, we detected frequent recombination events in the mcyB and mcyC genes between strains within the same genus. Frequent interdomain recombination events were also observed between mcyB and mcyC sequences in Anabaena and Microcystis. Recombination and mutation rate ratios suggest that the diversification of mcyB and mcyC genes is driven by recombination events as well as point mutations in all three genera. Sequence analysis suggests that generally the adenylation domains of the first domain of McyB and McyC are under purifying selection. However, we found clear evidence for positive selection acting on a number of amino acid residues within these adenylation domains. These include residues important for active site selectivity of the adenylation domain, strongly suggesting selection for novel microcystin variants. We provide the first clear evidence for positive selection acting on amino acid residues involved directly in the recognition and activation of amino acids incorporated into microcystin, indicating that the microcystin complement of a given strain may influence the ability of a particular strain to interact with its environment.


Pulmonary vasodilator response to vagal stimulation is blocked by N omega-nitro-L-arginine methyl ester in the cat.
The effect of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor production, on the vasodilator response to efferent vagal stimulation was investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was increased with U46619, efferent vagal stimulation decreased lobar arterial pressure in a stimulus-frequency-dependent manner. The decreases in lobar arterial pressure were enhanced by pretreatment with reserpine, were blocked by atropine, and were not altered by propranolol, indicating that the neurogenic vasodilator response was cholinergic in nature. The decreases in lobar arterial pressure in response to vagal stimulation and to exogenously administered acetylcholine were reduced after administration of L-NAME (100 mg/kg i.v.). Although L-NAME decreased pulmonary vasodilator responses to vagal stimulation and to acetylcholine, responses to adenosine, nicorandil, lemakalim, isoproterenol, prostaglandin E1, sodium nitroprusside, and 8-bromo-cGMP, agents that act by a variety of mechanisms, were not decreased. These results are consistent with the hypothesis that efferent vagal stimulation releases acetylcholine, which dilates the pulmonary vascular bed by stimulating the production of nitric oxide or a labile nitroso compound from L-arginine.


Vascular endothelial growth factor-mediated induction of manganese superoxide dismutase occurs through redox-dependent regulation of forkhead and IkappaB/NF-kappaB.
The mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) plays a critical cytoprotective role against oxidative stress. Vascular endothelial growth factor (VEGF) was shown previously to induce expression of Mn-SOD in endothelial cells by a NADPH oxidase-dependent mechanism. The goal of the current study was to determine the transcriptional mechanisms underlying this phenomenon. VEGF resulted in protein kinase C-dependent phosphorylation of IkappaB and subsequent translocation of p65 NF-kappaB into the nucleus. Overexpression of constitutively active IkappaB blocked VEGF stimulation of Mn-SOD. In transient transfection assays, VEGF increased Mn-SOD promoter activity, an effect that was dependent on a second intronic NF-kappaB consensus motif. In contrast, VEGF-mediated induction of Mn-SOD was enhanced by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and by dominant negative Akt and was decreased by constitutively active Akt. Overexpression of a constitutively active (phosphorylation-resistant) form of FKHRL1 (TMFKHRL1) resulted in increased Mn-SOD expression, suggesting that the negative effect of PI3K-Akt involves attenuation of forkhead activity. In co-transfection assays, the Mn-SOD promoter was transactivated by TMFKHRL1. Flavoenzyme inhibitor, diphenyleneiodonium (DPI), and antisense oligonucleotides against p47phox (AS-p47phox) inhibited VEGF stimulation of IkappaB/NF-kappaB and forkhead phosphorylation, supporting a role for NADPH oxidase activity in both signaling pathways. Like VEGF, hepatocyte growth factor (HGF) activated the PI3K-Akt-forkhead pathway. However, HGF-PI3K-Akt-forkhead signaling was insensitive to diphenyleneiodonium and AS-p47phox. Moreover, HGF failed to induce phosphorylation of IkappaB/NF-kappaB or nuclear translocation of NF-kappaB and had no effect on Mn-SOD expression. Together, these data suggest that VEGF is uniquely coupled to Mn-SOD expression through growth factor-specific reactive oxygen species (ROS)-sensitive positive (protein kinase C-NF-kappaB) and negative (PI3K-Akt-forkhead) signaling pathways.


Shoot-to-root communication via GmUVR8-GmSTF3 photosignaling and flavonoid biosynthesis fine-tunes soybean nodulation under UV-B light.
Legume nodulation requires light perception by plant shoots and precise long-distance communication between shoot and root. Recent studies have revealed that TGACG-motif binding factors (GmSTFs) integrate light signals to promote root nodulation; however, the regulatory mechanisms underlying nodule formation in changing light conditions remain elusive. Here, we applied genetic engineering, metabolite measurement, and transcriptional analysis to study soybean (Glycine max) nodules. We clarify a fine-tuning mechanism in response to ultraviolet B (UV-B) irradiation and rhizobia infection, involving GmUVR8-dependent UV-B perception and GmSTF3/4-GmMYB12-GmCHS-mediated (iso)flavonoid biosynthesis for soybean nodule formation. GmUVR8 receptor-perceived UV-B signal triggered R2R3-MYB transcription factors GmMYB12-dependent flavonoid biosynthesis separately in shoot and root. In shoot, UV-B-triggered flavonoid biosynthesis relied on GmUVR8a, b, c receptor-dependent activation of GmMYB12L-GmCHS8 (chalcone synthase) module. In root, UV-B signaling distinctly promotes the accumulation of the isoflavones, daidzein, and its derivative coumestrol, via GmMYB12B2-GmCHS9 module, resulting in hypernodulation. The mobile transcription factors, GmSTF3/4, bind to cis-regulatory elements in the GmMYB12L, GmMYB12B2, and GmCHS9 promoters, to coordinate UV-B light perception in shoot and (iso)flavonoid biosynthesis in root. Our findings establish a novel shoot-to-root communication module involved in soybean nodulation and reveal an adaptive strategy employed by soybean roots in response to UV-B light.


