Sequential evaporation of water molecules from protonated water clusters: measurement of the velocity distributions of the evaporated molecules and statistical analysis.
Velocity distributions of neutral water molecules evaporated after collision induced dissociation of protonated water clusters H+(H2O)n≤10 were measured using the combined correlated ion and neutral fragment time-of-flight (COINTOF) and velocity map imaging (VMI) techniques. As observed previously, all measured velocity distributions exhibit two contributions, with a low velocity part identified by statistical molecular dynamics (SMD) simulations as events obeying the Maxwell-Boltzmann statistics and a high velocity contribution corresponding to non-ergodic events in which energy redistribution is incomplete. In contrast to earlier studies, where the evaporation of a single molecule was probed, the present study is concerned with events involving the evaporation of up to five water molecules. In particular, we discuss here in detail the cases of two and three evaporated molecules. Evaporation of several water molecules after CID can be interpreted in general as a sequential evaporation process. In addition to the SMD calculations, a Monte Carlo (MC) based simulation was developed allowing the reconstruction of the velocity distribution produced by the evaporation of m molecules from H+(H2O)n≤10 cluster ions using the measured velocity distributions for singly evaporated molecules as the input. The observed broadening of the low-velocity part of the distributions for the evaporation of two and three molecules as compared to the width for the evaporation of a single molecule results from the cumulative recoil velocity of the successive ion residues as well as the intrinsically broader distributions for decreasingly smaller parent clusters. Further MC simulations were carried out assuming that a certain proportion of non-ergodic events is responsible for the first evaporation in such a sequential evaporation series, thereby allowing to model the entire velocity distribution.


Cancer of the cervix - from bleak past to bright future; a review, with an emphasis on cancer of the cervix in malaysia.
Cancer of the cervix has the potential to be eradicated since the initiating cause is known. There was not much known about this cancer until the time of the Renaissance. In Malaysia, it is the second most common cancer among females after breast cancer. The strategies on prevention in this country are still not optimal. This article highlights the problems and also discusses the pathogenesis of this disease. The key to prevention is screening and the future is the era of molecular pap smear.


MtrA Response Regulator Controls Cell Division and Cell Wall Metabolism and Affects Susceptibility of Mycobacteria to the First Line Antituberculosis Drugs.
The biological processes regulated by the essential response regulator MtrA and the growth conditions promoting its activation in Mycobacterium tuberculosis, a slow grower and pathogen, are largely unknown. Here, using a gain-of-function mutant, MtrAY 102C, which functions in the absence of the cognate MtrB sensor kinase, we show that the MtrA regulon includes several genes involved in the processes of cell division and cell wall metabolism. The expression of selected MtrA targets and intracellular MtrA levels were compromised under replication arrest induced by genetic manipulation and under stress conditions caused by toxic radicals. The loss of the mtrA gene in M. smegmatis, a rapid grower and non-pathogen, produced filamentous cells with branches and bulges, indicating defects in cell division and cell shape. The ΔmtrA mutant was sensitized to rifampicin and vancomycin and became more resistant to isoniazid, the first line antituberculosis drug. Our data are consistent with the proposal that MtrA controls the optimal cell division, cell wall integrity, and susceptibility to some antimycobacterial drugs.


The paradox of predation studies.
Understanding the causal relationships that contribute to mortality in populations is a priority for epidemiology, animal husbandry and ecology. Of all the sources of mortality in nature, predation is perhaps the most important, while simultaneously being one of the most difficult to study and understand. In this opinion piece, we use the epidemiological concept of the sufficient-component cause model to outline why we believe that predation studies often misrepresent predators as sufficient cause of death (or natural mortality) in ecological studies. This is pivotal in conservation biology because such studies have often led to demands for predator removal throughout the world. We use the sufficient-component cause model to illustrate the paradox that multiple studies, each studying singular putative causes of mortality (including predation), will sum to more than 100% mortality when added together. We suggest that the sufficient-component framework should be integrated into both fundamental and applied ecology to better understand the role of predators in natural ecosystems.


Evaluating the Accuracy of Step Tracking and Fall Detection in the Starkey Livio Artificial Intelligence Hearing Aids: A Pilot Study.
Purpose The primary purpose of this study was to examine the efficacy and the effectiveness of Starkey Livio Artificial Intelligence hearing aids in tracking step count. A secondary purpose was to investigate the accuracy of the fall detection and alert system of Livio hearing aids in detecting fall maneuvers. Method A participant wore Binaural Starkey Livio receiver-in-the-canal style hearing aids, a Sportline pedometer, and a Fitbit Charge 3 concurrently during both real-world and treadmill walking conditions. The real-world condition was conducted over a 5-day period. Step count for the treadmill protocol was assessed at six different treadmill speeds (2 mph, 2.5 mph, 3 mph, 3.5 mph, 4 mph, 4.5 mph, and 5 mph). The fall detection and alert system were assessed through falling maneuvers of activities of daily living. Results In the real-world condition, Livio, Sportline, and Fitbit recorded steps within 1 SD of each other. In addition, Livio recorded the most accurate steps compared to actual physical steps taken. In the treadmill condition, Livio recorded the least number of steps across all walking paces compared to the rest of the devices. Also, Livio hearing aids detected majority of the engaged falling maneuvers. Conclusions The Livio was found to be feasible, consistent, and sensitive in detecting steps and falls. Further research of higher sample size and recruitment of individuals with hearing loss are suggested.


[Surgical complications of peptic ulcer in children and adolescents].
The authors analyze 36 cases of operative procedures for surgical complications of ulcer disease in children and juveniles. Perforation of ulcer was noted in 30 cases, bleeding--in 4 cases, combination of penetration of ulcer into the pancreas head with bleeding--in one case, in the other case--perforation of gastric ulcer with bleeding. Emphasis is laid on the severity of complications and in relation with it a question arises of early diagnosis and treatment of ulcer disease in children and juveniles.


Phase-dependent deficits during reach-to-grasp after human spinal cord injury.
Most cervical spinal cord injuries result in asymmetrical functional impairments in hand and arm function. However, the extent to which reach-to-grasp movements are affected in humans with incomplete cervical spinal cord injury (SCI) remains poorly understood. Using kinematics and electromyographic (EMG) recordings in hand and arm muscles we studied the different phases of unilateral self-paced reach-to-grasp movements (arm acceleration, hand opening and closing) to a small cylinder in the more and less affected arms of individuals with cervical SCI and in age-matched controls. We found that SCI subjects showed prolonged movement duration in both arms during arm acceleration, and hand opening and closing compared with controls. Notably, the more affected arm showed an additional increase in movement duration at the time to close the hand compared with the less affected arm. Also, the time at which the index finger and thumb contacted the object and the variability of finger movement trajectory were increased in the more compared with the less affected arm of SCI participants. Participants with prolonged movement duration during hand closing were those with more pronounced deficits in sensory function. The muscle activation ratio between the first dorsal interosseous and abductor pollicis brevis muscles decreased during hand closing in the more compared with the less affected arm of SCI participants. Our results suggest that deficits in movement kinematics during reach-to-grasp movements are more pronounced at the time to close the hand in the more affected arm of SCI participants, likely related to deficits in EMG muscle activation and sensory function. NEW & NOTEWORTHY Humans with cervical spinal cord injury usually present asymmetrical functional impairments in hand and arm function. Here, we demonstrate for the first time that deficits in movement kinematics during reaching and grasping movements are more pronounced at the time to close the hand in the more affected arm of spinal cord injury. We suggest that this is in part related to deficits in muscle activation ratios between hand muscles and a decrease in sensory function.


Functional significance of prop-1 gene expression in pituitary adenomas.
Prophet of Pit-1 (Prop-1), which is a paired-like homeodomain transcription factor, is capable of binding to sites in an early enhancer of the Pit-1 gene and regulating its expression. As human Pit-1 is expressed considerably in pituitary adenomas, we studied human Prop-1 gene expression in pituitary adenomas. We also sequenced the Prop-1 cDNAs in pituitary adenomas. Human Prop-1 transcript was detected in all pituitary adenomas examined by RT-PCR analysis. The expression of human Prop-1 in pituitary adenomas was confirmed by in situ hybridization in one of the GH-producing adenomas. The sequence analysis of human Prop-1 cDNAs in these pituitary adenomas revealed that there were no mutations except 5 silent nucleic acid substitutions, suggesting that mutations of Prop-1 gene do not represent a frequent mechanism of human pituitary tumorigenesis.


Isolation and characterization of cDNA clones corresponding to transcripts from the BamHI H and F regions of the Epstein-Barr virus genome.
The Epstein-Barr virus (EBV) mutant P3HR1 is incapable of immortalizing B lymphocytes because of a 6.8-kilobase deletion in the BamHI W, Y, and H regions of the viral genome (M. Rabson, L. Gradoville, L. Heston, and G. Miller, J. Virol. 44:834-844, 1982). To characterize transcripts that are encoded in this region, poly(A)+ RNA from the EBV-transformed lymphoblastoid cell line JY was isolated, and this RNA was used to generate a cDNA library in lambda gt10. By screening 500,000 recombinant bacteriophages with the BamHI H fragment, we isolated 10 cDNA clones and characterized them in detail. One group of six cDNA clones was derived from a 2.9-kilobase early transcript encoded by the IR2 repeat element and showed restriction site polymorphism for the enzyme SmaI. The second group consisted of four cDNA clones, all of which contained the BamHI-H right reading frame (BHRF1), and used the polyadenylation signal at base pair 662 in the BamHI F fragment. Computer analysis of the hydrophobicity of the BHRF1 protein revealed that it is likely to be a membrane protein. Northern blotting experiments with RNA from an EBV producer line, B95-8, and a tightly latent lymphoblastoid B-cell line, IB4, revealed that BHRF1 is contained in at least two different mRNA species which can be detected during the latent cycle of EBV. These data and the recent characterization of a spliced transcript (containing five exons in common with other known latent messages [M. Bodescot and M. Perricaudet, Nucleic Acids Res. 14:7103-7113, 1986]) suggest that alternative splicing is used to generate transcripts containing BHRF1, as for the EBV nuclear antigen 1 transcripts. Furthermore, the observation that a potential oncogene activated in human follicular lymphomas is homologous to the BHRF1-encoded polypeptide (M. L. Cleary, S.D. Smith, and J. Sklar, Cell 47:19-28, 1986) suggests a possible role for this putative viral protein in EBV-induced growth transformation of B lymphocytes.


