The significance of covalent binding of catechols to proteins in vivo.
When rats were dosed with 14 microgram/kg 3H-isoproterenol, 3H-radioactivity was measurable in the liver until 48 h. This amount was not different in livers of animals which have been pretreated with diethyl maleate. After exhaustive extraction, a significant amount of 3H-radioactivity from isoproterenol could be detected in the proteins of total liver (homogenate), of cytosol and of microsomes. In the cytosol fraction of diethyl maleate pretreated animals twice the amount of isoproterenol-radioactivity was found in the extracted proteins compared to controls. In the microsomal fraction there was no difference between diethyl maleate pretreated and control animals in the amount of radioactivity incorporated into proteins. In all fractions the radioactivity measurable in the extracted proteins declined with a half life time of about 24 h. The in vivo results on covalent binding of isoproterenol are compared to the irreversible protein binding of ethinyloestradiol in vivo. Quantitatively, these in vivo data are compared to the results on irreversible protein binding obtained during incubations of isoproterenol or ethinyloestradiol with rat liver microsomes.


Ge on Si waveguide mid-infrared absorption spectroscopy of proteins and their aggregates.
Specific proteins and their aggregates form toxic amyloid plaques and neurofibrillary tangles in the brains of people suffering from neurodegenerative diseases such as Alzheimer's and Parkinson's. It is important to study these conformational changes to identify and differentiate these diseases at an early stage so that timely medication is provided to patients. Mid-infrared spectroscopy can be used to monitor these changes by studying the line-shapes and the relative absorbances of amide bands present in proteins. This work focusses on the spectroscopy of the protein, Bovine Serum Albumin as an exemplar, and its aggregates using germanium on silicon waveguides in the 1900-1000 cm-1 (5.3-10.0 µm) spectral region.


The mixture toxicity of environmental contaminants containing sulfonamides and other antibiotics in Escherichia coli: Differences in both the special target proteins of individual chemicals and their effective combined concentration.
Organisms in the environment are exposed to mixtures of multiple contaminants, leading to serious environmental harm. These mixtures pose an ecological risk and have attracted an increasing amount of attention; however there has been little in-depth research the toxicity of mixtures, such as antibiotics. To determine how different mixtures of antibiotics affect organisms, the individual and mixture toxicity of sulfonamides and several antibiotics were determined using Escherichia coli as a target organism in our study. The results show that additive effects occur between sulfonamides and quinolones or with a portion of β-lactams, synergistic effects appear between sulfonamides and their potentiators or cefotaxime sodium, and antagonistic effects arise between sulfonamides and tetracyclines or penicillin V potassium salt. In addition, the toxicity mechanism of binary mixtures is further discussed and the results reveal that the joint effect differences depend not only the target proteins of individual chemicals but also on their effective combined concentration based on the approach of Quantitative Structure Activity Relationships (QSARs) and molecular docking. This study introduces the concept of the "effective concentration" to provide insight into understanding the mechanism of binary mixtures, which will be beneficial for evaluating the ecological risk of antibiotics.


Synthesis and use of bifunctional chloromethylalkanedione derivatives of variable chain length for cross-linking thiol groups in oligomeric proteins. Specific cross-linking in glyceraldehyde 3-phosphate dehydrogenase.
Bischloromethylpentanedione, bischloromethylhexanedione, bischloromethyloctanedione and bischloromethyldecanedione were synthesized from their corresponding dicarboxylic acids via the bis-acyl chloride and the bisdiazomethylketone derivatives. These compounds proved to be highly specific cross-linking reagents for rabbit skeletal-muscle glyceraldehyde 3-phosphate dehydrogenase. Incubation of the enzyme with cross-linking reagents resulted in both a time- and concentration-dependent formation of covalently linked oligomeric structures. The major cross-linked product detected by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis was the dimer (mol. wt. 72000). Sepharose 6B chromatography of the cross-linked enzyme showed that it still existed as the tetramer. Cross-linking was dependent on the native structure of the enzyme, since it was abolished on denaturation of the enzyme. The actual covalently linked product depends on the conditions of modification and the chain length of the reagent. The maximum yield of dimer (70-80%) was obtained with bischloromethylhexanedione, and the yield decreased with either shorter- or longer-chain compounds. The calculated distance between the two reactive points in bischloromethylhexanedione is 1.21-1.45nm. Bischloromethylhexanedione modified at least two thiol groups per monomer. Modification of the active-site thiol, cysteine-149, was not essential for cross-linking, since glyceraldehyde 3-phosphate dehydrogenase carboxymethylated on cysteine-149 still reacted to form the dimer. The rate of chemical cross-linking was markedly decreased by increasing the NAD(+) occupancy of the enzyme active sites. These experiments are discussed in terms of the asymmetry of the enzyme structure in solution.


Single-step synthesis of D3h-symmetric bicyclooxacalixarenes.
Bicyclooxacalixarenes are obtained in up to 95% yield by condensation of phloroglucinol with electron-poor meta-dihalogenated benzenes or pyridines. Single-crystal X-ray analysis reveals that these compounds adopt highly symmetrical, all-1,3-alternate cage-like structures. [structure: see text]


Strategic Reduction of Package Time in Head and Neck Cancer.
Total package time, or the time from diagnosis to completion of definitive treatment, has been associated with outcomes for a variety of tumor sites, but especially to head and neck (HN) cancer. Patients with HN cancer often undergo a complex diagnosis and treatment process involving multiple disciplines both within and outside of oncology. This complexity can lead to longer package times, and each involved discipline has the responsibility to maintain an efficient and effective process. Strategic intervention to improve package time must involve not only new technology or tools, but also "soft" components such as accountability, motivation, and leadership. This combination is necessary to truly optimize radiation therapy for HN cancer, leading to shorter total package times for these patients. Two interventions were strategically executed to improve radiation therapy workflow: upgrade of the treatment planning system and implementation of an automated patient management and accountability system. The radiation therapy-related timelines of 112 patients with HN cancer treated over 2 years were reviewed, and the average time differences were compared between the patient populations before and after the strategic interventions. Purely upgrading the treatment planning system did not show significant improvements, but when combined with the patient management system, significant improvement in radiation-related package time can be noted for every time point. The overall reduction of radiation-related package time was statistically significant at 22.85 days (P = .002). On face value, the patient management system could be credited as responsible for the improvement, but on qualitative analysis, it is noted that the new system is only a tool that can be ignored or underused. Owing to the addition of important "soft" components such as accountability, motivation, and leadership, the patient management system was optimized and implemented in such a manner as to have the desired effect.


Genome-wide identification and analysis of the invertase gene family in tobacco (Nicotiana tabacum) reveals NtNINV10 participating the sugar metabolism.
Sucrose (Suc) is directly associated with plant growth and development as well as tolerance to various stresses. Invertase (INV) enzymes played important role in sucrose metabolism by irreversibly catalyzing Suc degradation. However, genome-wide identification and function of individual members of the INV gene family in Nicotiana tabacum have not been conducted. In this report, 36 non-redundant NtINV family members were identified in Nicotiana tabacum including 20 alkaline/neutral INV genes (NtNINV1-20), 4 vacuolar INV genes (NtVINV1-4), and 12 cell wall INV isoforms (NtCWINV1-12). A comprehensive analysis based on the biochemical characteristics, the exon-intron structures, the chromosomal location and the evolutionary analysis revealed the conservation and the divergence of NtINVs. For the evolution of the NtINV gene, fragment duplication and purification selection were major factors. Besides, our analysis revealed that NtINV could be regulated by miRNAs and cis-regulatory elements of transcription factors associated with multiple stress responses. In addition, 3D structure analysis has provided evidence for the differentiation between the NINV and VINV. The expression patterns in diverse tissues and under various stresses were investigated, and qRT-PCR experiments were conducted to confirm the expression patterns. Results revealed that changes in NtNINV10 expression level were induced by leaf development, drought and salinity stresses. Further examination revealed that the NtNINV10-GFP fusion protein was located in the cell membrane. Furthermore, inhibition of the expression of NtNINV10 gene decreased the glucose and fructose in tobacco leaves. Overall, we have identified possible NtINV genes functioned in leaf development and tolerance to environmental stresses in tobacco. These findings provide a better understanding of the NtINV gene family and establish the basis for future research.


Improved catalytic hydrogen release of quasi HKUST-1 compared to HKUST-1.
On-demand hydrogen release could be an important process for the transportation of fuel in the near future. Herein it is reported that the controlled thermolysis of HKUST-1 under optimal conditions generates structural defects resulting in a quasi-HKUST-1 material showing a 20-fold enhancement of the H2 release turnover frequency at room temperature in the absence of a base.


Glycolytic metabolism in cultured cells of the nervous system. I. Glucose transport and metabolism in the C-6 glioma cell line.
The transport and metabolism of glucose was examined in monolayers of C-6 glioma cells. 1) Glucose transport appeared to have both a low (Km = 7.74 mM) and a high (Km = 1.16 mM) affinity site in C-6cells; whereas 2-deoxyglucose had only one (Km = 3.7 mM). 2) A large portion of the accumulated glucose was rapidly metabolized to the two glycolytic end products, lactate and pyruvate, and then extruded into the medium. The temperature-dependent efflux of lactate and pyruvate was linear up to 2 hrs with 6 to 10 times more lactate being extruded into the medium than pyruvate. 3) The efflux of lactate and pyruvate increased with increasing extracellular (medium) pH. The presence of 5 percent CO2 not only inhibited the acid efflux but also inhibited the short-term uptake of glucose. The CO2 effect was attributed to a lowering of the medium pH since bicarbonate alone either increased or did not inhibit efflux. 4) Valinomycin increased the levels of cellular lactate but not those of pyruvate by almost three-fold. Lactate efflux was stimulated while that of pyruvate was inhibited. The addition of 5 percent CO2 increased the cellular levels of both lactate and pyruvate, but unlike valinomycin decreased the acid efflux. Idoacetate inhibited the acid efflux by 50 percent suggesting that glycolysis is necessary for efflux.