Determination of Co(II) in plant tissue by microwave digestion and ion chromatography coupled with luminol/perborate or luminol/percarbonate chemiluminescence detection.
The cobalt is an essential element for leguminous plants but may be harmful for other species; for that reason determination of Co(II) is very important for the management of polluted areas and for discover plants with capacity for the hyperaccumulation of heavy metals, which has produced a growing necessity of fast, sensitive and selective analytical techniques. To develop an analytical procedure for the determination of cobalt in plant tissue by coupling the ionic chromatography to the luminol-based chemiluminescence detection. The sample was digested in a mixture of concentrated nitric acid and hydrogen peroxide, using an microwave oven to dissolve the Co(II). The solution containing Co(II) ions was injected to an ionic chromatograph using oxalic acid as the eluent. The detection was based on the catalytic effect of Co(II) on the luminol chemiluminescence using perborate or percarbonate as oxidants. Experimental variables, such as concentrations, pH, flow rates and acid digestion conditions were optimised. Well-resolved chromatographic peaks were obtained. The height and area showed linear dependences with the Co(II) concentration, which were used to quantify the heavy metal, with recoveries up to 95%. The microwave irradiation (60 s) was sufficient for the complete mineralisation of 200 mg of sample, employing 2 mL of the acid mixture. The method was free from the interferences, requiring less than 12 minutes to complete the analysis. The method was simple and rapid for the determination of cobalt in plant tissue with detection limits comparable to those obtained with more sophisticated and expensive analytical equipment.


Vasopressin stimulates phosphoinositide hydrolysis in LLC-PK1 cells.
LLC-PK1 cells have been shown to possess vasopressin (VP) receptors (V2 type) that are coupled to adenyl cyclase to generate adenosine 3,5'-cyclic monophosphate (cAMP). To determine whether VP also stimulates phosphoinositide (PI) hydrolysis to generate inositol phosphate (IP) and diacylglycerol (DAG) messenger system in LLC-PK1 cells, we measured the release of IP in LLC-PK1 cells in the absence and presence of various concentrations of VP. In addition, we also determined the effect of an increase in osmolality of the incubation medium on VP-stimulated PI hydrolysis in LLC-PK1 cells. The methods involved the incubation of LLC-PK1 cells with [3H]inositol for its incorporation into membrane PI and the measurement of the release of [3H]IP in the presence of LiCl which prevents dephosphorylation. The osmolality of the incubation media was increased from 300 to 600, 900, and 1,200 mosmol/kgH2O by the addition of NaCl and urea. In an isosmotic incubation medium, VP (10(-8) M) produced a 100% increase in PI hydrolysis in LLC-PK1 cells. The effect was much greater at higher concentrations of the hormone. There was no effect of osmolality in VP-stimulated PI hydrolysis in LLC-PK1 cells up to 600 mosmol/kgH2O, but PI hydrolysis decreased significantly when the osmolality of the incubation medium was increased to 900 or 1,200 mosmol/kgH2O. Our results suggest that in LLC-PK1 cells, VP stimulates PI hydrolysis probably through VP receptors that are coupled to phospholipase C. Furthermore, VP-stimulated PI messenger system in LLC-PK1 cells is influenced by osmolality of the extracellular fluid.


Blast overpressure after tire explosion: a fatal case.
Fatal blast injuries are generally reported in literature as a consequence of the detonation of explosives in war settings. The pattern of lesion depends on the position of the victim in relation to the explosion, on whether the blast tracks through air or water, and whether it happens in the open air or within an enclosed space and the distance from the explosion. Tire explosion-related injuries are rarely reported in literature. This study presents a fatal case of blast overpressure due to the accidental explosion of a truck tire occurring in a tire repair shop. A multidisciplinary approach to the fatality involving forensic pathologists and engineers revealed that the accidental explosion, which caused a series of primary and tertiary blast wave injuries, was due to tire deterioration.


The impact of lung cancer on survival of idiopathic pulmonary fibrosis.
Lung cancer (LC) is frequently associated with idiopathic pulmonary fibrosis (IPF). Despite this well-known association, the outcome of LC in patients with IPF is unclear. The objective of this study was to evaluate the impact of LC on survival of patients with associated IPF. A total of 260 patients with IPF were reviewed, and 186 IPF cases had complete clinical and follow-up data. Among these, five cases were excluded because LC was radiologically suspected but not histologically proven. The remaining 181 cases were categorized in two groups: 23 patients with biopsy-proven LC and IPF (LC-IPF) and 158 patients with IPF only (IPF). Survival and clinical characteristics of the two groups were compared. Prevalence of histologically proven LC was 13%, and among those with LC-IPF cumulative incidence at 1 and 3 years was 41% and 82%. Patients with LC were more frequently smokers (91.3% vs 71.6%, P = .001), with combined pulmonary fibrosis and emphysema (52% vs 32%, P = .052). Survival in patients with LC-IPF was significantly worse than in patients with IPF without LC (median survival, 38.7 months vs 63.9 months; hazard ratio = 5.0; 95% CI, 2.91-8.57; P < .001). Causes of death in the study group were respiratory failure in 43% of patients, LC progression in 13%, and LC treatment-related complications in 17%. In patients with IPF, LC has a significant adverse impact on survival. Diagnosis and treatment of LC in IPF are burdened by an increased incidence of severe complicating events, apparently as lethal as the cancer itself.