[The predictive role of PET/CT imaging in clinical N and M staging and treatment decision process. Institutional experiences in Hungary].
The aim of our study was to investigate changes in clinical staging N (lymph node) and M (distant metastasis) in patients who receive PET/CT-based 3D radiotherapy within complex oncological treatment, and compare to conventional cross-sectional imaging staging technique. We also investigated the presence of PET/CT-detected second tumors and the effect of PET/CT on therapeutic decisions. From the 1st of January 2015 to the 30th of November 2016, 192 patients (n = 192) were treated with PET/CT-based radiation (109 head, 44 lung, 28 rectum and 11 cervical localization) in the Oncoradiology Institute of the Health Center of the University of Kaposvár. All patients received conventional cross-sectional and PET/CT imaging in accordance with the valid investigation protocol. The average time interval between the two cross-sectional investigations was 5.2 weeks. Clinical N and M staging was performed on the basis of the classification of the American Joint Committee on Cancer (AJCC) and the Union of International Cancer Control (UICC). By analyzing the clinical stages N and M separately, based on the results of the PET/CT studies, the N stage was changed in 77 cases and the M stage changed in 31 cases. Overall, the PET/CT study resulted in higher clinical stages in 68 (35.4%) patients and lower clinical stages in 14 (7.3%) patients. The treatment plan was changed in 9% of the patients (n = 18) (definitive versus palliative treatment) and the extension of radiotherapy treatment target volume (PTV) was indicated in 20% of the patients (n = 39) due to the change in clinical lymph node status. PET/CT also detected secondary tumors in 15 (8%) patients. Based on our results, the addition of PET/CT to conventional cross-sectional staging imaging permits a more accurate clinical classification of N and M stages and significantly influences therapeutic decisions. PET/CT imaging also provides a great help in detecting occult second tumors. The results of our Institute harmonize with the international data available in the literature. Orv Hetil. 2018; 159(39): 1593-1601.


Super-paramagnetic iron oxide nanoparticles for use in extrapulmonary tuberculosis diagnosis.
The limited sensitivity of serological tests for mycobacterial antigens has encouraged the development of a nanoparticle probe specific for the extrapulmonary form of Mycobacterium tuberculosis (Mtb). We developed an innovative probe comprised of super-paramagnetic iron oxide (SPIO) nanoparticles conjugated with Mtb surface antibody (MtbsAb-nanoparticles) to provide ultrasensitive imaging of biomarkers involved in extrapulmonary Mtb infection. MtbsAb-nanoparticles were significantly conjugated with Mtb bacilli. The extent of contrast enhancement reduction on magnetic resonance imaging (MRI) for Mtb and human monocytic THP1 cells was proportional to the concentration of MtbsAb-nanoparticles. When MtbsAb-nanoparticles were intravenously injected into mice bearing Mtb granulomas, the granulomatous site showed a 14-fold greater reduction in signal intensity enhancement on T(2) -weighted MR images compared with an opposing site that received PBS injection. Mtb sAb-nanoparticles represent a new non-invasive technology for the diagnosis of extrapulmonary Mtb.


Inferring genome-wide functional linkages in E. coli by combining improved genome context methods: comparison with high-throughput experimental data.
Cellular functions are determined by interactions among proteins in the cells. Recognition of these interactions forms an important step in understanding biology at the systems level. Here, we report an interaction network of Escherichia coli, obtained by training a Support Vector Machine on the high quality of interactions in the EcoCyc database, and with the assumption that the periplasmic and cytoplasmic proteins may not interact with each other. The data features included correlation coefficient between bit score phylogenetic profiles, frequency of their co-occurrence in predicted operons, and a new measure--the distance between translational start sites of the genes. The combined genome context methods show a high accuracy of prediction on the test data and predict a total of 78,122 binary interactions. The majority of the interactions identified by high-throughput experimental methods correspond to indirect interaction (interactions through neighbors) in the predicted network. Correlation of the predicted network with the gene essentiality data shows that the essential genes in E. coli exhibit a high linking number, whereas the nonessential genes exhibit a low linking number. Furthermore, our predicted protein-protein interaction network shows that the proteins involved in replication, DNA repair, transcription, translation, and cell wall synthesis are highly connected. We therefore believe that our predicted network will serve as a useful resource in understanding prokaryotic biology.


The dormancy dilemma: quiescence versus balanced proliferation.
Metastatic dissemination with subsequent clinical outgrowth leads to the greatest part of morbidity and mortality from most solid tumors. Even more daunting is that many of these metastatic deposits silently lie undetected, recurring years to decades after primary tumor extirpation by surgery or radiation (termed metastatic dormancy). As primary tumors are frequently curable, a critical focus now turns to preventing the lethal emergence from metastatic dormancy. Current carcinoma treatments include adjuvant therapy intended to kill the cryptic metastatic tumor cells. Because such standard therapies mainly kill cycling cells, this approach carries an implicit assumption that metastatic cells are in the mitogenic cycle. Thus, the pivotal question arises as to whether clinically occult micrometastases survive in a state of balanced proliferation and death, or whether these cells undergo at least long periods of quiescence marked by cell-cycle arrest. The treatment implications are thus obvious--if the carcinoma cells are cycling then therapies should target cycling cells, whereas if cells are quiescent then therapies should either maintain dormancy or be toxic to dormant cells. Because this distinction is paramount to rational therapeutic development and administration, we investigated whether quiescence or balanced proliferation is the most likely etiology underlying metastatic dormancy. We recently published a computer simulation study that determined that balanced proliferation is not the likely driving force and that quiescence most likely participates in metastatic dormancy. As such, a greater emphasis on developing diagnostics and therapeutics for quiescent carcinomas is needed.


[Expression of Fc- and C3-receptors on membranes of blast cells in myeloblastic leukemia and blast crisis of myelocytic leukemia].
The expression of Fc-receptors to immunoglobulins IgG, IgA, IgM, that of FcH-receptor and receptors to C3-components of the complement in peripheral blood blast cells were studied in 11 patients with acute myeloblast leukosis and 10 patients with chronic granulocytic leukemia at the stage of blast transformation. The data obtained show the lower level of differentiation and functional activity of blast cells in patients with acute myeloblast leukemia while in chronic granulocytic leukemia a degree of expression of surface receptor on myeloblasts is close to the data obtained in the study of membrane receptors on promyelocytes and myelocytes of healthy persons.


Drug-eluting stents: present and future.
In-stent restenosis (ISR) caused by neointimal hyperplasia is the major drawback after percutaneous coronary intervention (PCI) for obstructive coronary disease, occurring in up to 40% of lesions. Recently, one of the most intriguing new therapies developed is drug-eluting stents (DES) that target the central phenomenon of cellular proliferation that causes ISR. The benefits of stent-based drug delivery include maximizing the local tissue levels of therapeutic agents while minimizing systemic toxicity. Numerous DES using different thin-film polymeric drug carrier have been developed and tested, those eluting either antimitotic or antimicrotublar agents such as sirolimus and paclitaxel have been shown effective in clinical trials. Two DES, the J&J Cypher (sirolimus-eluting) and the Boston Scientific Taxus (paclitaxel-eluting) stents, are commercially available in the U.S. after a number of randomized trials demonstrated reductions in late lumen loss, binary restenosis rate, and need for repeat revascularization compared with bare-metal stents (BMS). Because ISR is multifactorial, ideal agents for DES should inhibit thrombus formation, inflammation and cellular proliferation as well as enhance re-endothelialization. The next generation of DES currently undergoing preclinical studies includes new technology, new stent designs and materials, biological polymers, bioabsorbable stents coated with new drugs including stent based gene, as well as cell delivery. The current paper will review and discuss the current and future status of DES.


Contextual factors in the activation of first diagnostic hypotheses: expert-novice differences.
According to Feltovich & Barrows (1984), the general frame used by medical experts to construct a mental representation of a particular patient problem contains a component part for those illness features that are associated with the acquisition of the illness. These 'enabling conditions' are related in several ways to the patient's disease. Examples are conditions like sex and age, or risk factors originating from work, behaviour and hereditary taint. Because of the sequential nature by which patient data become available during a clinical interview, contextual information is expected to play an important role in the generation of initial diagnostic hypotheses. To investigate the hypothesis that experienced doctors better utilize this kind of information, a group of 18 experts and 17 novices was confronted with 32 short case histories each presented on three slides: a portrait of the patient, the patient chart containing previous disease history, and a slide with the presenting complaint. It was hypothesized that differences in the number of correct diagnoses would emerge between the two groups, because the experts would use the contextual information, implicitly provided by picture and patient chart, in a more extensive way. If so, this would show in the amount of information that is explicitly recalled later. The data confirmed these predictions. The experts produced almost 50% more correct hypotheses as compared to the novices and were able to reproduce a larger amount of contextual information in particular information that was directly relevant to the patient's problem. Only the expert group showed a high correlation between accuracy of diagnoses and recall measures.