Transcriptomic analysis of Verbena bonariensis roots in response to cadmium stress.
Cadmium (Cd) is a serious heavy metal (HM) soil pollutant. To alleviate or even eliminate HM pollution in soil, environmental-friendly methods are applied. One is that special plants are cultivated to absorb the HM in the contaminated soil. As an excellent economical plant with ornamental value and sound adaptability, V. bonariensis could be adapted to this very situation. In our study, the Cd tolerance in V. bonariensis was analyzed as well as an overall analysis of transcriptome. In this study, the tolerance of V. bonariensis to Cd stress was investigated in four aspects: germination, development, physiological changes, and molecular alterations. The results showed that as a non-hyperaccumulator, V. bonariensis did possess the Cd tolerance and the capability to concentration Cd. Under Cd stress, all 237, 866 transcripts and 191, 370 unigenes were constructed in the transcriptome data of V. bonariensis roots. The enrichment analysis of gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed that differentially expressed genes (DEGs) under Cd stress were predominately related to cell structure, reactive oxygen species (ROS) scavenging system, chelating reaction and secondary metabolites, transpiration and photosynthesis. DEGs encoding lignin synthesis, chalcone synthase (CHS) and anthocyanidin synthase (ANS) were prominent in V. bonariensis under Cd stress. The expression patterns of 10 DEGs, validated by quantitative real-time polymerase chain reaction (qRT-PCR), were in highly accordance with the RNA-Sequence (RNA-Seq) results. The novel strategies brought by our study was not only benefit for further studies on the tolerance of Cd and functional genomics in V. bonariensis, but also for the improvement molecular breeding and phytoremediation.


Understanding Pig and Poultry Trade Networks and Farming Practices Within the Pacific Islands as a Basis for Surveillance.
Pacific Island countries have large pig and poultry populations. Yet little is known about patterns of contact between animals and how this influences disease spread in these islands. The objectives of this study were to examine farmer practices and the movements of pig and poultry within the Pacific Islands using questionnaires and social network analysis (SNA) tools to understand disease spread in the region. Questionnaire-based surveys were conducted in Fiji, Papua New Guinea (PNG), Solomon Islands and Vanuatu with interviews of 310 pig farmers and 491 poultry farmers. Pacific Island farmers were found to have few animals (median = 7 pigs/farm, IQR 4-12), (median = 50 chicken/farm, IQR 23-52), (median = 10 ducks/farm, IQR 4-25), (median = 12 Muscovy ducks/farm, IQR 7-28) and a diversified number of species. A large proportion of farmers (44.6-61.3%) do not implement any preventive or control measures, yet the majority (80.6-88%) did not experience any animal diseases over the past 12 months. Most farmers never ask for veterinary care, never engage in laboratory testing and do not report when their animals show clinical signs. Many pig farmers (31.8%) trade within their communities only and sell (24.5%) directly to consumers which reduces the risk of diseases spreading. Our results show an association between farmers that report having had disease on their farm in the past 12 months and movements of animals on and off their farms. The capitals of the studied provinces in PNG, Vanuatu and Solomon Islands were identified as the most connected nodes of both pig and poultry trade, while Fiji networks appeared much less connected. Our study found that farmer practices increased the risk of disease spread, but this was currently limited by trading practices. The SNA results serve as a basis for more targeted disease surveillance and better use of available resources for disease prevention and control.


FMRFamide-like midgut endocrine cells during the metamorphosis in Melipona quadrifasciata anthidioides (Hymenoptera, Apidae).
The FMRFamide, gastrin and cholecystokinin (CCK) occurrence in endocrine cells of insects has been described by several authors, although their functions are still not well defined for this group of animals. In the present study, the occurrence of endocrine cells producing FMRFamide, gastrin 1 and CCK-8 in the midgut (ventriculus) of Melipona quadrifasciata anthidioides (Hymenoptera, Apidae), before, during and after the metamorphosis, were investigated by means of pre-embedding immunofluorescence techniques. FMRFamide reactivity was found in the endocrine cells as well as in the nervous fibers and neurons of the intestine of these bees. 'Open' and 'closed' types of FMRFamide-like cells were observed in last instar larvae. In the black eyed pupae the producing cells of FMRFamide seemed to be immature, and, in the workers, where the FMRFamide producing cells were more abundant, the production of this substance seemed to occur only in the open cells. Reactivity of the nervous fibers and neurons were observed, during the prepupae, white eyed pupae, and pink eyed pupae. The same did not occur with the midgut endocrine cells. There were no immunoreactivity observations for gastrin 1 and for CCK-8. The FMRFamide-like cells were present in the midgut of these insects during or close to the period that they were eating, which indicates that the FMRFamide may be involved in the control of the digestive process.


Alveolar bone morphology of maxillary central incisors near grafted alveolar clefts after orthodontic treatment.
The aim of this study was to evaluate the thickness and the height of the maxillary central incisors' alveolar bone near the grafted alveolar cleft area, after comprehensive orthodontic treatment. The sample comprised 30 patients with unilateral alveolar cleft with a mean age of 20.5 years (range, 17-25.8 years). High-resolution cone-beam computed tomography images of the maxilla were obtained 6 to 24 months after the comprehensive orthodontic treatment. The contralateral maxillary central incisor was used as a comparison group. Axial sections at the level of the central incisor root were used to measure the labial and lingual alveolar bone thicknesses. Cross sections were used to measure the bone crest heights using the cementoenamel junction as the reference. Paired t and Wilcoxon tests were used to compare the cleft and noncleft sides. The labial and lingual bone thicknesses of the maxillary central incisors' alveolar bone were significantly thinner (0.16 and 0.39 mm, respectively), and the labial alveolar crest height distance was significantly greater on the cleft side compared with the noncleft side (-1.2 mm). In patients with unilateral cleft lip and palate, the maxillary central incisors adjacent to the grafted alveolar cleft had thinner labial and lingual alveolar bones and an apically displaced labial alveolar crest level than the controls.


Structure-activity relationships of simplified resiniferatoxin analogues with potent VR1 agonism elucidates an active conformation of RTX for VR1 binding.
We previously described a series of N-(3-acyloxy-2-benzylpropyl) homovanillate and N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives that were potent VR1 agonists with high-affinities and excellent analgesic profiles. The design of these simplified RTX analogues was based on our RTX-derived pharmacophore model which incorporates the 4-hydroxy-3-methoxyphenyl (A-region), C(20)-ester (B-region), orthophenyl (C1-region) and C(3)-keto (C2-region) groups of RTX. For the purpose of optimizing the spatial arrangement of the four principal pharmacophores on the lead agonists (1-4), we have modified the distances in the parent C-region, 3-acyloxy-2-benzylpropyl groups, by lengthening or shortening one carbon to vary the distances between the pharmacophores. We find that two of the amides, 4 and 19, possess EC(50) values <1 nM for induction of calcium influx in the VR1-CHO cells. As observed previously, the structure-activity relations for inhibition of RTX binding to VR1 and for induction of calcium uptake were distinct, presumably reflecting both intrinsic and methodological factors. In order to find the active conformation of VR1 ligands, the energy-minimized conformations of seven selected agonists were determined and the positions of their four pharmacophores were matched with those of five low energy RTX conformations. The rms values for the overlaps in the pharmacophores were calculated and correlated with the measured binding affinities (K(i)) and calcium influx (EC(50)) values. The binding affinities of the agonists correlated best with the RMS values derived from RTX conformation E (r(2)=0.92), predicting a model of the active conformation of RTX and related vanilloids for binding to VR1. Poorer correlation was obtained between any of the conformations and the EC(50) values for calcium influx.


Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.
Helicobacter pylori ( H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori -induced disease progression. We have established a Helicobacter -induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene ( Myd88 -/- ) with H. felis . Using this model, we report here that that progression of H. felis -induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis -induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-β (TRIF, Trif Lps 2 ) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.


Pulse oximetry: physical principles, technical realization and present limitations.
Oximetry for continuous patient monitoring has evolved to a mature technology that is clinically useful. Technologic limitations, however, still exist and there is need to develop more reliable, less expensive systems that will allow new applications such as fetal and home infant and adult monitoring. Although it is not possible to fully monitor patient blood gas status with a single variable, pulse oximetry provides an important view of the blood oxygen content that can be combined with other monitoring methods to more fully characterize patient status.


Acquisition of antibiotic-resistant Enterococcus faecium strains during long-term hospitalization and fast adaptation of enterococcal flora to antibiotic treatment: a case report.
Recently, it has been suspected that long durations of hospitalization might be a possible risk factor to get colonized by multiple VRE strains. Here we present the case of a patient who underwent stem cell transplantation and subsequently stayed at the hospital for about 4 months until death. At least four different Enterococcus faecium strains were identified from routinely taken microbiological specimens as demonstrated by pulsed-field gel-electrophoresis. Additionally, these strains showed variable susceptibility to quinupristine/dalfopristine, vancomycin, and/or linezolid depending on different antibiotic administrations. These findings indicate that patients might be colonized with multiple Enterococcus faecium strains and that the enterococcal flora quickly adapts due to antibiotic exposure.


Time-dependent toxicity of drugs used in cancer chemotherapy: separate and combined administration.
Time-dependent toxicity of 3 anti-cancer drugs was demonstrated in BALB/c mice. Cisplatinum, adriamycin and cyclophosphamide were injected at 4 different circadian stages, either together (combined injection) or separately, to different groups of mice. Toxicity was evaluated by body-weight changes, mortality and white blood cell counts. Maximal body-weight loss was caused by the administration of either Cisplatinum or the combination of all 3 drugs at 15.00 hr and 21.00 hr, i.e., 9 and 15 hr after light on (HALO). Only moderate body weight loss was induced when adriamycin was injected at 09.00 hr or at 21.00 hr (3 and 15 HALO). In contrast to Cisplatinum and adriamycin, cyclophosphamide induced no significant change in body weight when injected at either time. The highest level of mortality was caused by the injection of all 3 drugs together at 21.00 hr (15 HALO). No death occurred when drugs were administered separately. The rate of recovery (as assessed by weight regain) also exhibited dependence upon the time of drug administration and was the slowest after injections at 21.00 hr (15 HALO). It appears, therefore, that the time-dependence modes of toxicity and recovery (as assessed by body-weight change) are different. The decrease in white blood cell count also exhibited a time-dependence pattern which differed from that of weight loss and death.