ECORISK2050: An Innovative Training Network for predicting the effects of global change on the emission, fate, effects, and risks of chemicals in aquatic ecosystems.
By 2050, the global population is predicted to reach nine billion, with almost three quarters living in cities. The road to 2050 will be marked by changes in land use, climate, and the management of water and food across the world. These global changes (GCs) will likely affect the emissions, transport, and fate of chemicals, and thus the exposure of the natural environment to chemicals. ECORISK2050 is a Marie Skłodowska-Curie Innovative Training Network that brings together an interdisciplinary consortium of academic, industry and governmental partners to deliver a new generation of scientists, with the skills required to study and manage the effects of GCs on chemical risks to the aquatic environment. The research and training goals are to: (1) assess how inputs and behaviour of chemicals from agriculture and urban environments are affected by different environmental conditions, and how different GC scenarios will drive changes in chemical risks to human and ecosystem health; (2) identify short-to-medium term adaptation and mitigation strategies, to abate unacceptable increases to risks, and (3) develop tools for use by industry and policymakers for the assessment and management of the impacts of GC-related drivers on chemical risks. This project will deliver the next generation of scientists, consultants, and industry and governmental decision-makers who have the knowledge and skillsets required to address the changing pressures associated with chemicals emitted by agricultural and urban activities, on aquatic systems on the path to 2050 and beyond.


Pressure-decoupled magnetic and structural transitions of the parent compound of iron-based 122 superconductors BaFe2As2.
The recent discovery of iron ferropnictide superconductors has received intensive concern in connection with magnetically involved superconductors. Prominent features of ferropnictide superconductors are becoming apparent: the parent compounds exhibit an antiferromagnetic ordered spin density wave (SDW) state, the magnetic-phase transition is always accompanied by a crystal structural transition, and superconductivity can be induced by suppressing the SDW phase via either chemical doping or applied external pressure to the parent state. These features generated considerable interest in the interplay between magnetism and structure in chemically doped samples, showing crystal structure transitions always precede or coincide with magnetic transition. Pressure-tuned transition, on the other hand, would be more straightforward to superconducting mechanism studies because there are no disorder effects caused by chemical doping; however, remarkably little is known about the interplay in the parent compounds under controlled pressure due to the experimental challenge of in situ measuring both of magnetic and crystal structure evolution at high pressure and low temperatures. Here we show from combined synchrotron Mössbauer and X-ray diffraction at high pressures that the magnetic ordering surprisingly precedes the structural transition at high pressures in the parent compound BaFe2As2, in sharp contrast to the chemical-doping case. The results can be well understood in terms of the spin fluctuations in the emerging nematic phase before the long-range magnetic order that sheds light on understanding how the parent compound evolves from a SDW state to a superconducting phase, a key scientific inquiry of iron-based superconductors.


Incontinentia pigmenti and Behçet's syndrome: an unusual combination.
We describe an unusual case of a child who had had incontinentia pigmenti from birth and developed the clinical picture of Behçet's syndrome at five years of age. Among the various investigations performed, chemotactic activity of the polymorphonuclear leukocyte was found to be low. We discuss the possibility that there are common immunological abnormalities in the two syndromes.


ANIMAL BEHAVIOR AND WELL-BEING SYMPOSIUM: The Common Swine Industry Audit: Future steps to assure positive on-farm animal welfare utilizing validated, repeatable and feasible animal-based measures.
The Common Swine Industry Audit (CSIA) was developed and scientifically evaluated through the combined efforts of a task force consisting of university scientists, veterinarians, pork producers, packers, processers, and retail and food service personnel to provide stakeholders throughout the pork chain with a consistent, reliable, and verifiable system to ensure on-farm swine welfare and food safety. The CSIA tool was built from the framework of the Pork Quality Assurance Plus (PQA Plus) site assessment program with the purpose of developing a single, common audit platform for the U.S. swine industry. Twenty-seven key aspects of swine care are captured and evaluated in CSIA and cover the specific focal areas of animal records, animal observations, facilities, and caretakers. Animal-based measures represent approximately 50% of CSIA evaluation criteria and encompass critical failure criteria, including observation of willful acts of abuse and determination of timely euthanasia. Objective, science-based measures of animal well-being parameters (e.g., BCS, lameness, lesions, hernias) are assessed within CSIA using statistically validated sample sizes providing a detection ability of 1% with 95% confidence. The common CSIA platform is used to identify care issues and facilitate continuous improvement in animal care through a validated, repeatable, and feasible animal-based audit process. Task force members provide continual updates to the CSIA tool with a specific focus toward 1) identification and interpretation of appropriate animal-based measures that provide inherent value to pig welfare, 2) establishment of acceptability thresholds for animal-based measures, and 3) interpretation of CSIA data for use and improvement of welfare within the U.S. swine industry.