[Status of cell surface of hepatocytes after exposure to carbon tetrachloride].
In order to estimate contact interactions and deformity of the surface of hepatocytes at a toxic hepatitis, produced by means of carbon tetrachloride, a morphometric analysis of ultrastructures of the contacts and retractions of the surface of hepatocytes, formed at an increased intraorganic pressure has been performed. Carbon tetrachloride produces decrease in adhesive interactions of the cellular surfaces in the area of simple connections, decrease in amount of desmosomes and results in increasing deformity of the surface of hepatocytes. These data support that there exists a universal reaction of the intercellular contacts to a damaging action.


Dietary-Induced Chronic Hypothyroidism Negatively Affects Rat Follicular Development and Ovulation Rate and Is Associated with Oxidative Stress.
The long-term effects of chronic hypothyroidism on ovarian follicular development in adulthood are not well known. Using a rat model of chronic diet-induced hypothyroidism initiated in the fetal period, we investigated the effects of prolonged reduced plasma thyroid hormone concentrations on the ovarian follicular reserve and ovulation rate in prepubertal (12-day-old) and adult (64-day-old and 120-day-old) rats. Besides, antioxidant gene expression, mitochondrial density and the occurrence of oxidative stress were analyzed. Our results show that continuous hypothyroidism results in lower preantral and antral follicle numbers in adulthood, accompanied by a higher percentage of atretic follicles, when compared to euthyroid age-matched controls. Not surprisingly, ovulation rate was lower in the hypothyroid rats. At the age of 120 days, the mRNA and protein content of superoxide dismutase 1 (SOD1) were significantly increased while catalase (CAT) mRNA and protein content was significantly decreased, suggesting a disturbed antioxidant defense capacity of ovarian cells in the hypothyroid animals. This was supported by a significant reduction in the expression of peroxiredoxin 3 ( ITALIC! Prdx3), thioredoxin reductase 1 ( ITALIC! Txnrd1), and uncoupling protein 2 ( ITALIC! Ucp2) and a downward trend in glutathione peroxidase 3 ( ITALIC! Gpx3) and glutathione S-transferase mu 2 ( ITALIC! Gstm2) expression. These changes in gene expression were likely responsible for the increased immunostaining of the oxidative stress marker 4-hydroxynonenal. Together these results suggest that chronic hypothyroidism initiated in the fetal/neonatal period results in a decreased ovulation rate associated with a disturbance of the antioxidant defense system in the ovary.


Automatic detection of spinal injuries under dynamic compressive loading using high-speed cine-radiography.
Every year, new cases of individuals suffering from traumatic spinal injuries are detected. Advances in numerical models have allowed for the understanding of the damage caused by trauma and its impact on the patient's life. However, the kinematics and dynamics of vertebral fracture formation from its point of origin to the speed of propulsion of the fragments remain unknown. This is mainly due to the lack of data that essentially includes high-speed videos, load and displacement measurements during experimental tests reproducing spinal traumatic loading conditions. This lack of data can be addressed by the analysis of X-Ray images of animal specimens acquired during the traumatic spinal injury formation process. Thus, the purpose of this study was to develop an approach to automatically detect and track in vitro vertebral fractures using high-speed cine-radiography imaging. Four segments of porcine thoracolumbar vertebrae were dynamically compressed using a servo-hydraulic test bench. The compression process was filmed with a custom high-speed cine-radiography device, and the imaging parameters were optimized based on the physical properties of vertebrae. This paper demonstrates the feasibility of using high-speed cine-radiography imaging in this way, combined with an image processing pipeline to allow automatic documentation of the fracture's appearance and its evolution in the vertebra over time.Clinical Relevance- The proposed method will provide helpful information for proper handling of traumatic spinal injuries.


Reelin deficiency leads to aberrant lipid composition in mouse brain.
Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain.


Spontaneous reoccurrence of "scooping", a wild tool-use behaviour, in naïve chimpanzees.
Modern human technological culture depends on social learning. A widespread assumption for chimpanzee tool-use cultures is that they, too, are dependent on social learning. However, we provide evidence to suggest that individual learning, rather than social learning, is the driver behind determining the form of these behaviours within and across individuals. Low-fidelity social learning instead merely facilitates the reinnovation of these behaviours, and thus helps homogenise the behaviour across chimpanzees, creating the population-wide patterns observed in the wild (what here we call "socially mediated serial reinnovations"). This is the main prediction of the Zone of Latent Solutions (ZLS) hypothesis. This study directly tested the ZLS hypothesis on algae scooping, a wild chimpanzee tool-use behaviour. We provided naïve chimpanzees (n = 14, Mage = 31.33, SD = 10.09) with ecologically relevant materials of the wild behaviour but, crucially, without revealing any information on the behavioural form required to accomplish this task. This study found that naïve chimpanzees expressed the same behavioural form as their wild counterparts, suggesting that, as the ZLS theory predicts, individual learning is the driver behind the frequency of this behavioural form. As more behaviours are being found to be within chimpanzee's ZLS, this hypothesis now provides a parsimonious explanation for chimpanzee tool cultures.


Sex differences in frailty among older adults.
By definition, aging is a natural, gradual and continuous process. On the other hand, frailty reflects the increase in vulnerability to stressors and shortens the time without disease (health span) while longevity refers to the length of life (lifespan). The average life expectancy has significantly increased during the last few decades. A longer lifespan has been accompanied by an increase in frailty and decreased independence in older adults, with major differences existing between men and women. For example, women tend to live longer than men but also experience higher rates of frailty and disability. Sex differences prevent optimization of lifestyle interventions and therapies to effectively prevent frailty. Sex differences in frailty and aging are rooted in a complex interplay between uncontrollable (genetic, epigenetic, physiological), and controllable factors (psychosocial and lifestyle factors). Thus, understanding the underlying causes of sex differences in frailty and aging is essential for developing personalized interventions to promote healthy aging and improve quality of life in older men and women. In this review, we have discussed the key contributors and knowledge gaps related to sex differences in aging and frailty.


Use of doxorubicin plus cyclophosphamide followed by docetaxel as adjuvant chemotherapy for breast cancer.
We evaluated the feasibility and incidence of hematological toxicity in a series of 39 breast cancer patients treated at our institute with doxorubicin plus cyclophosphamide (AC) followed by docetaxel, using prophylactic G-CSF (pegfilgrastim). We prescribed G-CSF as secondary prophylaxis during the AC regimen and as primary prophylaxis during treatment with docetaxel. For the AC treatment, we recorded 6 cases of grade III (15.3%) and one case of grade IV (2.5%) neutropenia; we found one case of Grade IV anemia. For the docetaxel regimen, we registered one case of Grade IV (2.5%) neutropenia and three cases of Grade III leukopoenia without neutropenia. No patients experienced cardiac symptoms or baseline LVEF rate decrease. All patients concluded the programmed chemotherapy. Our experience shows the safety of docetaxel in combination with anthracyclines and the efficacy of prophylaxis with G-CSF in breast cancer adjuvant chemotherapy.


Ovariectomy does not alter CD4+/CD8+ ratio in peripheral blood T-lymphocytes in the rat.
Alterations in peripheral blood T-lymphocyte subsets have been implicated to play a role in the pathophysiology of estrogen deficiency-induced bone loss in postmenopausal women. The aim of this study was to investigate this hypothesis further by flow cytometric analysis of peripheral blood lymphocyte subpopulations together with bone histomorphometry using ovariectomized (OVX) rats as an experimental estrogen deficiency model. 104 female 6-month-old Wistar rats were either OVX or sham-operated (SHAM). Eight rats served as baseline controls. Groups of 8 SHAM and 8 OVX rats were killed 1, 2, 4, 6, 9, and 12 weeks after surgery. Blood was collected prior to sacrifice. In whole blood samples, subpopulations of peripheral lymphocytes were analyzed by flow cytometry using FITC- or PE-labeled monoclonal antibodies against rat CD5, CD4, and CD8. CD4 and CD8 positive T-lymphocytes were determined by a double-labeling technique. Serum samples were analyzed for estradiol and progesterone. The cancellous bone of the distal femoral metaphysis was analyzed by quantitative bone histomorphometry. Ovariectomy caused a statistically significant fall in serum estradiol and progesterone levels from 2 weeks postovariectomy until the end of the trial. Deterioration of cancellous bone structure and osteopenia in the distal femur of OVX rats became evident at 2 and 4 weeks postovariectomy, respectively. Flow cytometric analysis of peripheral blood lymphocytes revealed that, except for a transient increase in CD4 positive T-lymphocytes in OVX rats relative to SHAM animals at 1 week post-surgery, the number of CD5, CD4, or CD8 positive lymphocytes or the mean fluorescence per cell for these antigens in OVX rats remained unchanged throughout the study. Also the CD4+/CD8+ ratio of peripheral blood T-lymphocytes was not influenced by ovariectomy, and none of these parameters were significantly correlated with serum estradiol or progesterone levels. These results suggest that consistent changes in peripheral blood T-lymphocyte subpopulations are not demonstrable in OVX rats by the techniques applied in this study, and do not seem to play a pathogenetic role in the development of estrogen deficiency-induced bone loss in the rat.