Construction of photo-cross-linked microarrays of small molecules.
Small molecule microarrays are one of the most promising approaches to screen ligand molecules for individual proteins of interest. However, their potential has not been fully realized due to the limited number of methods to introduce small molecules onto the solid surfaces. To expand the compatibility of small molecule microarrays, we have developed a unique photo-cross-linking approach for immobilizing various small molecules, including natural products, on glass slides.


[Withdrawing and withholding treatments in acute severe stroke patients: clinical and ethical issues].
Stroke prognosis remains difficult to determine. It depends on stroke severity, patient's age and his rehabilitation ability. In essence, individual prediction is uncertain. Neurological severity is related to many factors such as low blood pressure or hyperthermia, which are important to consider before prognosticate. Do-not-resuscitate orders are given in up to 30% of acute stroke. More than 50% of them are given upon admission (in the first 24h of stroke). Withdrawing and withholding treatments are usually decided when neurological prognosis is supposed to be "catastrophic". Other factors, such as physician's disability representation or hospital use of aggressive procedures, certain daily routines or organizational constraints, are also probably implied. In France, end-of-life decisions are guided by the law: "loi relative aux droits des malades et à la fin de vie du 22 avril 2005". Palliative approach in severe stroke remains unknown and rarely developed, but is necessary to implement in such situations with high mortality rate. End-of-life decisions in severe stroke have several ethical issues such as the definition of what could be an "unacceptable" disability for the individual and/or the society.


Unveiling microbial structures during raw microalgae digestion and co-digestion with primary sludge to produce biogas using semi-continuous AnMBR systems.
Methane production from microalgae can be enhanced through anaerobic co-digestion with carbon-rich substrates and thus mitigate the inhibition risk associated with its low C:N ratio. Acclimated microbial communities for microalgae disruption can be used as a source of natural enzymes in bioenergy production. However, co-substrates with a certain microbial diversity such as primary sludge might shift the microbial structure. Substrates were generated in a Water Resource Recovery Facility (WRRF) and combined as follows: Scenedesmus or Chlorella digestion and microalgae co-digestion with primary sludge. The study was performed using two lab-scale Anaerobic Membrane Bioreactors (AnMBR). During three years, different feedstocks scenarios for methane production were evaluated with a special focus on the microbial diversity of the AnMBR. 57% of the population was shared between the different feedstock scenarios, revealing the importance of Anaerolineaceae members besides Smithella and Methanosaeta genera. The addition of primary sludge enhanced the microbial diversity of the system during both Chlorella and Scenedesmus co-digestion and promoted different microbial structures. Aceticlastic methanogen Methanosaeta was dominant in all the feedstock scenarios. A more remarkable role of syntrophic fatty acid degraders (Smithella, Syntrophobacteraceae) was observed during co-digestion when only microalgae were digested. However, no significant changes were observed in the microbial composition during anaerobic microalgae digestion when feeding only Chlorella or Scenedesmus. This is the first work revealing the composition of complex communities for semi-continuous bioenergy production from WRRF streams. The stability and maintenance of a microbial core over-time in semi-continuous AnMBRs is here shown supporting their future application in full-scale systems for raw microalgae digestion or co-digestion.


Twelve-Year Trajectory of Disease Burden and Mortality by Obesity Level in Korea: Analysis of the National Health Insurance Service Database.
Despite increases in obesity prevalence, awareness of obesity as a disease requiring active treatment remains lacking in Korea. We investigated differences in medical problems and expenditures and mortality across obesity categories using 12-year data from the National Health Insurance Service. Individuals aged 40-79 years who underwent medical examinations during 2003-2004 (n = 415,201) were divided based on Asian body mass index (kg/m2) criteria: normal weight (18.5 to < 23.0, 36.4%), overweight (23.0 to < 25.0, 28.3%), obesity (25.0 to < 30.0, 32.5%), and severe obesity (≥ 30.0, 2.8%). Medical problems and expenditures were fitted to linear mixed models. Mortality was analyzed via Cox proportional-hazards model. More severe obesity was associated with a higher rate of medical problems, relative to normal weight: coefficient = 0.31 (95% confidence interval [CI], 0.30-0.32) for overweight, 0.61 (0.60-0.61) for obesity, and 1.07 (1.04-1.09) for severe obesity. A similar association was observed for medical expenditure: coefficient = 8.85 (95%CI, 6.80-10.89) for overweight, 20.04 (18.07-22.01) for obesity, and 48.76 (43.66-53.86) for severe obesity. Relative to overweight participants, those with normal weight and severe obesity exhibited a higher mortality risk (hazard ratio [HR] 1.21 [95%CI, 1.18-1.25] for normal; 1.27 [1.19-1.36] for severe obesity). In age-specific analyses, mortality risk was the highest for participants with severe obesity, aged < 60 years (HR, 1.58 [95%CI, 1.41-1.77]). Disease burden including medical problems and expenditure, and mortality in middle-aged adults, increased proportionally to the degrees of obesity. Health policies and medical systems aimed at reducing the burden of obesity may help reduce the burden of disease on society.


Heteronuclear NMR provides an accurate assessment of therapeutic insulin's quality.
New generations of drugs are using more and more often therapeutic proteins as the active ingredient, prompting the regulation agencies to adapt their analytical methods. Fast and unambiguous information on the secondary, tertiary and quaternary structure of the protein should be provided to assess the quality of these biodrugs. Recent developments of heteronuclear NMR methods, enabling their use on pharmaceutical formulated unlabeled proteins, provide an efficient way to perform such analysis, a feature that is illustrated here using various commercial formulations of insulins.


The mechanism of Megalobrama amblycephala muscle injury repair based on RNA-seq.
Skeletal muscle myogenesis and injury-induced muscle regeneration contribute to muscle formation. Skeletal muscle stem cells, termed satellite cells (SCs), proliferate to repair injured muscle. To identify the molecular mechanism of regeneration after muscle injury as well as the genes related to muscle development in fish, in this study, the immunohistochemistry and the high-throughput RNA sequencing (RNA-seq) analysis were performed after Megalobrama amblycephala muscle was injured by needle stab. The results showed that paired box7-positive (Pax7+) SCs increased, and peaked at 96 to 144 h-post injury (hpi). The 6729 differentially expressed genes (DEGs), including 2125 up-regulated and 4604 down-regulated genes were found. GO terms significantly enriched by DEGs contained intercellular connections, signaling transduction and enzyme activity. KEGG enrichment analysis showed that most of the pathways were related to immunity, metabolism and cells related molecules, including actin skeleton regulation, Epstein Barr virus infection and plaque adhesion. The WGCNA results revealed that actin cytoskeleton and lipid metabolism related genes probably played crucial roles during repair after muscle injury. Collectively, all these results will provide new insights into the molecular mechanisms underlying muscle injury repair of fish.


Disturbed boundaries extraction in coal-grain overlap areas with high groundwater levels using UAV-based visible and multispectral imagery.
With high groundwater levels, coal-grain overlap areas (CGOAs) are vulnerable to subsidence and water logging during mining activities, thereby impacting crop yields adversely. Such damage requires full reports of disturbed boundaries for agricultural reimbursement and ongoing reclamation, but because direct measurements are difficult in such cases because of vast unreachable areas, it is necessary to be able to identify out-of-production boundaries (OBs) and reduced-production boundaries (RBs) in the corresponding region. In this study, an OB was extracted by setting a threshold via the characteristics of the cultivated-land elevation based on a digital surface model and a digital orthophoto map generated using an unmanned aerial vehicle (UAV). Meanwhile, the above-ground biomass (AGB), the soil plant analysis development (SPAD) value of chlorophyll contents, and leaf area index (LAI) were used to select the appropriate vegetation indices (VIs) to produce a reduced-production map (RM) based on power regression (PR), exponential regression (ER), multiple linear regression (MR), and random forest (RF) algorithms. Finally, an improved Otsu segmentation algorithm was used to extract mild and severe RBs. The results showed the following. (1) Crop growth heights in a typical ponding basin of the CGOA rendered a fast and efficient approach to distinguishing the OB. (2) In subsequent sample modeling, the red-edge microwave VI (MVIredge), the normalized difference VI (NDVI), and the red-edge modified simple ratio index (MSRredge) combined with RF were shown to be optimal estimators for AGB (R2 = 0.83, RMSE = 0.114 kg·m-2); the red-edge NDVI (NDVIredge), the green NDVI (GNDVI), and the red-edge chlorophyll index (CIredge) acted as strong tools in SPAD prediction using RF (R2 = 0.83, RMSE = 0.152 SPAD); the red-edge modified simple ratio index (MSRredge), the GNDVI, and the green chlorophyll index (CIgreen) via MR were more accurate when conducting the inversion of LAI (R2 = 0.88, RMSE = 1.070). (3) With the improved Otsu algorithm, multiple degrees of RB extraction can be achieved in RM. This study provides reference methods and theoretical support for determining disturbed boundaries in CGOAs with high groundwater levels for further agricultural compensation and reclamation processes.


Neurobiological perspective on the development of executive functions.
Executive functions are a set of top-down cognitive processes necessary for emotional self-regulation and goal-directed behaviour supporting, among others, academic abilities. Premature infants are at high risk for subsequent cognitive, psychosocial, or behavioural problems even in the absence of medical complications and in spite of normal brain imaging. Given that this is a sensitive period of brain growth and maturation, these factors may place preterm infants at high risk for executive function dysfunction, disrupted long-term development, and lower academic achievements. Therefore, careful attention to interventions at this age is essential for intact executive functions and academic development.


Incidence of and risk factors for postoperative ileus in women undergoing primary staging and debulking for epithelial ovarian carcinoma.
Thorough primary cytoreduction for epithelial ovarian carcinoma (EOC) improves survival. The incidence of postoperative ileus (POI) in these patients may be underreported because of varying POI definitions and the evolving, increasingly complex contemporary surgical approach to EOC. We sought to determine the current incidence of POI and its risk factors in women undergoing debulking and staging for EOC. We retrospectively identified the records of women who underwent primary staging and cytoreduction for EOC between 2003 and 2008. POI was defined as a surgeon's diagnosis of POI, return to nothing-by-mouth status, or reinsertion of a nasogastric tube. Perioperative patient characteristics and process-of-care variables were analyzed. Univariate analyses were used to identify POI risk factors; variables with P ≤.20 were included in multivariate analysis. Among 587 women identified, the overall incidence of POI was 30.3% (25.9% without bowel resection, 38.5% with bowel resection; P=.002). Preoperative thrombocytosis, involvement of bowel mesentery with carcinoma, and perioperative red blood cell transfusion were independently associated with increased POI. Postoperative ibuprofen use was associated with decreased POI risk. Women with POI had a longer length of stay (median, 11 vs 6 days) and increased time to recovery of the upper (7.5 vs 4 days) and lower (4 vs 3 days) gastrointestinal tract (P<.001 for each). The rate of POI is substantial among women undergoing staging and cytoreduction for EOC and is associated with increased length of stay. Modifiable risk factors may include transfusion and postoperative ibuprofen use. Alternative interventions to decrease POI are needed.


Evaluating a risk assessment tool to improve triaging of patients to colonoscopies.
Colonoscopy is the gold standard in the diagnosis of significant bowel disease (SBD), including colorectal cancer, high-risk adenoma and inflammatory bowel disease. As the demand for colonoscopy services is placing significant pressure on hospital resources, new solutions are needed to manage patients more efficiently and effectively. We investigated the impact of using a risk assessment tool (RAT) to improve selection of patients for colonoscopy procedures to detect SBD. A hybrid simulation model was constructed to replicate the current patient triage bookings and waiting times in a large metropolitan hospital. The model used data on 327 patients who were retrospectively assessed for risk of SBD. Risk assessment incorporated blood and faecal immunochemical test results, gender and age in addition to patient symptoms. The model was calibrated over 12 months to current outcomes and was compared with the RAT and a third scenario where low-risk patients did not proceed to a colonoscopy. One-way sensitivity analyses were undertaken. Using the RAT was expected to shorten waiting times by 153 days for moderately-urgent patients and 138 days for non-urgent patients. If low-risk patients did not proceed to colonoscopy, waiting times were expected to reduce for patients with SBD by 17 days producing cost-savings of AU$373 824 through avoided colonoscopies. A hybrid model that combines patient-level characteristics with hospital-level resource constraints can demonstrate improved efficiency in a hospital clinic. Further research on risk assessment is required to improve quality patient care and reduce low-value service delivery.


Waves in a Stochastic Cell Motility Model.
In Bhattacharya et al. (Sci Adv 6(32):7682, 2020), a set of chemical reactions involved in the dynamics of actin waves in cells was studied at two levels. The microscopic level, where the individual chemical reactions are directly modelled using Gillespie-type algorithms, and on a macroscopic level where a deterministic reaction-diffusion equation arises as the large-scale limit of the underlying chemical reactions. In this work, we derive, and subsequently study, the related mesoscopic stochastic reaction-diffusion system, or chemical Langevin equation, that arises from the same set of chemical reactions. We explain how the stochastic patterns that arise from this equation can be used to understand the experimentally observed dynamics from Bhattacharya et al. In particular, we argue that the mesoscopic stochastic model better captures the microscopic behaviour than the deterministic reaction-diffusion equation, while being more amenable for mathematical analysis and numerical simulations than the microscopic model.


Study of model systems to test the potential function of Artemia group 1 late embryogenesis abundant (LEA) proteins.
Embryos of the brine shrimp, Artemia franciscana, are genetically programmed to develop either ovoviparously or oviparously depending on environmental conditions. Shortly upon their release from the female, oviparous embryos enter diapause during which time they undergo major metabolic rate depression while simultaneously synthesize proteins that permit them to tolerate a wide range of stressful environmental events including prolonged periods of desiccation, freezing, and anoxia. Among the known stress-related proteins that accumulate in embryos entering diapause are the late embryogenesis abundant (LEA) proteins. This large group of intrinsically disordered proteins has been proposed to act as molecular shields or chaperones of macromolecules which are otherwise intolerant to harsh conditions associated with diapause. In this research, we used two model systems to study the potential function of the group 1 LEA proteins from Artemia. Expression of the Artemia group 1 gene (AfrLEA-1) in Escherichia coli inhibited growth in proportion to the number of 20-mer amino acid motifs expressed. As well, clones of E. coli, transformed with the AfrLEA-1 gene, expressed multiple bands of LEA proteins, either intrinsically or upon induction with isopropyl-β-thiogalactoside (IPTG), in a vector-specific manner. Expression of AfrLEA-1 in E. coli did not overcome the inhibitory effects of high concentrations of NaCl and KCl but modulated growth inhibition resulting from high concentrations of sorbitol in the growth medium. In contrast, expression of the AfrLEA-1 gene in Saccharomyces cerevisiae did not alter the growth kinetics or permit yeast to tolerate high concentrations of NaCl, KCl, or sorbitol. However, expression of AfrLEA-1 in yeast improved its tolerance to drying (desiccation) and freezing. Under our experimental conditions, both E. coli and S. cerevisiae appear to be potentially suitable hosts to study the function of Artemia group 1 LEA proteins under environmentally stressful conditions.


[Effects on exocrine pancreatic secretion in swine of the prolonged intravenous administration of glucose: application to the study of dietary adaptation mechanisms].
The effects of intravenous glucose perfusion were studied in the pancreatic juice of fistulated pigs. Perfusions were performed either discontinuously for 3 hrs in the fasted or for 6 hrs a day over 6 days in the fed animal. Pancreatic juice volume, total proteins and total activities of chymotrypsin, amylase and lipase were always significantly lowered by glucose given intravenously. Amylase seemed to be the most inhibited of the three enzymes studied. It appeared that prolonged intravenous glucose perfusion could not reproduce in the pig the pancreatic amylase adaptation seen after oral administration of glucose.


The compatibilization of poly (propylene carbonate)/poly (lactic acid) blends in presence of core-shell starch nanoparticles.
A novel core-shell starch-based nanoparticles (CSS NPs) with a "hard" starch core and a "soft" poly (methyl acrylate) (PMA) shell was prepared and incorporated into a PPC/PLA blend. The excellent compatibilization of CSS NPs was revealed by atomic force microscope (AFM), differential scanning calorimetry (DSC) and rheological test. More importantly, due to the excellent compatibilization the resulted PPC/PLA/CSS blend exhibited a strikingly improved mechanical and thermal properties. Compared to PPC/PLA (60/40), the elongation at break of PPC/PLA/CSS (60/40/20) increased greatly from 15 % to 272 % without sacrificing the tensile strength. Besides, the heat distortion temperature (HDT) of PPC/PLA/CSS (60/40/20) was improved to 47.3 °C, which was 20.5 °C higher than that of the neat PPC. These results established a novel and efficient strategy to improve the compatibility of polymer blends and to prepare polymer blends with balanced toughness and stiffness.


Empirical field mapping for gradient nonlinearity correction of multi-site diffusion weighted MRI.
Achieving inter-site / inter-scanner reproducibility of diffusion weighted magnetic resonance imaging (DW-MRI) metrics has been challenging given differences in acquisition protocols, analysis models, and hardware factors. Magnetic field gradients impart scanner-dependent spatial variations in the applied diffusion weighting that can be corrected if the gradient nonlinearities are known. However, retrieving manufacturer nonlinearity specifications is not well supported and may introduce errors in interpretation of units or coordinate systems. We propose an empirical approach to mapping the gradient nonlinearities with sequences that are supported across the major scanner vendors. Prospective observational study. A spherical isotropic diffusion phantom, and a single human control volunteer. 3 T (two scanners). Stejskal-Tanner spin echo sequence with b-values of 1000, 2000 s/mm2 with 12, 32, and 384 diffusion gradient directions per shell. We compare the proposed correction with the prior approach using manufacturer specifications against typical diffusion pre-processing pipelines (i.e., ignoring spatial gradient nonlinearities). In phantom data, we evaluate metrics against the ground truth. In human and phantom data, we evaluate reproducibility across scans, sessions, and hardware. Wilcoxon rank-sum test between uncorrected and corrected data. In phantom data, our correction method reduces variation in mean diffusivity across sessions over uncorrected data (p < 0.05). In human data, we show that this method can also reduce variation in mean diffusivity across scanners (p < 0.05). Our method is relatively simple, fast, and can be applied retroactively. We advocate incorporating voxel-specific b-value and b-vector maps should be incorporated in DW-MRI harmonization preprocessing pipelines to improve quantitative accuracy of measured diffusion parameters.


Factors influencing the prognosis of acute renal failure. (Analysis of 228 cases).
Two hundred and twenty-eight patients were treated for acute renal failure between October, 1964, and December 31, 1976. Complex antiuraemic therapy has been applied in 96, and haemodialysis or peritoneal dialysis in 132 cases. The overall mortality rate was 40.7%. The part played by age, primary process and possible complications of acute renal failure in the mortality figures is examined. From the analysis of clinical features, infections and septicaemia emerge as primary factors responsible for the high mortality. In conclusion the therapeutic measures which may minimize the hazard of inflammatory complications are summed up.


Periodontal outcomes associated with impacted maxillary central incisor and canine teeth following surgical exposure and orthodontic alignment: a systematic review and meta-analysis.
Maxillary incisor and canine teeth are commonly impacted and require multidisciplinary treatment to accommodate them in the dental arch. To assess the periodontal outcomes of impacted maxillary central incisor and canine teeth, which have been successfully aligned in the arch following surgical exposure and orthodontic traction with fixed appliance therapy. Systematic literature searches without restrictions were undertaken in eight databases. Studies reporting surgical interventions in combination with orthodontic traction with fixed appliance therapy to align impacted maxillary incisors or canines published up to January 2023. Duplicate independent study selection, data extraction, and risk of bias assessment. Random-effects meta-analyses of aggregate data. Twenty-three studies (21 retrospective and 2 prospective) were included in the final analysis. Three studies reported outcomes for maxillary central incisors and 20 reported outcomes for maxillary canines. For maxillary central incisors, all three studies were rated as being at moderate risk of bias. For maxillary canines, 17 studies and 1 study were rated at moderate and high risk of bias, respectively. Both prospective studies were rated at a low risk of bias. Meta-analyses comparing aligned impacted maxillary canines to their non-impacted contralateral counterparts found the former had increased Plaque Index scores (mean difference [MD] 0.19; 95% confidence interval [CI] 0.03, 0.35; P = 0.03), increased clinical attachment loss (MD 0.40 mm; 95% CI 0.17, 0.63; P = 0.01), increased pocket probing depth (MD 0.18 mm; 95% CI 0.07, 0.28; P = 0.001), increased bone loss (MD 0.51 mm; 95% CI 0.31, 0.72; P < 0.001), and reduced keratinized gingival width (MD -0.31 mm; 95% CI -0.61, -0.01; P = 0.04). Limited evidence suggests that surgical exposure and orthodontic alignment of impacted maxillary central incisor or canine teeth, results in modest adverse effects in the periodontium. These findings should be viewed with caution as our certainty for these outcomes is very low to low due to the bias and heterogeneity. Further well-conducted studies reporting patient centred outcomes are required. PROSPERO (CRD42020225639).


Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cł.
The enzyme DT-diaphorase (DTD; NAD(P)H:quinone oxidoreductase, EC 220.127.116.11), is an obligate two electron reductase which catalyzes reduction of a broad range of substrates, including quinones. We report here variations in DTD concentrations among different classes of lung tumors known also to vary in their responsiveness to cytotoxic agents. Small cell lung carcinomas (SCLCs) and cell lines derived from them have the low DTD activities and mRNA content characteristic of normal human lung, whereas non-small cell lung carcinomas (NSCLCs) have greatly elevated levels. DTD activity was increased up to 80-fold in NSCLC tumors relative to normal lung and 20-35-fold in NSCLC relative to SCLC cell lines. Increased DTD activity appeared to be a function of the NSCLC phenotype rather than a result of derivation from a cell type rich in DTD, since all histological classes of NSCLC showed this phenotype. In addition, where transfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to a NSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC, carcinoids, and a few NSCLC lines) typically had far lower DTD activities than did cell lines which lacked neuroendocrine markers (most NSCLC cells and mesotheliomas). High DTD activity may be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenografts derived from NSCLC cell lines with high DTD that were grown in athymic nude mice were more susceptible to the antitumor quinone, mitomycin C, than were xenografts derived from SCLC cells containing low DTD. These data provide a mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC.


General Didactics and Instructional Design: eyes like twins A transatlantic dialogue about similarities and differences, about the past and the future of two sciences of learning and teaching.
Although General Didactics (GD) and Instructional Design (ID) have not shown many points of contact in the past, there are some obvious parellels from the perspective of their historical development. This will be examined in detail in this article. More specifically, we speak about model building, which has characterized General Didactics and Instructional Design for some decades. However, the models of General Didactics and Instructional Design are not problem-free with regard to the continuity and advancement of both disciplines. First, we will describe the historical roots of both disciplines and examine which elements of theory are of central importance. Second, we will try to answer the question of which kind of model building could be considered as predominant and what problems result from this predominance. In order to do this, we will describe empirical studies on the use of instructional models and discuss these studies from the perspective of the philosophy of science. Third, we will draw inferences for future processes of model building in order to prevent the same problems that happened in the past from happening again. Finally, we will discuss the issue of what General Didactics can learn from Instructional Design and vice versa.


Diverse application platform for hard X-ray diffraction in SACLA (DAPHNIS): application to serial protein crystallography using an X-ray free-electron laser.
An experimental system for serial femtosecond crystallography using an X-ray free-electron laser (XFEL) has been developed. It basically consists of a sample chamber, fluid injectors and a two-dimensional detector. The chamber and the injectors are operated under helium atmosphere at 1 atm. The ambient pressure operation facilitates applications to fluid samples. Three kinds of injectors are employed to feed randomly oriented crystals in aqueous solution or highly viscous fluid. Experiments on lysozyme crystals were performed by using the 10 keV XFEL of the SPring-8 Angstrom Compact free-electron LAser (SACLA). The structure of model protein lysozyme from 1 µm crystals at a resolution of 2.4 Å was obtained.


Randomized phase 2b study of pralatrexate versus erlotinib in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) after failure of prior platinum-based therapy.
Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ≥1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.


Mental Health Support Provided Throughout the Bariatric Surgery Clinical Pathway in French Specialized Care Centers for Obesity.
Pre-operative psychological assessment is recommended by international guidelines for bariatric surgery candidates. Thereby, service teams caring for bariatric patients should include at least one mental health provider (e.g., a psychologist or psychiatrist). The objective of this study was to evaluate the psychology and psychiatry resources and practices in the 37 specialized obesity centers (CSOs) created by the French Ministry of Health. CSO coordinators were contacted by e-mail to collect general information on the centers (e.g., number of bariatric operations). Secondly, psychologists and psychiatrists of each center completed an anonymous questionnaire assessing their professional practices and their organization of care pathways. The vast majority of CSO coordinators (81%, n = 26/32) answered our survey. These results show significant differences and shortages in terms of the psychology/psychiatry resources available. Most of the psychologists (n = 26/31) and psychiatrists (n = 10/10) stated that they systematically meet new patients only before surgery (56%) or both before and after the operation (30%); however, some psychologists and psychiatrists (14%) do not systematically meet all the patients (before and/or after surgery). Nevertheless, all the professionals provide psychology assessments, and about 75% of them offer a psychological follow-up, indicating a similarity regarding the practices of psychologists and psychiatrists. Our results highlight the place of psychological/psychiatric evaluations in French CSOs and emphasize the absence of mental health providers in several of these services. Post-operative psychological follow-up is not usually provided. It would be appropriate to create clear recommendations for post-operative psychological or psychiatric long-term follow-up.


Interventions for End of Life Decision Making for Patients with Limited English Proficiency.
Patients with limited English proficiency (LEP) experience disparities in end-of-life decision making and advance care planning. Our objective was to conduct a systematic review to assess the literature about interventions addressing these issues. Our search strategy was built around end-of-life (EOL), LEP, ACP, and goals of care. The databases included Ovid MEDLINE(R), and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily from 1946 to November 9, 2018, Ovid EMBASE. Eight studies from the US and Australia were included (seven studies in Spanish and one study in Greek and Italian). Interventions used trained personnel, video images, web-based programs, and written materials. Interventions were associated with increased advance directive completion and decreased preferences for some life-prolonging treatments. Interventions were deemed to be feasible and acceptable. Few interventions exist to improve end-of-life care for patients with LEP. Data are limited regarding intervention effectiveness.


Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction.
Converging preclinical, and human epidemiological, neuroimaging, and genetic evidence suggests a central role for dopamine neurotransmission in modulating pain perception and analgesia. Dysregulation in dopamine signaling may modulate the experience of pain both directly, by enhancing or diminishing the propagation of nociceptive signals, and indirectly, by influencing affective and cognitive processes, which affect the expectation, experience, and interpretation of nociceptive signals. Hypersensitivity to pain and high rates of comorbid chronic pain are common in disorders linked with deficits in dopamine system function, including disorders of mood and affect, substance abuse, and Parkinson disease. Hyposensitivity to pain, however, is common in patients with schizophrenia, which has been linked with excessive dopamine neurotransmission. Although patients are typically affected most by the primary symptoms of their disorders, alterations in pain perception may further increase the burden of their illness, compromising their quality of life. The present review focuses on this relationship, and discusses clinical and potential therapeutic implications for both patients with dopamine-related disorders and those with chronic pain syndromes.


[Do anticoagulants improve survival in patients with cancer?].
Activation of haemostasis is a key factor for the progression of malignant disease. Experimental data suggest that unfractionated heparin or low molecular weight heparin (LMWH) may reduce tumour progression. LMWH have antiangiogeneic effects and inhibit the binding of cancer cell surface glycosaminoglycans with platelet and endothelial selectins. LMWH also inhibit the degradation of the intercellular matrix by tumour cells. Retrospective analysis of several randomized controlled trials evaluating LMWH in patients with venous thromboembolism suggests that LMWH may reduce cancer related mortality in these patients. More recently, randomized controlled trials have tested this hypothesis in patients with cancer who did not have associated venous thromboembolism with conflicting results. LMWH given at prophylactic dosage in patients with advanced cancer was associated with no or minor survival improvement, although some positive results were obtained with such a regimen in patients with non-small cell lung cancer. On the other hand, it has been shown that LMWH given at a higher dosage was associated with a significant and clinically important improvement on overall survival as compared to placebo in localized cancer. Patients included in those trials had however cancer from different sites and this limit the relevance of these findings. Several trials are under way in order to evaluate different LMWH preparations in patients suffering from the same cancer type. The results will help to confirm or to refute a clinical role of LMWH as adjuvant therapy in patients with cancer.


Apparent "mild depolarization of the inner mitochondrial membrane" as a result of a possible generation of the outer membrane potential.
Recently reported kinase-linked mild depolarization of mitochondria, which prevents the generation of the reactive oxygen species (ROS) and disappears in various organs of the old mice, has been assumed to represent a crucial component of the mitochondrial anti-aging program. To measure mitochondrial inner membrane potential (IMP), the authors used fluorescent probe safranin O+. It is widely accepted that the accumulation of such cationic probes in the mitochondrial matrix depends exclusively on IMP, thus completely ignoring the possibility of the outer membrane potential (OMP) generation. However, computational analysis performed in the presented work suggests that the kinase-linked generation of the positive OMP might take place under the described conditions, because the measured potential includes the algebraic sum of both IMP and OMP. Alternatively to the suggested mild depolarization of mitochondria, the reported experimental data might reflect mainly a change of the positive OMP generated by the VDAC-kinase complexes. We also demonstrate that the reported in the literature mitochondrial hyperpolarization induced by erastin (known to prevent VDAC-tubulin interactions) and the depolarization caused by the mitochondrial VDAC knockdowns in the cancer cells might actually represent a decrease or increase, respectively, of the magnitude of the kinase-linked positive OMP. This is consistent with our hypothesis that VDAC voltage gating by the kinase-linked metabolically-dependent OMP plays a very important physiological role in regulating the cell energy metabolism under normal and pathological conditions, in the maintenance of the cell death resistance and even in the genetic aging program.


[Alternative and complementary therapies in fibromyalgia syndrome].
Interdisciplinary S3 level guidelines were devised in cooperation with 8 medical, 2 psychological and 2 patient support groups. Results were elaborated in a multilevel group process. On the bases of the "Cochrane Library" (1993-2006), "Medline" (1980-2006), "PsychInfo" (2006) and "Scopus" (2006) controlled studies and meta-analyses of controlled studies were analyzed. Only few controlled studies were found supporting in part the effectiveness of CAM therapies in the treatment of fibromyalgia syndrome. Due to the lack of information on long term efficacy and cost-effectiveness, only limited recommendations for CAM therapies can be given. Within a multicomponent therapy setting, selective CAM therapies (acupuncture, vegetarian diet, homeopathy, Tai Chi, Qi Gong, music-oriented and body-oriented therapies) can be recommended for a limited period of time.


Neurophysiological Findings in Critical COVID-19 Patients With Peripheral Nervous System Manifestations.
Coronavirus disease 2019 patients hospitalized in intensive care units develop neuromuscular manifestations. However, to our knowledge, a study describing the neurophysiological findings in these patients has not been reported. The objective of this study was to diagnose the cause of neuromuscular deficit in severe coronavirus disease 2019 patients, through neurophysiological examination. This is a retrospective, observational case series. Data were collected from April 13, 2020, to May 31, 2020. Twenty-two coronavirus disease 2019 patients with generalized neuromuscular deficit during intensive care unit hospitalization were studied. Neurophysiological examinations included motor and sensory peripheral nerve conductions, needle electromyography, F waves, and repetitive nerve stimulation. The subjects were 14 men (63.6%) and eight women, ranged from 35 to 74 years old (58.0, interquartile ranges 50.7-66.2). Intensive care unit hospitalization time ranged from 14 to 82 days (median 37.5, interquartile ranges 22.7-55.0). Through neurophysiological examination, myopathy was diagnosed in 17 patients (77.3%) and polyneuropathy in four (18.2%). Focal neuropathies were diagnosed in 12 patients (54.6%), with a total of 19 affected nerves. Common peroneal nerve lesions at the fibular head (68.4%) and ulnar nerve lesions at the elbow level (21.1%) were the most frequent locations. No significant differences were established between neurophysiological findings and clinical or analytical data. In critical coronavirus disease 2019 patients with neuromuscular complaints, neurophysiological examination provides an accurate diagnosis-useful to select treatment measures and establish the prognosis of recovery. Neurophysiological findings are similar to those described for critical illness neuromuscular disease, with myopathy being the most frequent diagnosis.


Maxillary dentoskeletal changes 1-year after adenotonsillectomy.
To measure the maxillary dentoskeletal and soft tissue changes of severely obstructed mouth breathing (MB) young children who had their mode of breathing normalized after adenotonsillectomy (T&A), in comparison with a matched group of severely obstructed untreated MB children (CG). Seventy patients who had an Ear, Nose, and Throat examination (ENT), including flexible nasal endoscopy, to confirm the severe obstruction of the upper airways and the indication of T&A composed the sample. Cephalograms and dental casts were available from the patient's orthodontic records. Treatment group (TG) and CG included 35 children each. Groups were matched by gender (24 males and 11 females in each group), age (TG, 6.7 ± 1.8 years; CG, 6.9 ± 2.3 years), tooth development (TG, 13 primary dentition, 22 mixed dentition; CG, 14 primary dentition, 21 mixed dentition), and skeletal maturation status. Records were taken at baseline (T0) and 1-year after T&A (T1) for TG; while CG records were taken with a 1-year interval. Dentoskeletal measurements were performed in the lateral cephalograms, and dental casts were used to assess the palatal volume and occlusal changes. TG showed a significant increase (503.3 mm(3), P < 0.001) in the palatal volume (10% of change), while CG palatal volume was stable. No dimensional occlusal changes were detected between T0 and T1 in both groups. Significant downward (point A, 2.1 mm; ANS, 2.1 mm) and forward displacements (point A, 0.7 mm; ANS, 1 mm) of the anterior region of the maxilla were observed in the TG, but CG presented only significant downward displacement (point A, 1.8 mm; ANS, 1.4 mm). The maxillary posterior region (PNS, PTM, and Molar) displaced downward in both groups (P < 0.05), however no sagittal change was found. The palatal plane inclination was stable in both groups. TG presented significant increase in the palatal volume and in the forward displacement of the maxilla. No other significant maxillary dentoskeletal changes were found.


Multiple specificities of brain Ca2+- and calmodulin-dependent protein kinase for substrate.
The purified Ca2+- and calmodulin-dependent protein kinase from rat brain, which has a M.W. of 120,000 by gel filtration analysis, showed a broad substrate specificity. In addition to myosin light chain from chicken gizzard, the enzyme phosphorylated myelin basic protein, casein and two endogenous substrates in a Ca2+- and calmodulin-dependent manner. In contrast, chicken gizzard myosin light chain kinase exclusively phosphorylated myosin light chain.


A PmrB-Regulated Deacetylase Required for Lipid A Modification and Polymyxin Resistance in Acinetobacter baumannii.
Emerging resistance to "last-resort" polymyxin antibiotics in Gram-negative bacteria is a significant threat to public health. We identified the Acinetobacter baumannii NaxD deacetylase as a critical mediator of lipid A modification resulting in polymyxin resistance and demonstrated that naxD is regulated by the sensor kinase PmrB. This represents the first description of a specific PmrB-regulated gene contributing to polymyxin resistance in A. baumannii and highlights NaxD as a putative drug target to reverse polymyxin resistance.


Verification and Implementation of HIV Antibody Differentiation Testing to Improve Turnaround Time for the HIV Diagnostic Algorithm.
Relying on reference laboratories for HIV confirmation testing may lead to delays in treatment and can cause stress for patients who have positive HIV screening results. To internalize HIV-1/HIV-2 antibody differentiation testing within the hospital laboratory. We analytically verified an HIV antibody differentiation immunoassay and subsequently compared result turnaround times (TATs) for HIV antibody differentiation and HIV-1 qualitative RNA in the months before and after the test internalization. HIV antibody differentiation was successfully verified. TATs for HIV antibody differentiation and HIV-1 RNA significantly improved, from medians of 40.4 hours and 156.5 hours to medians of 17.7 hours and 56.5 hours, respectively, after the internalization. The 90th-percentile turnaround times declined by 72% and 44%, respectively. It is feasible for a hospital laboratory to verify HIV antibody-differentiation testing. Its implementation may considerably improve result TATs for the HIV diagnostic algorithm.


Chemiluminescent Probes with Long-Lasting High Brightness for In Vivo Imaging of Neutrophils.
Real-time optical imaging of immune cells can contribute to understanding their pathophysiological roles, which still remains challenging. Current sensitive chemiluminophores have issues of short half-lives and low brightness, limiting their ability for in vivo longitudinal monitoring of immunological processes. To tackle these issues, we report benzoazole-phenoxyl-dioxetane (BAPD)-based chemiluminophores with intramolecular hydrogen bonding for in vivo imaging of neutrophils. Compared with the classical counterpart, chemiluminescence half-lives and brightness of BAPDs in the aqueous solution are increased by ∼ 33- and 8.2-fold, respectively. Based on the BAPD scaffold, a neutrophil elastase-responsive chemiluminescent probe is developed for real-time imaging of neutrophils in peritonitis and psoriasis mouse models. Our study provides an intramolecular hydrogen bonding molecular design for improving the performance of chemiluminophores in advanced imaging applications.


Endometroid adenocarcinoma of the ovary with a paraneoplastic syndrome.
We present a case of paraneoplastic cerebellar degeneration complicating ovarian cancer.


Vertebral arteria lusoria: a life-threatening condition for oesophageal surgery.
A rare anatomic variant of the right vertebral artery is reported as an incidental finding in a 78-year-old female patient. The vessel originated from the aortic arch distal to the origin of the left subclavian artery and presented an unusual retroesophageal course, thus was named "vertebral arteria lusoria". As multi-detector row computed tomography examination is now widely used, this anatomical variant should be considered in any patient undergoing esophageal surgery. Misdiagnosis of such an aberrant vertebral artery may cause life-threatening issues.


Effect of Prematurity on Foveal Development in Early School-Age Children.
To evaluate the foveal development in preterm children with optical coherence tomography and OCT angiography. Retrospective cohort study. This study included children aged 6-8 years who were born prematurely and who did not receive retinopathy treatment. They were evaluated between September 2018 and July 2019, categorized according to gestational age (GA) (group I: GA ≤30 weeks; group II: GA between 31 and 34 weeks), and compared with full-term children (group III). Central foveal thickness (CFT), inner retinal thickness (IRT), outer retinal thickness (ORT), subfoveal choroidal thickness (CT), temporal and nasal CT, foveal avascular zone (FAZ) diameter, and vessel densities of superficial (SCP-VD) and deep capillary plexuses (DCP-VD) of the foveal and parafoveal areas were examined in detail. The study included 126 eyes of 63 patients (group I: 40 eyes; group II: 46 eyes; and group III: 40 eyes). In group I, CFT, IRT, ORT, foveal SCP-VD, and foveal DCP-VD were significantly greater than those in the other groups, and temporal CT and FAZ diameter were significantly lower (P < .05). GA showed a significant negative correlation with CFT, IRT, ORT, foveal SCP-VD, and foveal DCP-VD and a significant positive correlation with subfoveal CT, temporal and nasal CT, and FAZ diameter (P < .05). The morphological and vascular foveal structures in early school-age children who were born premature were different from those of full-term children. These differences were correlated with GA and more pronounced in those with GA of ≤30 weeks.


Effect of consumer-grade wearable device data on clinician decision making during post-discharge telephone calls after pediatric surgery.
During post-discharge telephone calls after pediatric surgery, clinicians must rely on parents/caregivers' assessment of symptoms, which can be inaccurate and often lead to unnecessary emergency department (ED) visits. Physiology (heart rate and physical activity) data from consumer-grade wearables, e.g., Fitbit™, may inform clinical decision making, yet there has been little study of clinician interpretation of this data. This study assessed whether wearable data availability, during simulated telephone calls about postoperative, post-discharge pediatric patients, affects clinician decision making. Three simulated telephone call scenarios were presented to a diverse group of pediatric surgery clinicians. The scenarios were based on actual postoperative patients (scenarios 1 and 3 have worrisome symptoms and scenario 2 has non-worrisome symptoms) who had worn a Fitbit™ postoperatively. Each scenario was presented to clinicians (1) without any wearable data; (2) with "concerning" wearable data; and (3) with "reassuring" wearable data. Clinicians rated their likelihood, on a scale of 1-10, of recommending an emergency department (ED) visit for the three instances of each scenario, 10 being definitely ED. Twenty-four (24) clinicians participated in the study. When presented with "reassuring" wearable data, clinicians' likelihood of recommending an ED visit decreased from a median score of 6 to 1 (p < 0.001) for scenario 1 and from 9 to 3 (p < 0.001) for scenario 3. When presented with "concerning" wearable data, the median likelihood of recommending an ED visit increased from 1 to 6 (p = 0.003) for scenario 2. This study showed that wearable data affect clinicians' decision making and may be useful in triaging postoperative, post-discharge pediatric patients. V.


Follicular response and pregnancy among infertile women undergoing ovulation induction and intrauterine insemination.
To determine the relationship between ovarian follicular response (number and diameter of follicles) to ovulation induction agents and pregnancy. Retrospective cohort study.Hospital-based center of reproductive medicine. Three hundred twenty-two clinically diagnosed infertile couples undergoing 1483 cycles of ovulation induction and IUI. Oral and injectable fertility drugs were administered for 2-10 cycles; ultrasound follicular measurements were recorded around time of ovulation; hCG was administered when follicles were 18-20 mm or more in diameter; IUI was performed 36-40 hours after administration of hCG. A first positive pregnancy test as indicative for conception. Women with follicular diameters >or=20 mm were less likely to become pregnant as compared to women with diameters between 15.00 and 19.99 mm (risk ratio [RR] = 0.58, 95% confidence interval [CI] = 0.35, 0.97). Women >or=30 years of age were half as likely to become pregnant as compared to women <30 years (RR = 0.51, 95% CI = 0.30, 0.85). Likelihood of pregnancy increased by 21% for each prior pregnancy (RR = 1.21, 95% CI = 1.00, 1.47). Maternal age, gravidity, and follicular diameters around the time of insemination are prognostic factors in the likelihood of pregnancy.


MusaMPK5, a mitogen activated protein kinase is involved in regulation of cold tolerance in banana.
Mitogen activated protein kinases (MAPKs) are known to play important functions in stress responses of plants. We have functionally characterized a MAPK, MusaMPK5 from banana and demonstrated its function in cold tolerance response of banana plants. Expression of MusaMPK5 showed positive response to cold, methyl-jasmonate and salicylic acid treatment. Transgenic banana plants harbouring PMusaMPK5::GUS after exposure to cold stress (8 °C) showed strong induction of GUS in cells surrounding central vascular cylinder of corm and cortical cells of pseudostem. Transgenic banana lines overexpressing MusaMPK5 were regenerated and four different transgenic lines were confirmed for T-DNA insertions by Southern blot and PCR analysis. In an in-vitro growth assay transgenic lines gained better shoot length and fresh weight during recovery from cold stress indicating improved cold tolerance ability of transgenic lines than control plants. Leaf discs of transgenic lines bleached less and retain lower MDA content than leaf discs of control plants after cold stress (4 °C and 8 °C). Cold stress tolerance analysis using two month old plants suggested that improved cold tolerance ability of transgenic lines might be associated with increased level of proline and reduced MDA content. MusaMPK5 gets localized in cytoplasm as observed in onion epidermal cells transiently overexpressing either MusaMPK5-GFP or MusaMPK5-GUS fusion protein. MusaMPK5 is a functional kinase as it autophosphorylate itself and phosphorylate myelin basic protein (MBP) in an in vitro reaction. Purified MusaMPK5 can phosphorylate NAC042 and SNAC67 transcription factors of banana which are important regulators of stress tolerance in banana plants.


Ganoderic Acid A exerts the cytoprotection against hypoxia-triggered impairment in PC12 cells via elevating microRNA-153.
Ganoderic Acid A (GAA) is often applied for healing cardiovascular and cerebrovascular ailments, but the influences in cerebral ischemia injury are still hazy. The research delved into the functions of GAA in hypoxia-triggered impairment in PC12 cells. PC12 cells received hypoxia management for 12 hr, and subsequently, cell viability, migration, apoptosis, and correlative protein levels were assessed. After preprocessing with GAA, above cell behaviors were monitored again. The vector of microRNA (miR)-153 inhibitor was utilized for PC12 cell transfection to further explore the functions of miR-153 in hypoxia-impaired cells. Pathways of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were investigated via executing western blot for uncovering the latent mechanism. Results revealed that hypoxia disposition triggered PC12 cells impairment via restraining cell viability and migration and accelerating apoptosis. However, GAA visibly mollified hypoxia-provoked impairment in PC12 cells. Interestingly, the enhancement of miR-153 triggered by GAA was observed in hypoxia-impaired PC12 cells. After miR-153 inhibitor transfection, the protective functions of GAA in hypoxia-impaired PC12 cells were dramatically inversed. Furthermore, GAA caused PI3K/AKT and mTOR activations via enhancement of miR-153 in hypoxia-impaired PC12 cells. The findings evinced that GAA exhibited the protective functions in PC12 cells against hypoxia-evoked impairment through activating PI3K/AKT and mTOR via elevating miR-153.


Meningococcal meningitis in a women with inherited deficiency of the ninth component of complement.
A 17-year-old woman presented with acute pyogenic meningitis; Neisseria meningitidis group C was isolated from blood on culture. Complement assays demonstrated a hemolytic complement titer of 12 u/ml; individual components were normal except for C9, which was absent by both functional and antigenic analysis. Family studies were consistent with a familial C9 deficiency, autosomal co-dominant inheritance. This is the first report of the association of C9 deficiency and disseminated neisserial infection; whether this complement deficiency predisposes to the neisserial infection remains to be established.


Phylogenetic analysis of freshwater sponges provide evidence for endemism and radiation in ancient lakes.
Morphologic and phylogenetic analysis of freshwater sponges endemic to lakes in Central Sulawesi, Siberia and South-East Europe is presented. We also analyzed several cosmopolitan sponge species from Eurasia and North America and included sponge sequences from public databases. In agreement with previous reports [Addis, J.S., Peterson, K.J., 2005. Phylogenetic relationships of freshwater sponges (Porifera, Spongillina) inferred from analyses of 18S rDNA, COI mtDNA, and ITS2 rDNA sequences. Zool. Scr. 34, 549-557], the metaniid sponge Corvomeyenia sp. was the most deeply branching species within a monophyletic lineage of the suborder Spongillina. Pachydictyum globosum (Malawispongiidae) and Nudospongilla vasta (Spongillidae), two morphologically quite distinct species from Sulawesi were found in a joint clade with Trochospongilla (Spongillidae) rendering Trochospongilla paraphyletic. Furthermore, Ochridaspongia sp., another Malawispongiidae, clustered far away from that clade, together with Ephydatia fluviatilis, making the latter family polyphyletic. The Lubomirskiidae endemic to Lake Baikal, Lubomirskia abietina, Baikalospongia bacillifera, B. intermedia, and Swartschewskia papyracea formed a well-supported clade that was most closely linked to the genus Ephydatia (99.9% identity over a total length of 2169 concatenated nucleotide positions). Our study indicates the frequent and independent origin of sponge species endemic to different freshwater ecosystems from a few cosmopolitan founder species. The highly specific primer sets newly developed here facilitate work on the molecular phylogeny and DNA barcoding of sponges.


Two-site enzyme immunoassay for pregnancy associated plasma protein A (PAPP-A).
Pregnancy associated plasma protein A (PAPP-A) is one of the newly isolated placental proteins whose concentration in the maternal circulation increases during pregnancy. The limited sensitivity of the immunoelectrophoretic techniques first developed to measure PAPP-A meant that assays could only be done in the second half of pregnancy but now radioimmunoassays have been set up in order to determine the concentration of this protein in early pregnancy as well. The two-site enzymometric immunoassay described here is characterised by a sensitivity and a precision which are comparable to the results obtained by radioimmunoassay. Neither the structurally similar alpha 2-macroglobulin, nor other pregnancy associated proteins interfered in the assay. The tracer, monospecific rabbit anti-PAPP-A coupled covalently to horseradish peroxidase, is stable for months when stored adequately.


Lentivirus technologies for modulation of the immune system.
Lentiviral vectors (LVV) are important tools for the treatment of immune system disorders. Integration of therapeutic genetic material into the haematopoietic stem cell compartment using LVV can mediate long-term correction of haematopoietic lineages, thereby correcting disease phenotypes. Twenty years of vector development have successfully brought LVV to the clinic, with follow up studies of clinical trials treating primary immunodeficiencies now being reported. Results have demonstrated clear improvements in the quality of life for patients with a number of conditions in the absence of the severe adverse events observed in earlier retroviral gene therapy trials. Growing interest in gene modified adoptive T cell transfer as an alternative strategy has driven further technology innovation, including characterisation of novel viral envelopes. We will also discuss the progression of gene editing technology to preclinical investigations in models of immune deficiency.


Radio Frequency Magnetron Sputtering Deposition of TiO2 Thin Films and Their Perovskite Solar Cell Applications.
In this work, we report a physical deposition based, compact (cp) layer synthesis for planar heterojunction perovskite solar cells. Typical solution-based synthesis of cp layer for perovskite solar cells involves low-quality of thin films, high-temperature annealing, non-flexible devices, limitation of large-scale production and that the effects of the cp layer on carrier transport have not been fully understood. In this research, using radio frequency magnetron sputtering (RFMS), TiO2 cp layers were fabricated and the thickness could be controlled by deposition time; CH3NH3PbI3 films were prepared by evaporation &immersion (E &I) method, in which PbI2 films made by thermal evaporation technique were immersed in CH3NH3I solution. The devices exhibit power conversion efficiency (PCE) of 12.1% and the photovoltaic performance can maintain 77% of its initial PCE after 1440 h. The method developed in this study has the capability of fabricating large active area devices (40 × 40 mm(2)) showing a promising PCE of 4.8%. Low temperature and flexible devices were realized and a PCE of 8.9% was obtained on the PET/ITO substrates. These approaches could be used in thin film based solar cells which require high-quality films leading to reduced fabrication cost and improved device performance.


A novel long non-coding RNA LINC00355 promotes proliferation of lung adenocarcinoma cells by down-regulating miR-195 and up-regulating the expression of CCNE1.
Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer affecting people all over the globe. Recent studies have indicated that long non-coding RNAs (lncRNAs) possess the ability to regulate gene expression. Initially, we uncovered increased LINC00355 expressions in lung adenocarcinoma tissues and cells. Functionally, our findings demonstrated that LINC00355 silencing suppressed the proliferation in vitro and in vivo. In addition, we found that LINC00355 negatively regulated miR-195 in lung adenocarcinoma cells. Simultaneously, silencing LINC00355 by shRNA resulted in suppressed proliferation, colony formation and promoted cell cycle arrest and apoptosis via miR-195. Moreover, silencing LINC00355 by shRNA inhibited the cyclin E1 (CCNE1) gene expression via miR-195 in lung adenocarcinoma cells. Collectively, this study demonstrates the novel lncRNA LINC00355 in regulatory network of CCNE1 via miR-195 in lung adenocarcinoma, highlighting LINC00355 as a new target for the treatment of lung adenocarcinoma.


Spinal manifestations of Neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) patients may present a wide spectrum of spinal pathologies. Osseous changes may lead to severe deformities with significant implications on growth and quality of life. Neurogenic tumors and soft tissue abnormalities may cause neuropathic pain and dysfunction ranging from minor paresthesias to profound motor and sensory deficits. Advanced imaging such as whole-body MRI, and volumetric tumor burden assessment have an evolving role in the evaluation and follow-up of patients with high spinal tumor load. Novel biological agents that target the hyperactivated ras pathway are currently under investigation and are reshaping current and future treatment paradigms. Surgical interventions for benign and malignant tumors, as well as deformity correction remain pivotal in treatment frameworks and require careful assessment by a dedicated multidisciplinary team. In this manuscript we review the various spinal manifestations of NF1 patients, indication for surgical intervention and oncological treatments.


Texture-based residual stress analysis of laser powder bed fused Inconel 718 parts.
Although layer-based additive manufacturing methods such as laser powder bed fusion (PBF-LB) offer an immense geometrical freedom in design, they are typically subject to a build-up of internal stress (i.e. thermal stress) during manufacturing. As a consequence, significant residual stress (RS) is retained in the final part as a footprint of these internal stresses. Furthermore, localized melting and solidification inherently induce columnar-type grain growth accompanied by crystallographic texture. Although diffraction-based methods are commonly used to determine the RS distribution in PBF-LB parts, such features pose metrological challenges in their application. In theory, preferred grain orientation invalidates the hypothesis of isotropic material behavior underlying the common methods to determine RS. In this work, more refined methods are employed to determine RS in PBF-LB/M/IN718 prisms, based on crystallographic texture data. In fact, the employment of direction-dependent elastic constants (i.e. stress factors) for the calculation of RS results in insignificant differences from conventional approaches based on the hypothesis of isotropic mechanical properties. It can be concluded that this result is directly linked to the fact that the {311} lattice planes typically used for RS analysis in nickel-based alloys have high multiplicity and less strong texture intensities compared with other lattice planes. It is also found that the length of the laser scan vectors determines the surface RS distribution in prisms prior to their removal from the baseplate. On removal from the baseplate the surface RS considerably relaxes and/or redistributes; a combination of the geometry and the scanning strategy dictates the sub-surface RS distribution.


A Multiannual Record of Gravity Wave Activity in Mars's Lower Atmosphere from On-Planet Observations by the Mars Climate Sounder.
Gravity waves in Mars's atmosphere strongly affect the general circulation as well as middle atmospheric cloud formation, but the climatology and sources of gravity waves in the lower atmosphere remain poorly understood. At Earth, the statistical variance in satellite observations of thermal emission above the instrumental noise floor has been used to enable measurement of gravity wave activity at a global scale. Here is presented an analysis of variance in calibrated radiance at 15.4 μm (635-665 cm-1) from off-nadir and nadir observations by the Mars Climate Sounder (MCS) on board Mars Reconnaissance Orbiter (MRO); a major expansion in the observational data available for validating models of Martian gravity wave activity. These observations are sensitive to gravity waves at 20-30 km altitude with wavelength properties (λ h =10-100 km, λ z > 5 km) that make them likely to affect the dynamics of the middle and upper atmosphere. We find that: (1) strong, moderately intermittent gravity wave activity is scattered over the tropical volcanoes and throughout the middle to high latitudes of both hemispheres during fall and winter, (2) gravity wave activity noticeably departs from climatology during regional and global dust storms; and (3) strong, intermittent variance is observed at night in parts of the southern tropics during its fall/winter, but frequent CO2 ice clouds prevents unambiguous attribution to GW activity. The spatial distribution of wave activity is consistent with topographic sources being dominant, but contributions from boundary layer convection and other convective processes are possible.


Cerebellar infarction originating from vertebral artery stenosis caused by a hypertrophied uncovertebral joint.
We report a case of cerebellar infarction originating from vertebral artery stenosis caused by a hypertrophied uncovertebral joint. A 38-year-old man presented with sudden onset of headache, dizziness, and dysarthria. The magnetic resonance imaging scan of the brain revealed acute infarction in the right cerebellar hemisphere in the territory of the posterior inferior cerebellar artery (PICA) and superior cerebellar artery (SCA). Magnetic resonance, 3-dimensional computed tomographic, and conventional angiography revealed severe right vertebral artery stenosis by extrinsic compression of the hypertrophied right C5-C6 uncovertebral joint. The diagnosis was acute cerebellar infarction, which was probably caused by embolism from the right vertebral artery stenosis that was caused by the hypertrophied C5-C6 uncovertebral joint. C5-C6 anterior discectomy and fusion were performed together with direct uncovertebral joint decompression. Postoperative 3-dimensional computed tomographic angiography revealed improvement in antegrade filling in the right vertebral artery. The imaging findings for this patient and the pathogenesis of cerebellar infarction for our patient are discussed.


The impact of urban irrigation on the temperature-carbon feedback in U.S. cities.
Urban areas experience numerous environmental challenges, among which the anthropogenic emissions of heat and carbon are two major contributors, the former is responsible for the notorious urban heat effect, the latter longterm climate changes. Moreover, the exchange of heat and carbon dioxide are closely interlinked in the built environment, and can form positive feedback loops that accelerate the degradation of urban environmental quality. Among a handful countermeasures for heat and carbon mitigation, urban irrigation is believed to be effective in cooling, yet the understanding of its impact on the co-evolution of heat and carbon emission remains obscure. In this study, we conducted multiphysics urban climate modeling for all urban areas in the contiguous United States, and evaluated the irrigation-induced cooling and carbon mitigation. Furthermore, we assessed the impact of urban irrigation on the potential heat-carbon feedback loop, with their strength of coupling quantified by an advanced causal inference method using the convergent cross mapping algorithms. It is found that the impact of urban irrigation varies vastly in geographically different cities, with its local and non-local effect unraveling distinct pathways of heat-carbon feedback mechanism.


AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis.
The receptor tyrosine kinase AXL is emerging as a key player in tumor progression and metastasis and its expression correlates with poor survival in a plethora of cancers. While studies have shown the benefits of AXL inhibition for the treatment of metastatic cancers, additional roles for AXL in cancer progression are still being explored. This review discusses recent advances in understanding AXL's functions in different tumor compartments including cancer, vascular, and immune cells. AXL is required at multiple steps of the metastatic cascade where its activation in cancer cells leads to EMT, invasion, survival, proliferation and therapy resistance. AXL activation in cancer cells and various stromal cells also results in tumor microenvironment deregulation, leading to modulation of angiogenesis, fibrosis, immune response and hypoxia. A better understanding of AXL's role in these processes could lead to new therapeutic approaches that would benefit patients suffering from metastatic diseases.


Hemichorea in a patient with ipsilateral cortical infarction: a case report.
Hemichorea is usually caused by contralateral deep structures of brain. It rarely results from acute cortical ischemic stroke and that caused by ipsilateral brain lesions is even rarer. A 64-year-old female presented with acute obtuseness and left-sided hemichorea. She had a history of right frontal lobe surgery and radiotherapy due to brain metastasis from lung cancer 8 years ago. MRI revealed acute left frontal lobe infarction in addition to an old right frontal lobe lesion. 18FDG PET-CT showed hypometabolism in the left frontal lobe and hypermetabolism in the right basal ganglia region and central sulcus. The choreatic movement remitted after antipsychotic treatment. The mechanism of hemichorea after ipsilateral cortical infarction is poorly understood. We assume both previous contralateral brain lesion and recent ipsilateral ischemic stroke contributed to the strange manifestation in this case.