Passive immunotherapy for mouse leukemias with antisera of "directed" specificity: synergism with the action of cyclophosphamide.
Antileukemia sera with "directed" specificity are produced by immunization of rabbits with mouse leukemia cells admixed with normal antigen blocking (NAB) serum. Addition of NAB serum to the leukemia cells inhibits production of antibodies to normal cell components and directs specificity toward leukemia cell antigens. The resulting antileukemia serum (ALK-NABS) was not sufficiently potent to produce more than moderate therapy in the standard L1210 leukemia therapy assay. When given together with noncurative doses of cyclophosphamide (CTX), ALK-NABS acts synergistically. It is most effective when given early after injection of the leukemia cells and prior to injection of CTX. Daily repeated injections of a given dose are more effective than a single injection of that dose. Most important, small doses of ALK-NABS produce a significant prolongation of lifespan in conjunction with CTX. Results of therapy for BW-A leukemia with ALK-NABS in conjunction with CTX were negative.


Bayesian hierarchical evaluation of dose-response for peanut allergy in clinical trial screening.
Risk-based labeling based on the minimal eliciting doses (EDs) in sensitized populations is a potential replacement for precautionary allergen labeling of food allergens. We estimated the dose-response distribution for peanut allergen using data from double-blind placebo-controlled food challenges (DBPCFCs) conducted in the US at multiple sites, testing a population believed to be similar to the general U.S. food allergic population. Our final (placebo-adjusted) dataset included 548 challenges of 481 subjects. Bayesian hierarchical analysis facilitated model fitting, and accounted for variability associated with various levels of data organization. The data are best described using a complex hierarchical structure that accounts for inter-individual variability and variability across study locations or substudies. Bayesian model averaging could simultaneously consider the fit of multiple models, but the Weibull model dominated so strongly that model averaging was not needed. The ED01 and ED05 (and 95% credible intervals) are 0.052 (0.021, 0.13) and 0.49 (0.22, 0.97) mg peanut protein, respectively. Accounting for challenges with severe reactions at the LOAEL, by using the dose prior to the LOAEL as the new LOAEL, the ED01 drops to 0.029 (0.014, 0.074) mg peanut protein. Our results could aid in establishing improved food labeling guidelines in the management of food allergies.


IgA deficiency in wolves.
Low mean concentrations of serum immunoglobulin A (IgA) and an increased frequency of overt IgA deficiency (IgAD) in certain dog breeds raises the question whether it is a breeding-enriched phenomenon or a legacy from the dog's ancestor, the gray wolf (Canis lupus). The IgA concentration in 99 serum samples from 58 free-ranging and 13 captive Scandinavian wolves, was therefore measured by capture ELISA. The concentrations were markedly lower in the wolf serum samples than in the dog controls. Potential differences in the IgA molecule between dogs and wolves were addressed by sequencing the wolf IgA heavy chain constant region encoding gene (IGHA). Complete amino acid sequence homology was found. Detection of wolf and dog IgA was ascertained by showing identity using double immunodiffusion. We suggest that the vast majority of wolves, the ancestor of the dog, are IgA deficient.


Amino acids and mechanistic target of rapamycin regulate the fate of live engulfed cells.
Metabolic stress contributes to the regulation of cell death in normal and diseased tissues. While different forms of cell death are known to be regulated by metabolic stress, how the cell engulfment and killing mechanism entosis is regulated is not well understood. Here we find that the death of entotic cells is regulated by the presence of amino acids and activity of the mechanistic target of rapamycin (mTOR). Amino acid withdrawal or mTOR inhibition induces apoptosis of engulfed cells and blocks entotic cell death that is associated with the lipidation of the autophagy protein microtubule-associated protein light chain 3 (LC3) to entotic vacuoles. Two other live cell engulfment programs, homotypic cell cannibalism (HoCC) and anti-CD47 antibody-mediated phagocytosis, known as phagoptosis, also undergo a similar vacuole maturation sequence involving LC3 lipidation and lysosome fusion, but only HoCC involves mTOR-dependent regulation of vacuole maturation and engulfed cell death similar to entosis. We further find that the regulation of cell death by mTOR is independent of autophagy activation and instead involves the 4E-BP1/2 proteins that are known regulators of mRNA translation. Depletion of 4E-BP1/2 proteins can restore the mTOR-regulated changes of entotic death and apoptosis rates of engulfed cells. These results identify amino acid signaling and the mTOR-4E-BP1/2 pathway as an upstream regulation mechanism for the fate of live engulfed cells formed by entosis and HoCC.


Possible interaction between visfatin, periodontal infection, and other systemic diseases: A brief review of literature.
Gingivitis and periodontitis are common bacterial infections caused by a variety of microorganisms. Despite the microorganisms' roles as etiologic agents, inflammation-induced substances also have crucial parts in the loss of connective tissue and the supporting alveolar bone. Visfatin is a pleiotropic mediator, which acts as growth factor, cytokine, and pre-B-cell colony-enhancing factor. A positive correlation was detected between the serum/plasma levels of visfatin and inflammatory disorders such as diabetes mellitus and cardiovascular disease. In addition, the visfatin level was higher in saliva and the gingival crevicular fluid (GCF) of subjects with periodontal disease. This review defined current, predictable patterns of possible interaction of visfatin with periodontal infection and other systemic diseases, using PubMed and Medline databases searching for articles written in English. Peer-reviewed articles were targeted using the following keywords: "visfatin," "periodontal disease," "inflammatory mediator," and "biomarker." Available full-text articles were read, and related articles were also scrutinized, while a hand search was also performed. Search was confined to human studies, and articles written in English and published between 1985 and 2016 were selected. It was concluded that periodontal infection and other systemic diseases could be related to the levels of visfatin in GCF, saliva, and serum as a biomarker of these diseases.