A Midterm Review of Lesser Toe Arthrodesis With an Intramedullary Implant.
Lesser toe deformities are one of the most common conditions encountered by podiatric surgeons. When conservative treatments fail surgical correction is indicated. Many surgical options have been described to address the complex nature of these deformities but no perfect solution has been reported to date. However, with the continued advancement of internal fixation technology, interphalangeal joint (IPJ) arthrodesis with an intramedullary implant may be a good option. This retrospective study presents patient reported outcomes and complications at 6 months and 3 years following lesser toe proximal interphalangeal joint (PIPJ) arthrodesis with a polyketone intrameduallary implant (Toe Grip, Orthosolutions, UK). Between September 2011 and November 2012, a total of 38 patients attended for second toe PIPJ arthrodesis by means of the Toe Grip device. At 6 months postoperation, 94.7% of patients and at 3 years postoperation, 92.8% of patients felt that their original complaint was better or much better. Health-related quality of life scores continued to improve overtime as measured by the Manchester Oxford Foot Questionnaire. Complications were generally observational and asymptomatic. The most common complications were floating toes (17.8%), mallet deformities (14.2%), metatarsalgia (17.8%), and transverse plane deformity of the toe (10.7%). This study demonstrates excellent patient-eported outcomes with minimal symptomatic complications making the "Toe Grip" implant a safe and effective alternative fixation device for IPJ arthrodesis when dealing with painful digital deformities. Therapeutic, Level IV: Case series.


Health and ecological risk assessment of emerging contaminants (pharmaceuticals, personal care products, and artificial sweeteners) in surface and groundwater (drinking water) in the Ganges River Basin, India.
Pharmaceuticals, personal care products (PPCPs), and artificial sweeteners (ASWs) are contaminants of emerging concern commonly found in the aquatic environments. In India, studies reporting environmental occurrence of these contaminants are scarce. In this study, we investigated the occurrence and distribution of 15 PPCPs and five ASWs in the river and groundwater (used untreated as drinking water) at several sites along the Ganges River. Based on the measured groundwater concentrations, we estimated the life-long human health risk from exposure to PPCPs through drinking. In addition, we estimated the risk of exposure to PPCPs and ASWs in the river water for aquatic organisms. The sum of detected PPCPs in the river water ranged between 54.7-826 ng/L, with higher concentrations in the severely anthropogenically influenced middle and lower reaches of the Ganges. The highest concentration among the PPCPs in the river water was of caffeine (743 ng/L). The sum of detected ASWs in river water ranged between 0.2-102 ng/L. Similar to PPCPs, the sum of ASWs in the river water was higher in the middle and lower reaches of the Ganges. In groundwater, the sum of detected PPCPs ranged between 34-293 ng/L, whereas of ASWs ranged between 0.5-25 ng/L. Negligible risk for humans was estimated from PPCPs in the drinking groundwater sources along the Ganges River, whereas moderate risks to PPCPs and ASWs (namely: caffeine, sulfamethoxazole, triclocarban, triclosan, and sucralose) were estimated for aquatic organisms in the Ganges River.


Ethyl Gallate Displays Elicitor Activities in Tobacco Plants.
Alkyl gallates showed elicitor activities on tobacco in both whole plants and cell suspensions. Methyl gallate (MG), ethyl gallate (EG), and propyl gallate (PG) infiltration into tobacco leaves induced hypersensitive reaction-like lesions and topical production of autofluorescent compounds revealed under UV light. When sprayed on tobacco plants at 5 mM, EG promoted upregulation of defense-related genes such as the antimicrobial PR1, β-1,3-glucanase PR2, Chitinase PR3, and osmotin PR5 target genes. Tobacco BY-2 cells challenged with EG underwent cell death in 48 h, which was significantly reduced in the presence of the protease inhibitor aprotinin. The three alkyl gallates all caused alkalinization of the BY-2 extracellular medium, whereas gallic acid did not trigger any pH variation. Using EGTA or LaCl3, we showed that Ca2+ mobilization occurred in BY-2 cells elicited with EG. Overall, our findings are the first evidence of alkyl gallate elicitor properties with early perception events on the plasma membrane, potential hypersensitive reactions, and PR-related downstream defense responses in tobacco.


Trigeminal Neuropathy After Mandibular Fractures: Epidemiology and Neurophysiologic Diagnosis.
To study the trigeminal nerve neuropathy prevalence after mandibular fractures and follow nerve recovery and to examine associations with clinical features. The files of 304 patients treated for 424 mandibular fractures in Hadassah Medical Center between 2001 and 2008 were analyzed. Twenty-five patients with paresthesia were examined by electro-diagnostic conduction test (quantitative sensory testing). The most common fracture sites were the symphysis (28.5%) and condyle (21.4%). A strong correlation between fracture severity and treatment modality was found. Nerve damage occurred in 13.4% of nondisplaced fractures and in 65.3% of >5 mm displaced fractures. Patients who were treated by open reduction internal fixation demonstrated the biggest difference in quantitative sensory testing values between the affected and nonaffected sides. C nerve fibers were the most damaged and least regenerated. There was correlation between damage perception and objective test results. There is a correlation between fracture type and displacement severity on neurologic deficit and prognosis. The objective neurosensory damage was manifested by higher nerve excitation threshold on the injured side. Patients should be informed on the prognosis of neurologic deficit according to fracture type.


Modification of cell differentiation, one of the mechanisms in the surveillance of malignancy.
Most humans carry the potentially life-endangering Epstein-Barr virus (EBV). The immediate danger after infection is imposed by proliferation of the B cells that carry the viral genome. Although a number of different cell types can be infected with EBV, B lymphocytes are exceptionally sensitive; they express a set of virus-encoded proteins, which collaborate with host proteins to induce proliferation. This phenomenon can be demonstrated in vitro with experimentally infected B cells. These viral genes are expressed only in B lymphocytes and are restricted to a defined differentiation stage. This limitation is of high importance for the maintenance of the controlled EBV-carrier state of humans. The emergence of EBV-induced B-cell malignancies is counteracted by highly efficient immunologic mechanisms. Recognition of EBV-transformed immunoblasts in an MHC class I-restricted manner by cytotoxic CD8 T cells and, to a lesser extent, by CD4 T cells, is thought to play the major role. The in vitro experimental results are in accordance with the emergence of EBV(+) B-cell malignancies in immunosuppressive conditions. In this Masters primer, we emphasize that in addition to eliminating B cells that carry the virus genome, the regulatory circuit of the immune response also operates in surveillance, particularly in the early phase of infection. This mechanism involves T-cell-mediated regulation of B-cell differentiation. Because of the strict dependence of the viral growth program on the expression of host cell factors, altering the differentiation state can curb the proliferation of B cells that harbor the viral genome.


Elevated ALT activity in volunteer blood donors.
By far, the most common cause of post-transfusion hepatitis (PTH) is infection with the non-A, non-B hepatitis (NANB) virus. Until very recently, no specific laboratory test existed to detect the presence of this virus in donated blood. However, a correlation has been established between high donor ALT (formerly SGPT) and recipient PTH and between positive donor core antibody and recipient PTH. To lower the current high incidence of NANB-induced PTH, in 1986, the American Association of Blood Banks (AABB) recommended testing for these PTH-associated "surrogate" markers on all donated units of blood. Accordingly, testing for Hepatitis B core antibody and for ALT activity were implemented. This practice produced large amounts of data on populational ALT activity levels and core antibody positivity. The ALT activity of 3108 healthy volunteer blood donors as recorded in the donor files of the Hospital Universitario Ramón Ruiz Arnau Blood Bank were analyzed retrospectively to determine what the local normal ALT activity was. It was determined that the average ALT was 35.91 units/liter. This average is much higher than averages reported by other blood banks in the literature. Possible causes of the high local ALT activity levels are discussed.


The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells.
The serine-threonine kinase Akt/PKB is activated downstream of phosphatidylinositol 3-kinase in response to several growth factor stimuli and has been implicated in the promotion of cell survival. Although both phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PI 3,4-P2) have been implicated in the regulation of Akt activity in vitro, the relative roles of these two phospholipids in vivo are not well understood. Co-ligation of the B cell receptor (BCR) and the inhibitory FcgammaRIIB1 on B cells results in the recruitment of the 5'-inositol phosphatase SHIP to the signaling complex. Since SHIP is known to cleave PIP3 to generate PI 3,4-P2 both in vivo and in vitro, and Akt activity has been reported to be regulated by either PIP3 or PI 3,4-P2, we hypothesized that recruitment of SHIP through FcgammaRIIB1 co-cross-linking to the BCR in B cells might regulate Akt activity. The nature of this regulation, positive or negative, might also reveal the relative contribution of PIP3 and PI 3,4-P2 to Akt activation in vivo. Here we report that Akt is activated by stimulation through the BCR in a phosphatidylinositol 3-kinase-dependent manner and that this activation is inhibited by co-cross-linking of the BCR to FcgammaRIIB1. Using mutants of FcgammaRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within FcgammaRIIB1 as well as SHIP. The SHIP-dependent inhibition of Akt activation also suggests that PIP3 plays a greater role in Akt activation than PI 3,4-P2 in vivo.