Water-Mediated Hydrogen Bond Network Drives Highly Crystalline Structure Formation of Crown Ether-Based Covalent Organic Framework for Sr Adsorption.
Covalent organic frameworks (COFs) with crown ether units have drawn great attention due to their potential applications in adsorption, catalysis, and sensing. However, employing crown ethers to construct COFs is still challenging in light of the flexible nature of macrocycles. Here, a highly crystalline one-dimensional covalent organic framework (1D-18C6-COF) with crown ether units on the ribbon edge was synthesized. The water-mediated hydrogen bond network and π-π stacking hold the 1D COF ribbons together. The combination of experimental and DFT studies demonstrated that the hydrogen bond network plays a crucial role in the structure crystallinity. The 1D-18C6-COF was applied as an adsorbent for strontium, and it exhibited rapid kinetics with good selectivity. In the competitive adsorption experiment, a separation factor of 1900 was achieved, representing one of the largest values for cesium/strontium separation. This work provides new insights into the design and functional exploration of crystalline COFs with flexible units.


The use of ultrasound in obstetrics and gynecology.
Advantages of ultrasound as a diagnostic tool are many. The patient experiences no discomfort, nor does she feel any sensation. The patient can be examined without moving from her bed. Unlike x-ray, there is no danger of exposing the fetus and the mother to adverse effects of radiation. Its application in determination of fetal death, early in pregnancy, diagnosis of hydatidiform mole and localization of the placenta in cases of antepartum hemorrhage are only some of the obvious applications of this method.


Young Children See a Single Action and Infer a Social Norm.
Human social life depends heavily on social norms that prescribe and proscribe specific actions. Typically, young children learn social norms from adult instruction. In the work reported here, we showed that this is not the whole story: Three-year-old children are promiscuous normativists. In other words, they spontaneously inferred the presence of social norms even when an adult had done nothing to indicate such a norm in either language or behavior. And children of this age even went so far as to enforce these self-inferred norms when third parties "broke" them. These results suggest that children do not just passively acquire social norms from adult behavior and instruction; rather, they have a natural and proactive tendency to go from "is" to "ought." That is, children go from observed actions to prescribed actions and do not perceive them simply as guidelines for their own behavior but rather as objective normative rules applying to everyone equally.


Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancer.
In human ovarian carcinoma, the endothelin-1 (ET-1) / endothelin A receptor (ETAR) axis is overexpressed, correlating with tumor grade. Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. ETAR blockade with zibotentan (ZD4054), a specific ETAR antagonist, significantly inhibits ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for cancer therapy. Since clinical trial results have defined the combination of platinum and taxane as the standard of care in the management of ovarian cancer, here we explored the therapeutic efficacy of the integration of zibotentan with cytotoxic drugs having different modes of action. We found that the combination of zibotentan with cisplatinum as well as zibotentan with paclitaxel was more effective at inhibiting ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined zibotentan, cisplatinum, and paclitaxel. Accordingly, in HEY xenografts the coadministration of zibotentan with cisplatinum enhanced the efficacy of the cytotoxic drug alone in controlling tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of zibotentan with both cisplatinum and paclitaxel was very effective in inhibiting tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination therapy in clinical trials.


Well-differentiated neuroendocrine tumor of tailgut cyst. A rare entity with controversial medical opportunities.
The incidence of neuroendocrine tumors is rising, and this rise is explained by more than just better diagnostic procedures. About 85% of these neoplasms arise in gastrointestinal or pulmonary sites, but cases where the location is more unusual also occur in clinical practice. The tailgut cyst is a rare entity well described in the medical literature, but a neuroendocrine tumor within such a cyst is a very rare event, with about 30 cases described in the literature to date. In this report we present the case of a young woman with this unusual diagnosis. The characteristics of the case differ from most previous case reports in a few respects: the patient was a young rather than middle-aged female; she had a presacral mass with a significant solid component; at diagnosis, there was evidence of a lytic lesion in the coccyx. Despite this particular medical presentation, radical surgery was accomplished. In this disease the greatest risk is local relapse, but adjuvant radiotherapy may compromise the patient's fertility. We therefore opted for strict control only, but this decision might be debatable.


Role of acidic amino acids in peptide substrates of the beta-adrenergic receptor kinase and rhodopsin kinase.
The beta-adrenergic receptor kinase (beta-ARK) phosphorylates G protein coupled receptors in an agonist-dependent manner. Since the exact sites of receptor phosphorylation by beta-ARK are poorly defined, the identification of substrate amino acids that are critical to phosphorylation by the kinase are also unknown. In this study, a peptide whose sequence is present in a portion of the third intracellular loop region of the human platelet alpha 2-adrenergic receptor is shown to serve as a substrate for beta-ARK. Removal of the negatively charged amino acids surrounding a cluster of serines in this alpha 2-peptide resulted in a complete loss of phosphorylation by the kinase. A family of peptides was synthesized to further study the role of acidic amino acids in peptide substrates of beta-ARK. By kinetic analyses of the phosphorylation reactions, beta-ARK exhibited a marked preference for negatively charged amino acids localized to the NH2-terminal side of a serine or threonine residue. While there were no significant differences between glutamic and aspartic acid residues, serine-containing peptides were 4-fold better substrates than threonine. Comparing a variety of kinases, only rhodopsin kinase and casein kinase II exhibited significant phosphorylation of the acidic peptides. Unlike beta-ARK, RK preferred acid residues localized to the carboxyl-terminal side of the serine. A feature common to beta-ARK and RK was a much greater Km for peptide substrates as compared to that for intact receptor substrates.