[Treatment of bronchial asthma by the Su-Jok therapy method].
To evaluate the influence of su-jok therapy (one of the methods of alternative medicine) in combination with chemotherapy on the course of bronchial asthma. 68 patients have undergone su-jok therapy in combination with drug treatment in accordance with international asthma consensus. Control group of 44 patients received only chemotherapy. The response was assessed by: quantitative indices of asthma course, FEV1, FEF 25, 75, 50, PEF, demand of beta2-agonists, long-term outcomes. The efficiency coefficient made up 2.64 in patients versus 1.48 in controls. Demand of beta2-agonists reduced 4 times versus 1.6 times, respectively. The degree of improvement of bronchial permeability at the level of distal bronchus was 2 times higher in the study group. Other functional parameters were not significantly different. The period free of exacerbations with hospital care was 1.7 times longer in patients on su-jok therapy. The su-jok therapy adjuvant to chemotherapy is highly effective.


Primary ciliary dyskinesia: overlooked and undertreated in children.
Primary ciliary dyskinesia (PCD) is a multi-organ disorder associated with chronic oto-sino-pulmonary disease, neonatal respiratory distress, situs abnormalities and reduced fertility. Repeated respiratory tract infections leads to the almost universal development of bronchiectasis. These clinical manifestations are a consequence of poorly functioning motile cilia. However, confirming the diagnosis is quite difficult and is often delayed, so the true incidence of PCD may be significantly higher than current estimates. Nasal nitric oxide has been earmarked as a useful screening tool for identifying patients, but its use is limited in pre-school-aged children. Due to the rarity of PCD, the evidence base for management is somewhat limited, and treatment regimens are extrapolated from other suppurative lung disorders, like cystic fibrosis.


Mass isotopomer study of the nonoxidative pathways of the pentose cycle with [1,2-13C2]glucose.
We present a single-tracer method for the study of the pentose phosphate pathway (PPP) using [1,2-13C2]glucose and mass isotopomer analysis. The metabolism of [1,2-13C2]glucose by the glucose-6-phosphate dehydrogenase, transketolase (TK), and transaldolase (TA) reactions results in unique pentose and lactate isotopomers with either one or two 13C substitutions. The distribution of these isotopomers was used to estimate parameters of the PPP using the model of Katz and Rognstad (J. Katz and R. Rognstad. Biochemistry 6: 2227-2247, 1967). Mass and position isotopomers of ribose, and lactate and palmitate (products from triose phosphate) from human hepatoma cells (Hep G2) incubated with 30% enriched [1,2-13C2]glucose were determined using gas chromatography-mass spectrometry. After 24-72 h incubation, 1.9% of lactate molecules in the medium contained one 13C substitution (m1) and 10% contained two 13C substitutions (m2). A similar m1-to-m2 ratio was found in palmitate as expected. Pentose cycle (PC) activity determined from incubation with [1,2-13C2]glucose was 5.73 +/- 0.52% of the glucose flux, which was identical to the value of PC (5.55 +/- 0.73%) determined by separate incubations with [1-13C] and [6-13C]glucose, 13C was found to be distributed in four ribose isotopomers ([1-13C]-, [5-13C]-, [1,2-13C2]-, and [4,5-13C2]ribose). The observed ribose isotopomer distribution was best matched with that provided from simulation by substituting 0.032 for TK and 0.85 for TA activity relative to glucose uptake into the model of Katz and Rognstad. The use of [1,2-13C2]glucose not only permits the determination of PC but also allows estimation of relative rates through the TK and TA reactions.


Assessment of epidemiological and genetic characteristics and clinical outcomes of resistance to bedaquiline in patients treated for rifampicin-resistant tuberculosis: a cross-sectional and longitudinal study.
Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19). Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR. Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. National Institute for Communicable Diseases of South Africa.


Eosinophilia and clinical outcome of chronic obstructive pulmonary disease: a meta-analysis.
Numerous studies have investigated the association between eosinophilia and clinical outcome of patients with chronic obstructive pulmonary disease (COPD) but the evidence is conflicting. We conducted a pooled analysis of outcome measures comparing eosinophilic and non-eosinophilic COPD patients. We searched articles indexed in four databases using Medical Subject Heading or Title and Abstract words including COAD, COPD, eosinophil, eosinophilia, eosinopenia from inception to December 2016. Observational studies and randomized controlled trials with parallel groups comparing COPD patients with and without eosinophilia were included. Comparing to the non-eosinophilic group, those with eosinophilic COPD had a similar risk for exacerbation in 12 months [Odds ratio = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55] and in-hospital mortality [OR = 0.52, 95% CI 0.25-1.07]. Eosinophilia was associated with reduced length of hospital stay (P = 0.04). Subsequent to therapeutic interventions, eosinophilic outpatients performed better in pulmonary function tests [Mean Difference = 1.64, 95% CI 0.05-3.23, P < 0.001]. Inclusion of hospitalized patients nullified the effect. Improvement of quality of life was observed in eosinophilic subjects [Standardized Mean Difference = 1.83, 95% CI 0.02-3.64, P = 0.05], independent of hospitalization status. In conclusion, blood eosinophilia may be predictive of favorable response to steroidal and bronchodilator therapies in patients with stable COPD.


Enhancing discovery and saving money with MERIT.
The National Institutes of Health and many of our biomedical institutions face significant budgetary challenges that are likely to persist for the foreseeable future. The paylines for Research Project Grant (RO1) applications to the NIH will be near or below the tenth percentile, and many investigators are growing increasingly concerned about maintaining their research programs. One of the most concerning potential results of limited grant dollars is the natural tendency for researchers to propose conservative projects that are more likely to succeed, to do well in peer review, and to be funded, but that may not dramatically advance the field, and a concurrent tendency among study sections to reward proposals that are seen as safe, if uninspiring. Established and well-respected investigators may be (perhaps appropriately) given the benefit of the doubt when compared with less-established colleagues and may therefore command a growing percentage of the total available grant dollars, while simultaneously avoiding bold and potentially groundbreaking approaches. At the same time, fewer dollars are available for new investigators with unproven track records and for the expansion of newly successful programs.


Molecular Cloning, Expression Analysis, and Functional Analysis of Nine IbSWEETs in Ipomoea batatas (L.) Lam.
Sugar Will Eventually be Exported Transporter (SWEET) genes play an important regulatory role in plants' growth and development, stress response, and sugar metabolism, but there are few reports on the role of SWEET proteins in sweet potato. In this study, nine IbSWEET genes were obtained via PCR amplification from the cDNA of sweet potato. Phylogenetic analysis showed that nine IbSWEETs separately belong to four clades (Clade I~IV) and contain two MtN3/saliva domains or PQ-loop superfamily and six~seven transmembrane domains. Protein interaction prediction showed that seven SWEETs interact with other proteins, and SWEETs interact with each other (SWEET1 and SWEET12; SWEET2 and SWEET17) to form heterodimers. qRT-PCR analysis showed that IbSWEETs were tissue-specific, and IbSWEET1b was highly expressed during root growth and development. In addition to high expression in leaves, IbSWEET15 was also highly expressed during root expansion, and IbSWEET7, 10a, 10b, and 12 showed higher expression in the leaves. The expression of SWEETs showed a significant positive/negative correlation with the content of soluble sugar and starch in storage roots. Under abiotic stress treatment, IbSWEET7 showed a strong response to PEG treatment, while IbSWEET10a, 10b, and 12 responded significantly to 4 °C treatment and, also, at 1 h after ABA, to NaCl treatment. A yeast mutant complementation assay showed that IbSWEET7 had fructose, mannose, and glucose transport activity; IbSWEET15 had glucose transport activity and weaker sucrose transport activity; and all nine IbSWEETs could transport 2-deoxyglucose. These results provide a basis for further elucidating the functions of SWEET genes and promoting molecular breeding in sweet potato.


Enhanced stability and water solubilizing capacity of water-in-oil microemulsions based on protic ionic liquids.
In an attempt to increase the stability and water uptake capacity of water-in-oil (W/O) microemulsions, here we study the physicochemical behavior of a series of protic ionic liquid based water/oil microemulsions, wherein solute amounts of biocompatible tetramethylguanidinium cation-based ionic liquids (ILs) are added to the aqueous phase of water-in-oil (W/O) microemulsions. FTIR and time-resolved fluorescence measurements showed an increased water uptake in these reverse micellar droplets, compared to conventional W/O microemulsions of similar compositions. Dynamic light scattering and differential scanning calorimetric measurements suggested greater thermal stability of the droplets in presence of the ILs. NMR and FTIR measurements and ab initio calculations explained these findings by showing an extended hydrogen bonding network between interfacial water and protic IL ions and strong electrostatic associations between the surfactant headgroups and IL anions. Our results pave the way for potential applications of protic ionic liquids in emulsion and microemulsion science and technology.


Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension.
Blockade of neuronal nitric oxide synthase (nNOS) in the brain induced an increase in mean arterial pressure of spontaneously hypertensive rats (SHR). We hypothesize that increased nitric oxide (NO) synthesis in the brain compensates for hypertension. Therefore, we measured NOS activity in different brain regions in SHR at prehypertensive, onset and established hypertension, and compared with age-matched Wistar-Kyoto (WKY) rats. NOS activity was measured by the ability of tissue homogenate to convert [3H]l-arginine to [3H]l-citrulline in a Ca2+- and NADPH-dependent manner. NOS activity was impaired in the cerebral cortex and brainstem of prehypertensive SHR. At established hypertension, SHR showed an augmentation in NOS activity in hypothalamus and brainstem. Chronic treatment of SHR with the angiotensin-1 converting enzyme (ACE)-inhibitor, enalapril, and the AT(1) receptor antagonist, losartan, normalized NOS activity in the hypothalamus but not in the brainstem. Treatment with a peripheral vasodilator, hydralazine, did not affect NOS activity. Attenuated NOS activity in the cortex and brainstem of prehypertensive SHR may play a role in the pathogenesis of hypertension. The upregulated NOS activity in the hypothalamus and brainstem of SHR possibly serves to compensate for hypertension. Hypothalamic, but not brainstem, NO is involved in antihypertensive effects of ACE inhibition and AT(1) receptor blockade. Since a blood pressure decrease per se had no effect on NOS activity, it appears that central sympathetic activity influenced by endogenous angiotensin II, rather than blood pressure, represents the stimulus for the increased NOS activity in the hypothalamus of SHR.


Treatment of basilar tip aneurysms with horizontal PCA to PCA stent-assisted coiling: case series.
Coiling of wide-necked basilar tip aneurysms is technically challenging and is often assisted by the placement of a stent. Stent placement in an anterograde fashion either with a single or Y-stent is typical. However, in some cases the posterior cerebral artery (PCA) angle of origin at the base of the aneurysm precludes anterograde catheterization. A series of patients with wide-necked basilar tip aneurysms treated with a single stent placed via the posterior communicating artery from PCA to PCA is presented. A retrospective database review was performed to identify all stent-coiled basilar tip aneurysms. Patients with attempted horizontal P1-P1 stenting via the posterior communicating artery were identified. Procedural imaging, follow-up angiography and clinical notes were reviewed. P1-P1 stenting was attempted in 10 patients and was successful in eight. Angiographic follow-up was available in six patients, all of whom had >90% obliteration at last follow-up. There was one procedure-related subarachnoid hemorrhage that resulted in patient death. There were no cases of significant PCA stenosis on angiographic follow-up. This stenting technique is an effective way to treat wide-necked basilar tip aneurysms but is limited by the anatomy of the posterior communicating arteries and P1 segments.


Enhanced central response to dehydration in mice lacking angiotensin AT(1a) receptors.
The objective was to determine the central nervous system (CNS) responses to dehydration (c-Fos and vasopressin mRNA) in mice lacking the ANG AT(1a) receptor [ANG AT(1a) knockout (KO)]. Control and AT(1a) KO mice were dehydrated for 24 or 48 h. Baseline plasma vasopressin (VP) was not different between the groups; however, the response to dehydration was attenuated in AT(1a) KO (24 +/- 11 vs. 10.6 +/- 2.7 pg/ml). Dehydration produced similar increases in plasma osmolality and depletion of posterior pituitary VP content. Neuronal activation was observed as increases in c-Fos protein and VP mRNA. The supraoptic responses were not different between groups. In the paraventricular nucleus (PVN), c-Fos-positive neurons (57.4 +/- 10.7 vs. 98.4 +/- 7.4 c-Fos cells/PVN, control vs. AT(1a) KO) and VP mRNA levels (1.0 +/- 0.1 vs. 1.4 +/- 0.1 microCi, control vs. AT(1a) KO) were increased with greater responses in AT(1a) KO. A comparison of 1- to 2-day water deprivation showed that plasma VP, brain c-Fos, and VP mRNA returned toward control on day 2, although plasma osmolality remained high. Data demonstrate that AT(1a) KO mice show a dichotomous response to dehydration, reduced for plasma VP and enhanced for PVN c-Fos protein and VP mRNA. The results illustrate the importance of ANG AT(1a) receptors in the regulation of osmotic and endocrine balance.


Screening of potent RIPK3 inhibitors to attenuate necroptosis and inflammation in mouse traumatic brain injury models.
Necroptosis is a type of cell death that occurs when cells are exposed to external stressors such as inflammation, infections, or injury. In necroptosis, cells use a different set of proteins including: receptor-interacting kinase 1 (RIPK1 or RIP1), receptor-interacting kinase 3 (RIPK3 or RIP3) and the phosphorylation of its substrate mixed lineage kinase domain-like protein (MLKL) and pathways to trigger their own death. Mutations in the gene encoding RIPK3 have been associated with many diseases, including neurodegenerative diseases, neuroinflammatory diseases, inflammatory diseases,tumors, and it is being studied as a potential target for inflammatory injury therapy. RIPK3 has also been implicated in the pathology of neuroinflammation following Traumatic brain injury and is currently being explored as a potential therapy. We screened through necroptosis blocking compounds, a library of FDA-approved compounds. We found four compounds:1D6-Foretinib GSK1363089; 15F6-Poziotinib (HM781-36B); 15F9-Dasatinib monohydrate; 15A10-Pexmetinib (ARRY-614); acts as potent inhibitors of necroptosis (Necroptosis Blocking Compounds, NBCs) by blocking the RIPK3 kinase activity. These four compounds effectively block necroptosis induced by death receptor ligands Toll-like receptors as well as viral infections in human, rat and mouse cells. The cellular activation of RIPK3 and MLKL stimulated by necroptosis was strongly inhibited by NBCs. The compounds are promising for targeting RIPK3 kinase activity, thereby preventing necroptosis and inflammatory responses. In our study, we explored the role of NBCs in neuroprotection after traumatic brain injury. It's effectiveness in traumatic brain injury animal models and favorable safety profiles make it a potential candidate for the advances of new therapies for necroptosis-associated neuroinflammatory disorders.


Hypergravity and microgravity exhibited reversal effects on the bone and muscle mass in mice.
Spaceflight is known to induce severe systemic bone loss and muscle atrophy of astronauts due to the circumstances of microgravity. We examined the influence of artificially produced 2G hypergravity on mice for bone and muscle mass with newly developed centrifuge device. We also analyzed the effects of microgravity (mostly 0G) and artificial produced 1G in ISS (international space station) on mouse bone mass. Experiment on the ground, the bone mass of humerus, femur and tibia was measured using micro-computed tomography (μCT), and the all bone mass was significantly increased in 2G compared with 1G control. In tibial bone, the mRNA expression of bone formation related genes such as Osx and Bmp2 was elevated. The volume of triceps surae muscle was also increased in 2G compared with 1G control, and the mRNA expression of myogenic factors such as Myod and Myh1 was elevated by 2G. On the other hand, microgravity in ISS significantly induced the loss of bone mass on humerus and tibia, compared with artificial 1G induced by centrifugation. Here, we firstly report that bone and muscle mass are regulated by the gravity with loaded force in both of positive and negative on the ground and in the space.


Agmatine attenuates stress- and lipopolysaccharide-induced fever in rats.
Physiological stress evokes a number of responses, including a rise in body temperature, which has been suggested to be the result of an elevation in the thermoregulatory set point. This response seems to share similar mechanisms with infectious fever. The aim of the present study was to investigate the effect of agmatine on different models of stressors [(restraint and lipopolysaccharide (LPS)] on body temperature. Rats were either restrained for 4 h or injected with LPS, both of these stressors caused an increase in body temperature. While agmatine itself had no effect on body temperature, treatment with agmatine (20, 40, 80 mg/kg intraperitoneally) dose dependently inhibited stress- and LPS-induced hyperthermia. When agmatine (80 mg/kg) was administered 30 min later than LPS (500 microg/kg) it also inhibited LPS-induced hyperthermia although the effect became significant only at later time points and lower maximal response compared to simultaneous administration. To determine if the decrease in body temperature is associated with an anti-inflammatory effect of agmatine, the nitrite/nitrate levels in plasma was measured. Agmatine treatment inhibited LPS-induced production of nitrates dose dependently. As an endogenous molecule, agmatine has the capacity to inhibit stress- and LPS-induced increases in body temperature.


SAVE Testis-sparing score: A multicenter retrospective study of a novel predictive tool for quantifying testicular tumors.
Testis-sparing surgery (TSS) is a safe treatment for patients with benign testicular tumors. Presently, assessments for evaluating the suitability of TSS are poorly standardized, partially because testicular anatomical elements cannot be quantitatively described. We developed a scoring method known as SAVE testis-sparing score based on four critical and accessible anatomical features of testicular tumor. The SAVE score ranges from 0 to 8 and is divided into four risk classes (low, medium, high, and extremely high) to evaluate the feasibility of TSS, wherein low risk indicates high feasibility and vice versa. This study included 444 testicular tumor patients from eight centers. Among them, 216 patients (model group: 151 patients, validation group: 65 patients) were included in the modeling analysis, and the other 228 patients from children's centers were included in the proportion analysis. Using retrospective data, patient characteristics associated with surgical methods were identified. Furthermore, multivariate logistic regression model was built quantify the associations between these characteristics and the surgery method. The receiver operator characteristic curve was used to evaluate the classification efficiency of SAVE. The SAVE testis-sparing score includes size (tumor size as maximal diameter), available testicular tissue volume, volume ratio of the tumor to the testis, and the exophytic/endophytic properties of the tumor. The SAVE scoring system accurately classified the suitability of TSS based on the complexity of benign testicular tumors. The SAVE score is a reproducible and robust tool for quantitatively describing the anatomical characteristics of benign testicular tumors and guide the preoperative evaluation of TSS.


Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2.
Mutations in the gene encoding the canalicular bile salt export pump (BSEP) can result in progressive familial intrahepatic cholestasis type 2 (PFIC-2). Treatment options are limited, and PFIC-2 often necessitates liver transplantation. We report on a young woman and a boy who clinically presented with PFIC-2 phenotypes and dramatically improved with steroid treatment. Gene sequencing of ABCB11 encoding for BSEP revealed 2 relevant mutations in both patients. The young woman was compound heterozygous for p.T919del and p.R1235X. At the age of 5 years, partial biliary diversion was performed and rescued liver function but left serum bile salt levels elevated. At age 23 she developed systemic lupus erythematosus. Unexpectedly, steroid therapy normalized serum bile salt levels, with a strong correlation with the steroid dose. She is currently in clinical remission. The boy was compound heterozygous for the ABCB11 mutations c.150+3A>C and p.R832C and presented with intractable pruritus. When he developed colitis, he was treated with steroids. The pruritus completely disappeared and relapsed when steroids were withdrawn. To date, with low-dose budesonide, the boy has been symptom-free for >3 years. In conclusion, the clinical courses suggest that patients with BSEP deficiency and residual BSEP activity may benefit from steroid-based therapy, which represents a new treatment option.