Retrobiosynthetic nuclear magnetic resonance analysis of amino acid biosynthesis and intermediary metabolism. Metabolic flux in developing maize kernels.
Information on metabolic networks could provide the basis for the design of targets for metabolic engineering. To study metabolic flux in cereals, developing maize (Zea mays) kernels were grown in sterile culture on medium containing [U-(13)C(6)]glucose or [1,2-(13)C(2)]acetate. After growth, amino acids, lipids, and sitosterol were isolated from kernels as well as from the cobs, and their (13)C isotopomer compositions were determined by quantitative nuclear magnetic resonance spectroscopy. The highly specific labeling patterns were used to analyze the metabolic pathways leading to amino acids and the triterpene on a quantitative basis. The data show that serine is generated from phosphoglycerate, as well as from glycine. Lysine is formed entirely via the diaminopimelate pathway and sitosterol is synthesized entirely via the mevalonate route. The labeling data of amino acids and sitosterol were used to reconstruct the labeling patterns of key metabolic intermediates (e.g. acetyl-coenzyme A, pyruvate, phosphoenolpyruvate, erythrose 4-phosphate, and Rib 5-phosphate) that revealed quantitative information about carbon flux in the intermediary metabolism of developing maize kernels. Exogenous acetate served as an efficient precursor of sitosterol, as well as of amino acids of the aspartate and glutamate family; in comparison, metabolites formed in the plastidic compartments showed low acetate incorporation.


Ecological uncertainty favours the diversification of host use in avian brood parasites.
Adaptive responses to ecological uncertainty may affect the dynamics of interspecific interactions and shape the course of evolution within symbioses. Obligate avian brood parasites provide a particularly tractable system for understanding how uncertainty, driven by environmental variability and symbiont phenology, influences the evolution of species interactions. Here, we use phylogenetically-informed analyses and a comprehensive dataset on the behaviour and geographic distribution of obligate avian brood parasites and their hosts to demonstrate that increasing uncertainty in thermoregulation and parental investment of parasitic young are positively associated with host richness and diversity. Our findings are consistent with the theoretical expectation that ecological risks and environmental unpredictability should favour the evolution of bet-hedging. Additionally, these highly consistent patterns highlight the important role that ecological uncertainty is likely to play in shaping the evolution of specialisation and generalism in complex interspecific relationships.


[Properties of E. coli of serological group 06:K13(L) isolated in acute intestinal diseases].
A study of 88 E. coli strains belonging to serological group 06: K13 (L) isolated from 50 children and 5 adults suffering from acute intestinal disturbances permitted to refer them to the serological types 06: K13 (L):H1 (82 strains) and 06: K13 (L): H--(6 strains), and to 5 biochemical types. Repeated isolation of E. coli belonging to serlogical group 06: K13 (L) in patients with acute intestinal diseases, and their absence in healthy children and adults indicated these microbes to be a possible etiological factor of the disease and to refer to the group group of enteropathogenic ones. Wide introduction of agglutinating sera 06: K13(L) into the work of practical laboratories is of expedience in connection with this.


Linking post-translational modifications and protein turnover by site-resolved protein turnover profiling.
Proteome-wide measurements of protein turnover have largely ignored the impact of post-translational modifications (PTMs). To address this gap, we employ stable isotope labeling and mass spectrometry to measure the turnover of >120,000 peptidoforms including >33,000 phosphorylated, acetylated, and ubiquitinated peptides for >9,000 native proteins. This site-resolved protein turnover (SPOT) profiling discloses global and site-specific differences in turnover associated with the presence or absence of PTMs. While causal relationships may not always be immediately apparent, we speculate that PTMs with diverging turnover may distinguish states of differential protein stability, structure, localization, enzymatic activity, or protein-protein interactions. We show examples of how the turnover data may give insights into unknown functions of PTMs and provide a freely accessible online tool that allows interrogation and visualisation of all turnover data. The SPOT methodology is applicable to many cell types and modifications, offering the potential to prioritize PTMs for future functional investigations.


Induction of neutralizing antibodies by type 1 poliovirus VP1 capsid polypeptide.
Sera against purified VP1, VP2, and VP3 poliovirus capsid polypeptides of type 1 poliovirus were prepared in rabbits. Each serum was demonstrated to be specific for the polypeptide against which it was raised by immunoprecipitation with labeled, individualized capsid polypeptides. One of the anti-VP1 sera had a neutralizing capacity against type 1 poliovirus. It was the only one which reacted in immunoprecipitation with D-antigenic infectious particles.


Evaluation of a portocaval venograft and ameroid ring for the occlusion of intrahepatic portocaval shunts in dogs.
To evaluate the use of a portocaval venograft and ameroid constrictor in the surgical management of intrahepatic portosystemic shunts (PSS). Prospective, clinical study. Ten client-owned dogs with intrahepatic PSS. Portal pressure was measured after temporary suture occlusion of the intrahepatic PSS. In dogs with an increase in portal pressure greater than 8 mm Hg, a single extrahepatic portocaval shunt was created using a jugular vein. An ameroid ring was placed around the venograft and the intrahepatic PSS was attenuated. Transcolonic pertechnetate scintigraphy was performed before surgery, 5 days after surgery, and 8 to 10 weeks after surgery. Dogs with continued portosystemic shunting were evaluated further by laparotomy or portography. Clinical outcome and complications were recorded. Mean (+/- SD) portal pressure increased from 6 +/- 3 to 19 +/- 6 mm Hg with PSS occlusion; in all 10 dogs, the increase in portal pressure was greater than 8 mm Hg. There were no intraoperative complications, and, after creation of the portocaval shunt, the intrahepatic PSS could be completely ligated in 8 of 10 dogs. The final portal pressure was 9 +/- 4 mm Hg. Postoperative complications included coagulopathy and death (1 dog), ascites (3 dogs), and incisional discharge (3 dogs). Five of 8 dogs had continued portosystemic shunting at 8 to 10 weeks after surgery. Multiple extrahepatic PSS were demonstrated in 4 of these dogs. Clinical outcome was excellent in all 9 surviving dogs. The surgical technique resulted in a high incidence of multiple extrahepatic PSS. Short-term clinical results were promising, but long-term outcome must be evaluated further.


Resilience in family caregiving for people with dementia: A systematic review.
The objective of this review is to critically examine, evaluate, and synthesize the literature on resilience in family caregiving for people with dementia. A systematic literature review was conducted according to PRISMA guidelines to identify articles which examined resilience and related concepts in family caregiving for people with dementia. The review was based on a systematic search of scholarly databases, to yield peer-reviewed articles and grey literature, published between 2006 and 2016. Two independent reviewers prescreened the search results and conducted formal assessments and quality appraisals of the retrieved articles. A total of 13 863 articles were identified by the systematic search, and 52 articles were included in the review. Based on a critical narrative synthesis of the literature, the study proposes a model of resilience for family carers of people with dementia, which incorporates the context of caring, social and cultural characteristics, and psychological dimensions of caring. The results indicate that there is no single approach to enhancing resilience among family carers of people with dementia. Resilience is a multifaceted response to the caregiving role, and is influenced by a multitude of interrelated factors. However, the factors and resources outlined have been addressed, with limited success in some cases, by psychosocial interventions in the field. While the work conducted to date to develop resilience-enhancing interventions has been marked with some success, the next wave of carer research could usefully examine ecological perspectives on carer outcomes, including carer resilience.


Unusual Complication of Hemodialysis Cuffed Catheter Tunnel Infection and Unconventional Therapeutical Decision: A Report of Two Cases.
Infectious complications are the most common chronic complications observed in patients undergoing hemodialysis with central venous catheters. However, despite the efforts of a large number of medical professionals, tunnel catheters are increasingly being used for hemodialysis in the everyday practice. We describe two cases of an equal complication of a tunnel infection wherein the catheter becomes naked after self-rupture of the purulent secretion. We did not replace the tunnel catheter but applied a skin plastic by rotation flaps over the affected area, which proved to be sufficient. Six months after the intervention, the patients continue their hemodialysis treatment using the same cuffed catheters; the taken chemocultures do not give rise only to bacterial growth and skin plastic has been healed primary. The two cases described by us represent one treatment option, which may be discussed with reference to such specific two cases in practice.


B-Lymphocyte Phenotype Determines T-Lymphocyte Subset Differentiation in Autoimmune Diabetes.
Previous studies indicate that B-lymphocytes play a key role activating diabetogenic T-lymphocytes during the development of autoimmune diabetes. Recently, two transgenic NOD mouse models were generated: the NOD-PerIg and the 116C-NOD mice. In NOD-PerIg mice, B-lymphocytes acquire an activated proliferative phenotype and support accelerated autoimmune diabetes development. In contrast, in 116C-NOD mice, B-lymphocytes display an anergic-like phenotype delaying autoimmune diabetes onset and decreasing disease incidence. The present study further evaluates the T- and B-lymphocyte phenotype in both models. In islet-infiltrating B-lymphocytes (IIBLs) from 116C-NOD mice, the expression of H2-Kd and H2-Ag7 is decreased, whereas that of BAFF, BAFF-R, and TACI is increased. In contrast, IIBLs from NOD-PerIg show an increase in CD86 and FAS expression. In addition, islet-infiltrating T-lymphocytes (IITLs) from NOD-PerIg mice exhibit an increase in PD-1 expression. Moreover, proliferation assays indicate a high capacity of B-lymphocytes from NOD-PerIg mice to secrete high amounts of cytokines and induce T-lymphocyte activation compared to 116C B-lymphocytes. This functional variability between 116C and PerIg B-lymphocytes ultimately results in differences in the ability to shape T-lymphocyte phenotype. These results support the role of B-lymphocytes as key regulators of T-lymphocytes in autoimmune diabetes and provide essential information on the phenotypic characteristics of the T- and B-lymphocytes involved in the autoimmune response in autoimmune diabetes.


Editorial: Residual vision and plasticity after visual system damage.
This is an introduction to a special issue of the journal Restorative Neurology and Neuroscience which contains a series of papers presented at a satellite symposium held in conjunction with the European Forum of Neuroscience, Berlin, July 1-2, 1998, entitled "Visual System Damage: Residual Vision and Plasticity". The symposium highlighted research findings both from animals and humans which sustained brain injury in early development and in adulthood. The findings demonstrate the degree of residual vision the injured brain possesses and summarize the effects of drugs and training on the plasticity of the visual system. As this conference demonstrated, the visual system is able to respond in many ways in an adaptive manner to lesions inflicted early in life and in adulthood. These changes may bring about spontaneous recovery of visual functions as long as the brain contains a sufficient capacity of residual vision. Both in children and in adults, systematic visual training can help patients to regain some visual functions which have previously been considered to be irrevocably lost. By carefully assessing residual vision it is proposed that the potential for plasticity of the visual system can be utilized to achieve clinical improvement using appropriate training paradigms.


Maximum Classifier Discrepancy Generative Adversarial Network for Jointly Harmonizing Scanner Effects and Improving Reproducibility of Downstream Tasks.
Multi-site collaboration is essential for overcoming small-sample problems when exploring reproducible biomarkers in MRI studies. However, various scanner-specific factors dramatically reduce the cross-scanner replicability. Moreover, existing harmony methods mostly could not guarantee the improved performance of downstream tasks. we proposed a new multi-scanner harmony framework, called 'maximum classifier discrepancy generative adversarial network', or MCD-GAN, for removing scanner effects in the original feature space while preserving substantial biological information for downstream tasks. Specifically, the adversarial generative network was utilized for persisting the structural layout of each sample, and the maximum classifier discrepancy module was introduced for regulating GAN generators by incorporating the downstream tasks. We compared the MCD-GAN with other state-of-the-art data harmony approaches (e.g., ComBat, CycleGAN) on simulated data and the Adolescent Brain Cognitive Development (ABCD) dataset. Results demonstrate that MCD-GAN outperformed other approaches in improving cross-scanner classification performance while preserving the anatomical layout of the original images. To the best of our knowledge, the proposed MCD-GAN is the first generative model which incorporates downstream tasks while harmonizing, and is a promising solution for facilitating cross-site reproducibility in various tasks such as classification and regression. The codes of the MCD-GAN are available at https://github.com/trendscenter/MCD-GAN.


Photoacclimation responses of the brown macroalga Sargassum Cymosum to the combined influence of UV radiation and salinity: cytochemical and ultrastructural organization and photosynthetic performance.
The photoacclimation responses of the brown macroalga Sargassum cymosum were studied to determine its cytochemical and ultrastructural organization, as well as photosynthetic pigments and performance. S. cymosum was cultivated in three salinities (30, 35 and 40 psu) under four irradiation treatments: PAR-only, PAR + UVA, PAR + UVB and PAR + UVA + UVB. Plants were exposed to PAR at 70 μmol photons m(-2) s(-1), PAR + UVB at 0.35 W m(-2) and PAR +UVA at 0.70 W m(-2) for 3 h per day during 7 days in vitro. Growth rate was not significantly affected by any type of radiation or salinity. The amount of pigments in S. cymosum was significantly influenced by the interaction of salinity and radiation treatments. Compared with PAR-only, UVR treatments modified the kinetics patterns of the photosynthesis/irradiance curve. After exposure to UVR, S. cymosum increased cell wall thickness and the presence of phenolic compounds. The number of mitochondria increased, whereas the number of chloroplasts showed few changes. Although S. cymosum showed insensitivity to changes in salinity, it can be concluded that samples treated under four irradiation regimes showed structural changes, which were more evident, but not severe, under PAR + UVB treatment.


Detection of novel coronaviruses in bats in Myanmar.
The recent emergence of bat-borne zoonotic viruses warrants vigilant surveillance in their natural hosts. Of particular concern is the family of coronaviruses, which includes the causative agents of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and most recently, Coronavirus Disease 2019 (COVID-19), an epidemic of acute respiratory illness originating from Wuhan, China in December 2019. Viral detection, discovery, and surveillance activities were undertaken in Myanmar to identify viruses in animals at high risk contact interfaces with people. Free-ranging bats were captured, and rectal and oral swabs and guano samples collected for coronaviral screening using broadly reactive consensus conventional polymerase chain reaction. Sequences from positives were compared to known coronaviruses. Three novel alphacoronaviruses, three novel betacoronaviruses, and one known alphacoronavirus previously identified in other southeast Asian countries were detected for the first time in bats in Myanmar. Ongoing land use change remains a prominent driver of zoonotic disease emergence in Myanmar, bringing humans into ever closer contact with wildlife, and justifying continued surveillance and vigilance at broad scales.


Chalcomycin biosynthesis gene cluster from Streptomyces bikiniensis: novel features of an unusual ketolide produced through expression of the chm polyketide synthase in Streptomyces fradiae.
Chalcomycin, a 16-membered macrolide antibiotic made by the bacterium Streptomyces bikiniensis, contains a 2,3-trans double bond and the neutral sugar D-chalcose in place of the amino sugar mycaminose found in most other 16-membered macrolides. Degenerate polyketide synthase (PKS)-specific primers were used to amplify DNA fragments from S. bikiniensis with very high identity to a unique ketosynthase domain of the tylosin PKS. The resulting amplimers were used to identify two overlapping cosmids encompassing the chm PKS. Sequencing revealed a contiguous segment of >60 kb carrying 25 putative genes for biosynthesis of the polyketide backbone, the two deoxysugars, and enzymes involved in modification of precursors of chalcomycin or resistance to it. The chm PKS lacks the ketoreductase and dehydratase domains in the seventh module expected to produce the 2,3-double bond in chalcomycin. Expression of PKS in the heterologous host Streptomyces fradiae, from which the tyl genes encoding the PKS had been removed, resulted in production of at least one novel compound, characterized as a 3-keto 16-membered macrolactone in equilibrium with its 3-trans enol tautomer and containing the sugar mycaminose at the C-5 position, in agreement with the structure predicted on the basis of the domain organization of the chm PKS. The production of a 3-keto macrolide from the chm PKS indicates that a discrete set of enzymes is responsible for the introduction of the 2,3-trans double bond in chalcomycin. From comparisons of the open reading frames to sequences in databases, a pathway for the synthesis of nucleoside diphosphate-D-chalcose was proposed.