Phytochemical characterization of the Ziziphus joazeiro Mart. metabolites by UPLC-QTOF and antifungal activity evaluation.
The aim of this study was to evaluate the antifungal and modulatory potential of the Ziziphus joazeiro bark and leaf extracts, both in isolation and in association with fluconazole, against resistant species from the Candida genus. Antifungal assays were used to determine the half maximal inhibitory concentration (IC50) of the extract in isolation and in combination with fluconazole using the broth microdilution method and spectrophotometric readings, followed by verification of the minimum fungicidal concentration by solid medium subculture. According to the cell viability curve, both extracts inhibited fungal growth in a concentration dependent manner, in addition to showing inhibitory concentrations similar to fluconazole. However, the extracts behaved in a fungistatic manner with minimum inhibitory concentration > 8.19 mg/mL and IC50 values ranging from 0.450 mg/mL to 9 mg/mL. The minimum inhibitory concentration for both extracts decreased when in combination with fluconazole, with the AEL standing out against Candida albicans URM 4387, displaying an IC50 equal to that of fluconazole (0.002 mg/mL). Nevertheless, fluconazole antagonism was observed against the tested strains. Overall, the evaluation of both extracts against Candida spp. presented inhibitory concentration values greater than fluconazole. Moreover, despite these being chemically complex crude extracts, they did demonstrate antifungal effects and properties that concur with their ethno-biological aspect.


Intracranial dural empyema.
Intracranial dural empyema is a neurosurgical emergency with potentially devastating complications. The prognosis is adversely affected by delay in diagnosis. Modern imaging techniques, especially contrast enhanced CT and MRI, have improved the speed and accuracy of radiological diagnosis of this condition, with an associated reduction in mortality. Despite this, there may still be a delay in diagnosis, partly owing to the subtlety of early radiological signs, especially on unenhanced CT. We present cases that illustrate some of the radiological manifestations, complications and potential pitfalls in diagnosis.


Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases.
Organisms are constantly exposed to microbial pathogens in their environments. When a pathogen meets its host, a series of intricate intracellular interactions shape the outcome of the infection. The understanding of these host-pathogen interactions is crucial for the development of treatments and preventive measures against infectious diseases. Over the past decade, proteomic approaches have become prime contributors to the discovery and understanding of host-pathogen interactions that represent anti- and pro-pathogenic cellular responses. Here, we review these proteomic methods and their application to studying viral and bacterial intracellular pathogens. We examine approaches for defining spatial and temporal host-pathogen protein interactions upon infection of a host cell. Further expanding the understanding of proteome organization during an infection, we discuss methods that characterize the regulation of host and pathogen proteomes through alterations in protein abundance, localization, and post-translational modifications. Finally, we highlight bioinformatic tools available for analyzing such proteomic datasets, as well as novel strategies for integrating proteomics with other omic tools, such as genomics, transcriptomics, and metabolomics, to obtain a systems-level understanding of infectious diseases.


Gene copy-number polymorphism caused by retrotransposition in humans.
The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance.


Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.
DNAX-activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT-PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12-coupled receptors, in particular TREM-1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid-binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild-type mice, but when these mice were re-derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP, lymphocytes from the DAP12-deficient mice housed in the two facilities proliferated and produced opposite profiles of pro-inflammatory and anti-inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.


Thoracic Surgeons' Beliefs and Practices on Smoking Cessation Before Lung Resection.
Smoking is a risk factor for complications after lung resection. Our primary aim was to ascertain thoracic surgeons' beliefs and practices on smoking cessation before lung resection. An anonymous survey was emailed to 846 thoracic surgeons who participate in The Society of Thoracic Surgeons General Thoracic Surgery Database. The response rate was 23.6% (n = 200). Surgeons were divided when asked whether it is ethical to require that patients quit smoking (yes, n = 96 [48%]) and whether it is fair to have their outcomes affected by patients who do not quit (yes, n = 87 [43.5%]). Most do not require smoking cessation (n = 120 [60%]). Of those who require it, the most common required period of cessation is 2 weeks or more. Most believe that patient factors are the main barrier to quitting (n = 160 [80%]). Risk of disease progression (39% vs 17.5%, p = 0.02) and alienating patients (17.5% vs 8.8%, p = 0.04) were very important considerations of those who do not require smoking cessation versus those who do. Only 19 (9.5%) always refer to a smoking cessation program and prescribe nicotine replacement therapy and even fewer, 9 (4.5%), always refer to a program and prescribe medical therapy. Thoracic surgeons are divided on their beliefs and practices regarding smoking cessation before lung resection. Most believe patient factors are the main barrier to quitting and have concerns about disease progression while awaiting cessation. Very few surgeons refer to a smoking cessation program and prescribe nicotine replacement therapy or medical therapy.


A model to facilitate outcome assessment of obstructive sleep apnea.
Obstructive sleep apnea is a common disorder with significant morbidity and effects on quality of life. Management can include a range of mechanical, behavioral, and surgical approaches. This paper aims to devise a model of management options to assist in initial cost-effectiveness investigations. In the absence of practice pattern data and widely accepted guidelines, we reviewed published literature and devised a model of treatment options to facilitate initial studies of outcomes, costs, and cost-effectiveness. Obstructive sleep apnea is rarely addressed by conservative behavioral-based strategies because these options, while inexpensive, have only limited effectiveness. Effective treatment most often relies on nasal continuous positive airway pressure, but poor tolerance or compliance sometimes leads to treatment with oral appliances or surgery. Patients treated by one modality may try another if the initial strategy is ineffective. Laboratory evidence that sleep apnea is effectively treated, and long-term follow-up, are necessary regardless of the treatment modality chosen. Each patient's treatment plan must be individually tailored, but the management model proposed here reflects available evidence-based literature and the authors' impression of current practice patterns. This model should be useful for initial cost-effectiveness investigations.


Rapid and easy detection of low-level resistance to vancomycin in methicillin-resistant Staphylococcus aureus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
Vancomycin-intermediately resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with treatment failure. hVISA contains only a subpopulation of cells with increased minimal inhibitory concentrations, and its detection is problematic because it is classified as vancomycin-susceptible by standard susceptibility testing and the gold-standard method for its detection is impractical in clinical microbiology laboratories. Recently, a research group developed a machine-learning classifier to distinguish VISA and hVISA from vancomycin-susceptible S. aureus (VSSA) according to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) data. Nonetheless, the sensitivity of hVISA classification was found to be 76%, and the program was not completely automated with a graphical user interface. Here, we developed a more accurate machine-learning classifier for discrimination of hVISA from VSSA and VISA among MRSA isolates in Japanese hospitals by means of MALDI-TOF MS data. The classifier showed 99% sensitivity of hVISA classification. Furthermore, we clarified the procedures for preparing samples and obtaining MALDI-TOF MS data and developed all-in-one software, hVISA Classifier, with a graphical user interface that automates the classification and is easy for medical workers to use; it is publicly available at https://github.com/bioprojects/hVISAclassifier. This system is useful and practical for screening MRSA isolates for the hVISA phenotype in clinical microbiology laboratories and thus should improve treatment of MRSA infections.


Magnetite nanoparticle interactions with insulin amyloid fibrils.
Accumulation of amyloid fibrils is one of the likely key factors leading to the development of Alzheimer's disease and other amyloidosis associated diseases. Magnetic nanoparticles (NPs) have been developed as promising medical materials for many medical applications. In this study, we have explored the effects of Fe3O4 NPs on the fibrillogenesis process of insulin fibrils. When Fe3O4 NPs were co-incubated with insulin, Fe3O4 NPs had no effect on the structural transformation into amyloid-like fibrils but had higher affinity toward insulin fibrils. We demonstrated that the zeta potential of insulin fibrils and Fe3O4 NPs were both positive, suggesting the binding forces between Fe3O4 NPs and insulin fibrils were van der Waals forces but not surface charge. Moreover, a different amount of Fe3O4 NPs added had no effect on secondary structural changes of insulin fibrils. These results propose the potential use of Fe3O4 NPs as therapeutic agents against diseases related to protein aggregation or contrast agents for magnetic resonance imaging.


Tyrosine phosphate in melanoma progression.
Cellular tyrosine phosphorylation is regulated by two large families of enzymes. Protein tyrosine kinases (PTK) mediate addition, and protein tyrosine phosphatases (PTP), removal of phosphate from protein substrates. PTKs are oncogenes and PTPs have been hypothesized to function as tumour suppressor genes. To determine changes in tyrosine phosphate and PTP activity that occur during melanoma progression. Immunohistochemistry was used to study phosphotyrosine in melanocytic lesions. In addition, PTP activity of normal melanocytes and melanoma cell lines was measured using an enzyme-linked immunosorbent assay-based system. Melanocytes in normal skin and most (67%) benign naevi were not immunostained. Neither were early malignant lesions (80% of malignant melanoma in situ and radial growth phase melanomas) stained. However, most advanced melanomas (100% of vertical growth phase, and 90% of metastatic melanomas) were immunoreactive. When total PTP enzyme activity was assayed in normal melanocytes and malignant melanoma cell lines, there was a significant increase in activity associated with melanoma progression. Taken together, the data suggest increased phosphotyrosine signalling occurs during melanoma progression at the stage when cells first become competent for metastasis.


IV. Uterine fibroid embolization: follow-up.
Patients generally notice some relief of both menorrhagia and mass-effect symptoms during the first few weeks after uterine fibroid embolization (UFE). Shrinkage of the fibroids continues to take place over several months, peaking somewhere between 3 and 6 months, with measurable shrinkage sometimes noted for up to 1 year. The timing of follow-up visits is intended to coincide with the time course of improvement so that diagnostic imaging and intervention can be performed if symptoms worsen or relief does not appear to be on schedule. The amount of shrinkage of fibroids correlates neither with the intensity of immediate postprocedure symptoms or the degree of symptom relief. Affected fibroids undergo hyaline degeneration, a process in which the hard, cellular tumor is replaced by softer, acellular material. A nationwide registry has been constructed for the accumulation of procedural and follow-up data so that success and complication rates can be accurately determined and long-term issues about the durability of UFE and possible side effects can be addressed.


SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.
Infection or vaccination induces a population of long-lived bone marrow plasma cells (BMPCs) that are a persistent and essential source of protective antibodies1-5. Whether this population is induced in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unknown. Recent reports have suggested that SARS-CoV-2 convalescent patients experience a rapid decay in their antigen-specific serum antibodies, raising concerns that humoral immunity against this virus may be short-lived6-8. Here we show that in patients who experienced mild infections (n=73), serum anti-SARS-CoV-2 spike (S) antibodies indeed decline rapidly in the first 3 to 4 months after infection. However, this is followed by a more stable phase between 4- and 8-months after infection with a slower serum anti-S antibody decay rate. The level of serum antibodies correlated with the frequency of S-specific long-lived BMPCs obtained from 18 SARS-CoV-2 convalescent patients 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy subjects with no history of SARS-CoV-2 infection. Comparable frequencies of BMPCs specific to contemporary influenza virus antigens or tetanus and diphtheria vaccine antigens were present in aspirates in both groups. Circulating memory B cells (MBCs) directed against the S protein were detected in the SARS-CoV-2 convalescent patients but not in uninfected controls, whereas both groups had MBCs against influenza virus hemagglutinin. Overall, we show that robust antigen specific long-lived BMPCs and MBCs are induced after mild SARS-CoV-2 infection of humans.


Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options.
The negative symptoms of schizophrenia represent an impairment of normal emotional responses, thought processes and behaviors, and include blunting or flattening of affect, alogia/aprosody, avolition/apathy, anhedonia, and asociality. Negative symptoms contribute to a reduced quality of life, increased functional disability, increased burden of illness, and poorer long-term outcomes, to a greater degree than positive symptoms. Primary negative symptoms are prominent and persistent in up to 26% of patients with schizophrenia, and they are estimated to occur in up to 58% of outpatients at any given time. Negative symptoms respond less well to medications than positive symptoms, and to date treatment options for negative symptoms have been limited, with no accepted standard treatment. Modest benefits have been reported with a variety of different agents, including second-generation antipsychotics and add-on therapy with antidepressants and other pharmacological classes. Recent clinical research focusing on negative symptoms target novel biological systems, such as glutamatergic neurotransmission. Different approaches include: enhancing N-methyl-D-aspartate receptor function with agents that bind directly to the glycine ligand site or with glycine reuptake inhibitors; influencing the metabotropic glutamate receptor (mGluR2/3) with positive allosteric modulators; and stimulating nicotinic acetylcholine receptors. In conclusion, the lack of clearly efficacious pharmacological treatments for the management of negative symptoms represents a significant unmet need, especially considering the importance of these symptoms on patient outcomes. Hence, further research to identify and characterize novel pharmacological treatments for negative symptoms is greatly needed.


The effect of vitamin E (alpha-tocopherol) supplementation on hepatic levels of vitamin A and E in ethanol and cod liver oil fed rats.
Eight groups of 5 rats were fed 8 differing liquid diets with and without ethanol, cod liver oil and/or increased levels of vitamin E. Hepatic levels of vitamins A and E were determined following the 28-day feeding time. Ethanol consumption decreased the levels of hepatic vitamin E (p less than 0.05), vitamin A (p less than 0.05) and the ratio of vitamin A/E (p less than 0.05). Hepatic levels of vitamins A and E were unaffected in rats fed cod liver oil. Supplementation of the normal dietary level of 30 IU of vitamin E per kg diet, with an additional 142 IU alpha tocopherol/kg diet, restored hepatic concentrations of vitamin E to normal levels in alcohol-fed rats. The hepatic levels of vitamin A in rats fed ethanol diets supplemented with vitamin E were less than that of control rats but were 4.3 times greater than that of rats on ethanol diets unsupplemented with vitamin E. However, the vitamin A and E ratio was equal to normal in this group of rats. The vitamin A/E ratio was reduced in liver of rats fed non-alcoholic diets supplemented with vitamin E due to increased levels of hepatic vitamin E. Additionally, rats fed cod liver oil diets containing ethanol also indicated decreased hepatic vitamin A and E levels. However, these levels were greater than that of rats fed only alcoholic diets suggesting that these vitamins are replaced by the vitamin A and E content in the cod liver oil.(ABSTRACT TRUNCATED AT 250 WORDS)


Abdominal CT Segmentation for Body Composition Assessment Using Network Consistency Learning.
Estimating skeletal muscle (SM) and adipose tissues is an invaluable prognostic indicator in cancer treatment, major surgeries, and general health screening. Body composition is usually measured with abdominal computed tomography (CT) scans acquired in clinical settings. The whole-body SM volume is correlated with the estimated SM based on the measurement of a single two-dimensional vertebral slice. It is necessary to label a CT image at the pixel level to estimate SM, known as semantic segmentation. In this work, we trained a segmentation model using the labeled abdominal CT slices and the additional unlabeled slices. In particular, we trained two identical segmentation networks with differently initialized weights. Network Consistency Learning (NCL) allowed learning from unlabeled images by forcing the predictions from both networks to be the same. We segmented abdominal CT images from a newly created in-house dataset. The proposed approach gained 10% better performance in terms of Dice similarity score (DSC) than that obtained by a standard supervised network demonstrating the effectiveness of NCL in exploiting unlabeled images.Clinical relevance- An efficient and cost-effective method is proposed for assessing body composition from limited labeled and abundant unlabeled CT images to facilitate fast diagnosis, prognosis, and interventions.


Sidedness studies of thylakoid phosphatidylglycerol in higher plants.
The transmembrane distribution of phosphatidylglycerol was determined in thylakoids from barley (Hordeum vulgare), lettuce (Lactuca sativa) and pea (Pisum sativum) chloroplasts. Phospholipase A2 and phospholipase D digestion and chemical-labelling methods were used. Phosphatidylglycerol was preferentially localized in the outer (stromal) leaflet. The proportion of the phospholipid in this leaflet ranged from about 66% in pea to about 75% for barley and lettuce thylakoids. One of the main fatty acids, trans-delta 3-hexadecenoic acid, was exclusively located in the outer leaflet in all three plant types. The data are discussed in relation to suggested roles for phosphatidylglycerol in thylakoid function.


Boosting Reactive Oxygen Species Generation with a Dual-Catalytic Nanomedicine for Enhanced Tumor Nanocatalytic Therapy.
Generating lethal reactive oxygen species (ROS) within tumors by nanocatalytic medicines is an advanced strategy for tumor-specific therapy in recent years. Nevertheless, the low yield of ROS restrains its therapeutic efficiency. Herein, a dual-catalytic nanomedicine based on tumor microenvironment (TME)-responsive liposomal nanosystem co-delivering CuO2 and dihydroartemisinin (DHA) (LIPSe@CuO2&DHA) is developed to boost ROS generation against tumor. The liposomal nanosystem can degrade in the ROS-overexpressed TME and liberate CuO2 and DHA to initiate Cu-based dual-catalytic ROS generation. Serving as generators of H2O2 and Cu2+, CuO2 can self-produce plenty of toxic hydroxyl radicals via Fenton-like reaction in the acidic TME. Meanwhile, the released Cu2+ can catalyze DHA to generate cytotoxic C-centered radicals. Together, the self-supplied H2O2 and Cu-based dual-catalytic reaction greatly increase the intratumoral level of lethal ROS. Importantly, Cu2+ can decrease the GSH-mediated scavenging effect on the produced ROS via a redox reaction and undergo a Cu2+-to-Cu+ conversion to enhance the Fenton-like reaction, further guaranteeing the high efficiency of ROS generation. Resultantly, LIPSe@CuO2&DHA induces remarkable cancer cell death and tumor growth inhibition, which may present a promising nanocatalytic medicine for cancer therapy.


Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro.
Low molecular weight heparin (LMWH) is widely used in recurrent miscarriage treatment. The anti-coagulant effects are established, while immunological effects are not fully known. Our aim was to assess LMWH effects on activation and polarization of central regulatory immune cells from healthy women, and on placenta tissues from women undergoing elective abortions. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured with or without LMWH. Flow cytometry showed that LMWH exposure induced increased expression of HLA-DR and CD206 in macrophages. This phenotype was associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory T-cells, intensified IFN-γ secretion and showed a tendency to increase the lymphoblast proportions. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells. Although the biological significancies of these in vitro findings are uncertain and need to be confirmed in vivo, they suggest the possibility that immunological effects of LMWH may be beneficial mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage.