Regulation of human vascular protease-activated receptor-3 through mRNA stabilization and the transcription factor nuclear factor of activated T cells (NFAT).
Thrombin promotes vascular smooth muscle cell (SMC) proliferation and inflammation via protease-activated receptor (PAR)-1. A further thrombin receptor, PAR-3, acts as a PAR-1 cofactor in some cell-types. Unlike PAR-1, PAR-3 is dynamically regulated at the mRNA level in thrombin-stimulated SMC. This study investigated the mechanisms controlling PAR-3 expression. In human vascular SMC, PAR-3 siRNA attenuated thrombin-stimulated interleukin-6 expression and extracellular signal-regulated kinases 1/2 phosphorylation, indicating PAR-3 contributes to net thrombin responses in these cells. Thrombin slowed the decay of PAR-3 but not PAR-1 mRNA in the presence of actinomycin D and induced cytosolic shuttling and PAR-3 mRNA binding of the mRNA-stabilizing protein human antigen R (HuR). HuR siRNA prevented thrombin-induced PAR-3 expression. By contrast, forskolin inhibited HuR shuttling and destabilized PAR-3 mRNA, thus reducing PAR-3 mRNA and protein expression. Other cAMP-elevating agents, including the prostacyclin-mimetic iloprost, also down-regulated PAR-3, accompanied by decreased HuR/PAR-3 mRNA binding. Iloprost-induced suppression of PAR-3 was reversed with a myristoylated inhibitor of protein kinase A and mimicked by phorbol ester, an inducer of cyclooxygenase-2. In separate studies, iloprost attenuated PAR-3 promoter activity and prevented binding of nuclear factor of activated T cells (NFAT2) to the human PAR-3 promoter in a chromatin immunoprecipitation assay. Accordingly, PAR-3 expression was suppressed by the NFAT inhibitor cyclosporine A or NFAT2 siRNA. Thus human PAR-3, unlike PAR-1, is regulated post-transcriptionally via the mRNA-stabilizing factor HuR, whereas transcriptional control involves NFAT2. Through modulation of PAR-3 expression, prostacyclin and NFAT inhibitors may limit proliferative and inflammatory responses to thrombin after vessel injury.


[Peptidases of preparations of proteolytic enzymes from several species of bacteria, molds and actinomycetes].
The activity of carboxy- and aminopeptidases of enzymic preparations obtained from bacteria Bacillus subtilis 1 M, 17, Bacillus mesentericus 100/26, 100/56, 16; Pseudomonas aeruginosa 1/7a, 1/4; Bacillus thermophilicus S. sp. nov B-22, moulds Aspergillus oryzae 1-746, Aspergillus flavus 716 and actinomycete Streptomyces griseus 32-13 was studied. In the bacterial preparations the proteolytic activity was 1.5-2.5 times lower than in the fungal and actinomycete preparations. The carboxypeptidase activity of bacterial preparations was comparable with that of the moulds and by one order of magnitude lower than that of the actinomycete. The aminopeptidase activity of the bacterial preparations was different; however, it was comparable with that of the moulds and was higher than that in some cases. In the Streptomyces preparation the aminopeptidase activity was significantly higher than in the bacterial and fungal preparations. In most preparations Co2+ and Mn2+ influenced the activity of carboxy- and amino-peptidases. This suggests that these proteins can be referred to metal enzymes.


Capecitabine based postoperative accelerated chemoradiation of pancreatic carcinoma. A dose-escalation study.
The objective of this study was to evaluate the safety of escalating up to 55 Gy within five weeks, the dose of external beam radiotherapy to the previous tumor site concurrently with a fixed daily dose of capecitabine, in patients with resected pancreatic cancer. Patients with resected pancreatic carcinoma were eligible for this study. Capecitabine was administered at a daily dose of 1600 mg/m (2). Regional lymph nodes received a total radiation dose of 45 Gy with 1.8 Gy per fractions. The starting radiation dose to the tumor bed was 50.0 Gy (2.0 Gy/fraction, 25 fractions). Escalation was achieved up to a total dose of 55.0 Gy by increasing the fraction size by 0.2 Gy (2.2 Gy/fraction), while keeping the duration of radiotherapy to five weeks (25 fractions). A concomitant boost technique was used. Dose limiting toxicity (DLT) was defined as any grade>3 hematologic toxicity, grade>2 liver, renal, neurologic, gastrointestinal, or skin toxicity, by RTOG criteria, or any toxicity producing prolonged (> 10 days) radiotherapy interruption. Twelve patients entered the study (median age: 64 years). In the first cohort (six patients), no patient experienced DLT. Similarly in the second cohort, no DLT occurred. All 12 patients completed the planned regimen of therapy. Nine patients experienced grade 1-2 nausea and/or vomiting. Grade 2 hematological toxicity occurred in four patients. The results of our study indicate that a total radiation dose up to 55.0 Gy/5 weeks can be safely administered to the tumor bed, concurrently with capecitabine (1600 mg/m (2)) in patients with resected pancreatic carcinoma.


Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer's disease.
Previous studies have demonstrated that temporarily increasing the permeability of the blood-brain barrier using focused ultrasound can reduce β-amyloid plaque load and improve cognitive function in animal models of Alzheimer's disease. However, the underlying mechanism and duration for which the effects of one treatment persists for are unknown. Here, we used in vivo two-photon fluorescence microscopy to track changes in β-amyloid plaque sizes in the TgCRND8 mouse model of Alzheimer's disease after one focused ultrasound treatment. We found that one treatment reduced plaques to 62 ± 16% (p ≤ 0.001) of their original volume two days post-sonication; this decrease in size persisted for two weeks. We then sought to evaluate the effectiveness of biweekly focused ultrasound treatments using magnetic resonance imaging-guided focused ultrasound treatments. Three to five biweekly treatments resulted in a 27 ± 7% (p ≤ 0.01) decrease in plaque number and 40 ± 10% (p ≤ 0.01) decrease in plaque surface area compared to untreated littermates. This study demonstrates that one focused ultrasound treatment reduces the size of existing β-amyloid plaques for two weeks, and that repeated biweekly focused ultrasound treatments is an effective method of reducing β-amyloid pathology in moderate-to-late stages of Alzheimer's disease.


Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas.
Regional lymph node status is the strongest prognostic determinant in early-stage melanoma. Lymphatic mapping and sentinel lymphadenectomy (LM/SL) is standard to stage regional nodes because it is accurate and minimally morbid, yet its role for thin (<or= 1.5 mm) primary melanomas is unknown. Our melanoma database of more than 10,000 patients was reviewed for patients with melanomas <or= 1.50 mm thick who underwent LM/SL. All had lymphoscintigrams and LM/SL via dye alone or with radiopharmaceutical. Patients with tumor-positive sentinel nodes (SNs) underwent completion dissections. Five hundred twelve patients underwent LM/SL. Most were men (57%), and median age was 49 years. Most primary melanomas were on the torso (44%). Twenty-five patients (4.9%) had tumor-positive SNs. The thinnest lesion with a nodal metastasis was 0.35 mm. The SN-negative and SN-positive cohorts were equivalent by sex, but SN+ patients tended to be younger (P =.053), with significantly more SN metastases in those younger than 44 years (P =.005). No consistent pathology among SN-positive primary melanomas was found. Among those with 1.01- to 1.05-mm primaries, 7.1% were SN-positive. Among 272 patients with lesions <or= 1.00 mm, 2.9% had positive SNs and 1.7% with lesions <or= 0.75 mm had SN metastases. All 13 deaths were in SN-negative patients. Median follow-up durations in SN-positive and SN-negative patients were 25 and 45 months, respectively. The high nodal positivity rate associated with primary melanomas 1.01 to 1.50 mm thick suggests that LM/SL is indicated in this group. Younger age may be correlated with nodal metastases in patients with lesions <or= 1.00 mm. Lesions <or= 0.75 mm have minimal metastatic potential, and therefore LM/SL is rarely indicated.


Engagement of Fas on Macrophages Modulates Poly I:C induced cytokine production with specific enhancement of IP-10.
Viral double-stranded RNA (dsRNA) is recognised by pathogen recognition receptors such as Toll-Like Receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), and results in cytokine and interferon production. Fas, a well characterised death receptor, has recently been shown to play a role in the inflammatory response. In this study we investigated the role of Fas in the anti-viral immune response. Stimulation of Fas on macrophages did not induce significant cytokine production. However, activation of Fas modified the response of macrophages to the viral dsRNA analogue poly I:C. In particular, poly I:C-induced IP-10 production was significantly enhanced. A similar augmentation of IP-10 by Fas was observed following stimulation with both poly A:U and Sendai virus. Fas activation suppressed poly I:C-induced phosphorylation of the MAP kinases p38 and JNK, while overexpression of the Fas adaptor protein, Fas-associated protein with death domain (FADD), activated AP-1 and inhibited poly I:C-induced IP-10 production. Consistent with an inhibitory role for AP-1 in IP-10 production, mutation of the AP-1 binding site on the IP-10 promoter resulted in augmented poly I:C-induced IP-10. These results demonstrate that engagement of the Fas receptor plays a role in modifying the innate immune response to viral RNA.


Effect of Different Evasion Maneuvers on Anticipation and Visual Behavior in Elite Rugby League Players.
This study examined the anticipation and visual behavior of elite rugby league players during two different evasion maneuvers (side- and split-steps). Participants (N = 48) included elite rugby league players (n = 38) and controls (n = 10). Each participant watched videos consisting of side- and split-steps, and anticipation of movement and eye behavior were measured. No significant differences between the groups or evasion maneuvers were found. The split-step was significantly harder to predict. Elite players appeared to spend more time viewing the torso and mid-region of the body compared with the controls.


Spectroscopic studies on the interactions between CdTe quantum dots coated with different ligands and human serum albumin.
This paper investigates the interactions between human serum albumin (HSA) and CdTe quantum dots (QDs) with nearly identical hydrodynamic size, but capped with four different ligands (MPA, NAC, and GSH are negatively charged; CA is positively charged) under physiological conditions. The investigation was carried out using fluorescence spectroscopy, circular dichroism (CD) spectra, UV-vis spectroscopy, and dynamic light scattering (DLS). The results of fluorescence quenching and UV-vis absorption spectra experiments indicated the formation of the complex of HSA and negatively charged QDs (MPA-CdTe, NAC-CdTe, and GSH-CdTe), which was also reconfirmed by the increasing of the hydrodynamic radius of QDs. The K(a) values of the three negatively charged QDs are of the same order of magnitude, indicating that the interactions are related to the nanoparticle itself rather than the ligands. ΔH<0 and ΔS>0 implied that the electrostatic interactions play predominant roles in the adsorption process. Furthermore, it was also proven that QDs can induce the conformational changes of HSA from the CD spectra and the three-dimensional fluorescence spectra of HSA. However, our results demonstrate that the interaction mechanism between the positively charged QDs (CA-CdTe) and HSA is significantly different from negatively charged QDs. For CA-CdTe QDs, both the static and dynamic quenching occur within the investigated range of concentrations. According to the DLS results, some large-size agglomeration also emerged.


The interaction of block copolymers of ethylene oxide and propylene oxide and their polymer-protein conjugates with lipids.
The interaction of block copolymers of ethylene oxide and propylene oxide with lipid structures-monolamellar and multilamellar vesicles from egg yolk lecithin and dipalmitoylphosphatidylcholine-was studied by differential scanning calorimetry, light scattering, and electron spin resonance. Copolymers with different ratios of hydrophilic: hydrophobic portions, numbers of polymers, and arrangements or positions of the blocks, as well as conjugates of polymers with proteins, were used. Peculiarities in the macromolecular structure of the copolymers influence the character of their interactions with lipids. The effects of copolymers which become incorporated into the lipid bilayer are compared with that of polyethyleneglycol which influences lipid structure in an indirect manner.


Oligoclonal CD8+ T cells play a critical role in the development of hypertension.
Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis of hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8(+) cells, but not CD4(+) cells, in the kidney exhibited altered T-cell receptor transcript lengths in Vβ3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4(-/-) and MHCII(-/-) mice was similar to that observed in wild-type mice, whereas CD8(-/-) mice and OT1xRAG-1(-/-) mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8(+) T cells but not CD4(+)/CD25(-) cells conferred hypertension to RAG-1(-/-) mice. In contrast, transfer of CD4(+)/CD25(+) cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4(+) and CD8(+) T cells. In response to a sodium/volume challenge, wild-type and CD4(-/-) mice infused with angiotensin II retained water and sodium, whereas CD8(-/-) mice did not. CD8(-/-) mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8(+) cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction.


The Impact of COVID-19 on Conspiracy Hypotheses and Risk Perception in Italy: Infodemiological Survey Study Using Google Trends.
COVID-19 has caused the worst international crisis since World War II. Italy was one of the countries most affected by both the pandemic and the related infodemic. The success of anti-COVID-19 strategies and future public health policies in Italy cannot separate itself from the containment of fake news and the divulgation of correct information. The aim of this paper was to analyze the impact of COVID-19 on web interest in conspiracy hypotheses and risk perception of Italian web users. Google Trends was used to monitor users' web interest in specific topics, such as conspiracy hypotheses, vaccine side effects, and pollution and climate change. The keywords adopted to represent these topics were mined from Bufale.net-an Italian website specializing in detecting online hoaxes-and Google Trends suggestions (ie, related topics and related queries). Relative search volumes (RSVs) of the time-lapse periods of 2016-2020 (pre-COVID-19) and 2020-2021 (post-COVID-19) were compared through percentage difference (∆%) and the Welch t test (t). When data series were not stationary, other ad hoc criteria were used. The trend slopes were assessed through Sen slope (SS). The significance thresholds have been indicatively set at P=.05 and t=1.9. The COVID-19 pandemic drastically increased Italian netizens' interest in conspiracies (∆% ∈ [60, 288], t ∈ [6, 12]). Web interest in conspiracy-related queries across Italian regions increased and became more homogeneous compared to the pre-COVID-19 period (average RSV=80±2.8, t min=1.8, ∆min%=+12.4, min∆SD%=-25.8). In addition, a growing trend in web interest in the infodemic YouTube channel ByoBlu has been highlighted. Web interest in hoaxes has increased more than interest in antihoax services (t 1=11.3 vs t 2=4.5; Δ1%=+157.6 vs Δ2%=+84.7). Equivalently, web interest in vaccine side effects exceeded interest in pollution and climate change (SSvaccines=0.22, P<.001 vs SSpollution=0.05, P<.001; ∆%=+296.4). To date, a significant amount of fake news related to COVID-19 vaccines, unproven remedies, and origin has continued to circulate. In particular, the creation of SARS-CoV-2 in a Chinese laboratory constituted about 0.04% of the entire web interest in the pandemic. COVID-19 has given a significant boost to web interest in conspiracy hypotheses and has made it more uniform across regions in Italy. The pandemic accelerated an already-growing trend in users' interest toward some fake news sources, including the 500,000-subscriber YouTube channel ByoBlu, which was removed from the platform by YouTube for disinformation in March 2021. The risk perception related to COVID-19 vaccines has been so distorted that vaccine side effect-related queries outweighed those relating to pollution and climate change, which are much more urgent issues. Moreover, a large amount of fake news has circulated about COVID-19 vaccines, remedies, and origin. Based on these findings, it is recommended that the Italian authorities implement more effective infoveillance systems, and that communication by the mass media be less sensationalistic and more consistent with the available scientific evidence. In this context, Google Trends can be used to monitor users' response to specific infodemiological countermeasures. Further research is needed to understand the psychological mechanisms that regulate risk perception.


Detection of methicillin-resistant Staphylococcus aureus (MRSA) from nasal samples by multiplex real-time PCR based on dual priming AT-rich primers.
In this study, we reported on the design of a multiplex real-time PCR assay based on SYBR Green I, incorporating dual priming adenine-thymine (AT)-rich primers for direct detection of MRSA from nasal samples. The multiplex real-time polymerase chain reaction (RT-PCR) assay reported in this study is based on SYBR Green I with incorporation of six dual priming AT-rich primers designed from the SCCmec/orf junction. A string (4-6 bp) of low-melting bases, such as adenine and thymine, was incorporated into the primers, which virtually divided a single primer in two functional regions, thus decreasing non-specific PCR products. The analytical sensitivity and specificity of the RT-PCR assay was determined with genomic DNA of reference strains (MRSA, MSSA, and MRCoNS). RT-PCR assay was performed for analysis of 72 nasal swab specimens, and the results were confirmed by use of a culture method. Furthermore, the results of RT-PCR were compared with LightCycler MRSA advance test. The multiplex RT-PCR assay reproducibly detected a minimum of 1 pg genomic DNA (31.5 copy of genome) of MRSA reference strains and clinical isolates, with a specific melting peak at 83.5 ± 1.5°C, and neither fluorescence nor a melting peak was detected in non-target isolates. The concordance rate between RT-PCR assay and culture method was 87.5% with Cohen's kappa value (κ) 0.75, which showed good agreement between the two assays. The sensitivity, specificity, positive predictive value, and negative predictive value of the assay were 93.5%, 82.9%, 80.5%, and 94.4%, respectively. In a comparative study for the detection of 72 nasal samples, the sensitivity, specificity, positive predictive value, and negative predictive value of the multiplex RT-PCR assay with respect to LightCycler MRSA advance test was 84.2%, 88.2%, 89%, and, 83.3%, respectively. The results of RT-PCR assay demonstrated high specificity (88.2%) and positive predictive value (89%) for the direct detection of MRSA from nasal samples.


Meeting report: targeting the kinome--20 years of tyrosine kinase inhibitor research in Basel.
With basic and pharmaceutical researchers, chemists, pharmacologists, and clinicians, the Targeting the Kinome meeting brought together a tremendous group of scientists to discuss the past, present, and future of protein kinase research, with a special emphasis on cancer therapy development. The topics ranged from the kinases themselves as drug targets through the interactions that the actions of these enzymes promote, to the physiological and pathological processes they regulate. Attendees gained insight into drug development, as well as increased understanding of how normal cellular processes are subverted during oncogenesis, which may lead to new targets for intervention.


Quantitative ultrasound characterization of tumor cell death: ultrasound-stimulated microbubbles for radiation enhancement.
The aim of this study was to assess the efficacy of quantitative ultrasound imaging in characterizing cancer cell death caused by enhanced radiation treatments. This investigation focused on developing this ultrasound modality as an imaging-based non-invasive method that can be used to monitor therapeutic ultrasound and radiation effects. High-frequency (25 MHz) ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human prostate xenografts grown in severe combined immunodeficiency (SCID) mice were treated using 8, 80, or 1000 µL/kg of microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. The increase in backscatter intensity compared to the control ranged from 1.9±1.6 dB for the clinical imaging dose of microbubbles (8 µL/kg, 250 kPa, 2 Gy) to 7.0±4.1 dB for the most extreme treatment condition (1000 µL/kg, 750 kPa, 8 Gy). In parallel, in situ end-labelling (ISEL) staining, ceramide, and cyclophilin A staining demonstrated increases in cell death due to DNA fragmentation, ceramide-mediated apoptosis, and release of cyclophilin A as a result of cell membrane permeabilization, respectively. Quantitative ultrasound results indicated changes that paralleled increases in cell death observed from histology analyses supporting its use for non-invasive monitoring of cancer treatment outcomes.


Erythrocyte deformability responses to intermittent and continuous subhemolytic shear stress.
Previous studies have demonstrated that red blood cells (RBC) either lyse or at least experience mechanical damage following prolonged exposure to high shear stress (≥100 Pa). Conversely, prolonged shear stress exposure within the physiological range (5-20 Pa, 300 s) was recently reported to improve RBC deformability. This study investigated the relationships between shear stress and RBC deformability to determine the breakpoint between beneficial vs. detrimental exposure to shear stress (i.e., "subhemolytic threshold"). A second aim of the study was to determine whether the frequency of intermittent application of shear stress influenced the subhemolytic threshold. RBC were exposed to various levels of shear stress (0-100 Pa) in a Couette type shearing system for 300 s. RBC deformability was then immediately measured via ektacytometry. Parallel experiments were conducted at the same shear stresses, except the application time differed while keeping constant the total exposure time: shear stress was applied either for 30 s and repeated 10 times (10×30 s) or applied for 15 s and repeated 20 times (20×15 s). For a range of donors, the subhemolytic threshold with constant shear stress application was between 30-40 Pa. When physiological shear stress was applied in an intermittent manner, more frequent applications tended to improve (i.e., increase) RBC deformability. However, when supra-physiological shear stress was applied, both continuous and intermittent protocols damaged RBC. Changes of RBC mechanical behavior occurred without increases of hemoglobin in the suspending media, thus attesting to the absence of hemolysis. Shear stress has a biphasic effect on the mechanical properties of RBC, with the duration and rate of exposure appearing to have minimal impact on the subhemolytic threshold when compared with the magnitude of applied shear stress.


[Diagnostic errors in esophageal cancer].
Cases of esophageal cancer are often admitted to oncological establishments at relatively late stages of tumor process: in 85%, the record of symptoms exceeds three months. The average duration of case histories before admission is 7.4 months. Diagnostic errors were established in the patients who had consulted the doctor during a period of less than 3 months after symptom development. This was due to the frequent appearance (41%) at initial stages of symptoms other than dysphagia which was misleading. However, even if dysphagia was apparent, primary X-ray examination failed to detect esophageal tumors in 20.1% of cases. Therefore, an endoscopic examination must be performed in cases of dysphagia. Whenever dysphagia is a consequence of esophageal burns, patients should undergo examinations at specialized oncological establishments for some years.


Post-influenzal depression.
A prospective study was carried out on post-influenzal depression. Four hundred patients presenting with psychiatric illness for the first time took part. The results show that there is no correlation between depressive illness and the demonstration of influenza antibody titres, an indication of recent influenza infection.


Release of granulocyte-macrophage colony stimulating factors from major histocompatibility complex class II antigen-positive monocytes is enhanced by human gamma interferon.
Human gamma interferon (HuIFN gamma) was assessed for its capacity to enhance release of granulocyte-macrophage colony stimulating factors (GM-CSF) from human peripheral blood monocytes. Natural HuIFN gamma (2 X 10(7) NIH reference units per milligram) at concentrations as low as 0.01 U/mL to 10 U/mL reproducibly enhanced release of GM-CSF. This enhancement was detected when T lymphocytes were depleted from monocyte preparations and when T lymphocytes and monocytes were depleted from populations of human bone marrow cells stimulated by monocyte-conditioned media to form colonies and clusters. T lymphocytes alone or in the presence of HuIFN gamma did not release GM-CSF. The enhancing activity of HuIFN gamma was removed by preincubating HuIFN gamma with neutralizing concentrations of monoclonal anti-HuIFN gamma, and recombinant HuIFN gamma mimicked the effects of natural HuIFN gamma, suggesting that the effects were due to HuIFN gamma itself. HuIFN gamma suppression of the release of inhibitory activity from monocytes was ruled out as a reason for the noted enhancing activity of HuIFN gamma. The enhancing activity of HuIFN gamma was confined to the MHC class II antigen-positive population of monocytes. Removal of these cells with monoclonal antibody plus complement (C') ablated the enhancing activity, high concentrations of certain monoclonal antibodies in the absence of C' blocked the enhancing activity and, when monocytes were sorted into MHC class II antigen-positive and -negative cells by fluorescence-activated cell sorting, it was only the positive cell fraction that responded to the enhancing activity of HuIFN gamma.


[Valproate-induced hyperammononemic encefalopathy].
The authors report a case of valproate-induced hyperammononemic encefalopathy whose initial clinical features were represented by increase of pre-existing disturbed-aggressive behaviour.


Colossal cages in zeolitic imidazolate frameworks as selective carbon dioxide reservoirs.
Zeolitic imidazolate frameworks (ZIFs) are porous crystalline materials with tetrahedral networks that resemble those of zeolites: transition metals (Zn, Co) replace tetrahedrally coordinated atoms (for example, Si), and imidazolate links replace oxygen bridges. A striking feature of these materials is that the structure adopted by a given ZIF is determined by link-link interactions, rather than by the structure directing agents used in zeolite synthesis. As a result, systematic variations of linker substituents have yielded many different ZIFs that exhibit known or predicted zeolite topologies. The materials are chemically and thermally stable, yet have the long-sought-after design flexibility offered by functionalized organic links and a high density of transition metal ions. Here we report the synthesis and characterization of two porous ZIFs-ZIF-95 and ZIF-100-with structures of a scale and complexity previously unknown in zeolites. The materials have complex cages that contain up to 264 vertices, and are constructed from as many as 7,524 atoms. As expected from the adsorption selectivity recently documented for other members of this materials family, both ZIFs selectively capture carbon dioxide from several different gas mixtures at room temperature, with ZIF-100 capable of storing 28 litres per litre of material at standard temperature and pressure. These characteristics, combined with their high thermal and chemical stability and ease of fabrication, make ZIFs promising candidate materials for strategies aimed at ameliorating increasing atmospheric carbon dioxide levels.


Expression of epidermal growth factor and platelet-derived growth factor receptors during cervical carcinogenesis.
Altered expression of epidermal growth factor receptor (EGFR) is common in a variety of epithelial malignancies, including cervical cancer. However, the prognostic significance of EGFR expression is controversial for cervical cancer. Platelet-derived growth factor receptor (PDGFR) expression status is unknown in cervical cancer. Our results demonstrated that expression of EGFR and PDGFR was greatly enhanced in vivo and in organotypic cultures of low-grade cervical dysplastic tissues, but levels were decreased in high-grade lesions. To our knowledge, this is the first report identifying the expression of PDGFR in human epithelium. When low-grade dysplastic organotypic culture tissues were induced to differentiate more completely, EGFR expression, but not PDGFR expression, was relocalized to the basal layer as seen in normal tissues. Differentiation also induced phosphorylation of EGFR but not PDGFR. Our results suggest a role for EGFR and PDGFR during the early stages of cervical carcinogenesis, and demonstrate the facility of organotypic cultures to study the role of these growth factors in the development of cervical cancer.


Cell cultures from bronchial subepithelial myofibroblasts enhance eosinophil survival in vitro.
Mechanisms of eosinophil accumulation and activation in the bronchial mucosa are crucial for the pathogenesis of asthma. The location of specialized fibroblasts, myofibroblasts, beneath the bronchial basement membrane and their proximity to infiltrating eosinophils potentially enable the myofibroblasts to modulate eosinophil survival and function in asthma. The aim of this study was to investigate the effects of bronchial myofibroblasts on eosinophil survival in vitro. Eosinophils from human peripheral blood were exposed to cell cultures from bronchial myofibroblasts and to myofibroblast-conditioned media. Eosinophil viability was assessed and granulocyte/macrophage colony-stimulating factor (GM-CSF) production was examined in co-culture supernatants and as messenger ribonucleic acid (mRNA) in myofibroblasts. Eosinophil survival was significantly increased and eosinophil apoptosis was inhibited by co-culture with myofibroblasts. Conditioned medium from tumour necrosis factor-alpha (TNF-alpha)-stimulated myofibroblasts also prolonged eosinophil survival. This effect could be blocked by GM-CSF antibody. GM-CSF mRNA and secretion from myofibroblasts were increased in co-cultures and by eosinophil-conditioned medium. Addition of antibodies to TNF-alpha and interleukin-1 alpha (IL-1 alpha) to co-cultures resulted in significant reduction both in eosinophil survival and GM-CSF levels. Blocking of fibronectin in the co-cultures did not affect the eosinophil survival enhancing activity. Prednisolone inhibited the eosinophil survival enhancing activity of the co-cultures by suppression of GM-CSF production. Soluble eosinophil-derived cytokines are involved in the interaction of eosinophils with myofibroblasts, which results in a tumour necrosis factor-alpha/interleukin-1 alpha mediated release of granulocyte/macrophage colony-stimulating factor from myofibroblasts. Bronchial myofibroblasts can, thereby, contribute to allergic inflammation by granulocyte/macrophage colony-stimulating factor-mediated inhibition of eosinophil apoptosis.


Purification and characterization of the N-terminal propeptide of human type III procollagen.
The N-terminal propeptide of type III procollagen was purified from human ascitic fluid by using (NH4)2SO4 precipitation, DEAE-Sephacel chromatography at pH 8.6, Sephacryl S-300 chromatography and another DEAE-Sephacel chromatography at pH 4.5. The Mr of the human peptide was about 42 000, which corresponds in size to the propeptide released by the specific N-proteinase during the extracellular processing of collagen. Bacterial-collagenase digestion of the human peptide produced three fragments, which could be separated on a Bio-Gel P-10 column. The human propeptide and its collagenase-derived fragments, an N-terminal non-collagenous domain Col 1, a C-terminal non-helical domain Col 2 and a collagenous domain Col 3, resembled those derived from the N-terminal segment of bovine type III procollagen in their amino acid composition. The human peptide was found to contain sulphate, which may explain its extremely low isoelectric point (3.1). Antibodies against the human N-terminal propeptide reacted similarly with both the purified human peptide and a corresponding segment of bovine type III procollagen. The human propeptide could be used in developing radioimmunoassays for monitoring fibrotic processes.


Luteinizing hormone receptor activation in ovarian granulosa cells promotes protein kinase A-dependent dephosphorylation of microtubule-associated protein 2D.
The actions of LH to induce ovulation and luteinization of preovulatory follicles are mediated principally by activation of cAMP-dependent protein kinase (PKA) in granulosa cells. PKA activity is targeted to specific locations in many cells by A kinase-anchoring proteins (AKAPs). We previously showed that FSH induces expression of microtubule-associated protein (MAP) 2D, an 80-kDa AKAP, in rat granulosa cells, and that MAP2D coimmunoprecipitates with PKA-regulatory subunits in these cells. Here we report a rapid and targeted dephosphorylation of MAP2D at Thr256/Thr259 after treatment with human chorionic gonadotropin, an LH receptor agonist. This event is mimicked by treatment with forskolin or a cAMP analog and is blocked by the PKA inhibitor myristoylated-PKI, indicating a role for cAMP and PKA signaling in phosphoregulation of granulosa cell MAP2D. Furthermore, we show that Thr256/Thr259 dephosphorylation is blocked by the protein phosphatase 2A (PP2A) inhibitor, okadaic acid, and demonstrate interactions between MAP2D and PP2A by coimmunoprecipitation and microcystin-agarose pull-down. We also show that MAP2D interacts with glycogen synthase kinase (GSK) 3beta and is phosphorylated at Thr256/Thr259 by this kinase in the basal state. Increased phosphorylation of GSK3beta at Ser9 and the PP2A B56delta subunit at Ser566 is observed after treatment with human chorionic gonadotropin and appears to result in LH receptor-mediated inhibition of GSK3beta and activation of PP2A, respectively. Taken together, these results show that the phosphorylation status of the AKAP MAP2D is acutely regulated by LH receptor-mediated modulation of kinase and phosphatase activities via PKA.


Biomarkers of Dietary Polyphenols in Cancer Studies: Current Evidence and Beyond.
Polyphenols, commonly contained in fruits and vegetables, have long been associated with a protective role against multiple diseases and adverse health effects. Generally, in vitro and animal experiments have provided strong positive evidence, whereas evidence from in vivo and human epidemiological studies is not strong enough. Most epidemiological studies to date use food frequency questionnaire based dietary intake estimations, which inevitably incur imprecision. Biomarkers of polyphenol have the potential to complement and enhance current studies. This review performed a literature search of all epidemiological studies or controlled clinical/intervention trials which employed biomarkers of exposure for polyphenols to help assess their anticarcinogenic role, using studies on green tea polyphenols as a study model. Currently, studies on this topic are still limited; breast cancer and prostate cancer were the only widely studied cancer types. Isoflavone is the only widely studied polyphenol. In addition to associations between polyphenols and cancer risks, factors such as host genetic susceptibility, epigenetic modification, and gut microbiome patterns may also impact on the protective roles of polyphenols. More evidence should be collected by utilizing biomarkers of exposure for polyphenols in future epidemiological studies before a clear conclusion can be made.


Journeying Apart: Exploring Informal Caregiver Experiences and Unmet Closures in Caring for COVID-19 Deceased.
The current study investigates the experiences and expectations of informal caregivers who lost their loved ones to the COVID-19 virus. The unusual circumstances of the deaths including physical isolation from their loved ones during the final hours before death significantly impacted their grieving process. In this interpretative phenomenological study, caregivers' experiences are explored through the lens of grief models and Gestalt perspectives. By thematic coding, seven superordinate themes emerged: Inability to accept death, Unfair nature of death, Helplessness, Regret and self-blame, Shattering of assumptive world, Using work as a distraction and Lack of government facilities. The findings of this study suggest that a significant number of informal caregivers continue suffering through the distress caused by the death of their loved ones in the pandemic, highlighting the need for grief counselling interventions for such bereaved informal caregivers.


NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy.
Nuclear receptor binding SET domain 2 (NSD2)-mediated metabolic reprogramming has been demonstrated to regulate oncogenesis via catalyzing the methylation of histones. The present study aimed to investigate the role of NSD2-mediated metabolic abnormality in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH rat model was established and infected with adeno-associated virus carrying short hairpin RNA (shRNA) targeting NSD2. Hemodynamic parameters, ventricular function, and pathology were evaluated by microcatheter, echocardiography, and histological analysis. Metabolomics changes in lung tissue were analyzed by LC-MS. The results showed that silencing of NSD2 effectively ameliorated MCT-induced PAH and right ventricle dysfunction, and partially reversed pathological remodeling of pulmonary artery and right ventricular hypertrophy. In addition, the silencing of NSD2 markedly reduced the di-methylation level of H3K36 (H3K36me2 level) and inhibited autophagy in pulmonary artery. Non-targeted LC-MS based metabolomics analysis indicated that trehalose showed the most significant change in lung tissue. NSD2-regulated trehalose mainly affected ABC transporters, mineral absorption, protein digestion and absorption, metabolic pathways, and aminoacyl-tRNA biosynthesis. In conclusion, we reveal a new role of NSD2 in the pathogenesis of PAH related to the regulation of trehalose metabolism and autophagy via increasing the H3K36me2 level. NSD2 is a promising target for PAH therapy.


The pathology associated with diabetic retinopathy.
This review summarizes the pathological features of diabetic retinopathy. The lesions occurring in the diabetic retina have been described over many decades using descriptive and experimental approaches based on clinical studies on patients, human post-mortem material, animal models and various in vitro systems. We have also accumulated a wealth of knowledge about basic molecular mechanisms and key pathogenic processes that drive these abnormalities in diabetic retina. Despite these advances, there are still limited therapeutic options for diabetic retinopathy with those currently available only addressing late-stage disease. With a particular focus on the earlier stages of diabetes, there is growing appreciation the complex neuronal, glial and microvascular abnormalities which progressively disrupt retinal function. This is especially true from the perspective of the neurovascular unit during health and disease. Based on a strong appreciation of cellular and molecular pathology that underpins diabetic retinopathy, further advances are anticipated as we drive towards development of efficacious therapeutic options that can address all stages of disease.


Sporadic clear cell renal cell carcinoma with diffuse cytokeratin 7 immunoreactivity.
Clear cell renal cell carcinoma (CRCC) with diffuse immunoreactivity for CK7 is described. All cases of CRCC, measuring 20 mm or less in diameter over a period of 10 years, were examined. Areas of regenerative epithelial cell nests (REC) were also examined. Fifteen specimens containing 29 nodules were diagnosed as CRCC due to the characteristic clear cytoplasm. Of these 29 nodules, 21 showed diffuse CK7 positivity while eight showed CK7 negativity. The CK7 positive CRCC measured less than 16 mm and contained varying proportions of tumour cells with chromophil cytoplasm. Architecturally, CK7 positive CRCC consisted of cysts and solid cell nests with tubulo-acinar formations or papillary formations. Immunostaining for AMACR, CD10 and RCC showed negative or focal reactivity in the CK7 positive CRCC, frequently positive reactivity in CK7 negative CRCC and negative reactivity in REC which also displayed strong CK7 reactivity. The ten patients with 21 CK7 positive CRCC developed no metastatic disease over a follow up time that ranged from 1 to 10 years (mean of 3 years). CRCC characterised by diffuse CK7 positivity represents a distinct type of CRCC with characteristic histopathological and immunohistochemical features.


Profuse diversity and acidogenicity of the candida-biome of deep carious lesions of Severe Early Childhood Caries (S-ECC).
Introduction: The retentive niches of deep caries lesions have a distinct biome. Methods: We evaluated the site-specific (occlusal and proximal) Candida-biome of Severe-Early Childhood Caries (S-ECC) in 66- children (132 lesions). Asymptomatic primary molars fitting the definition of the International Caries Detection and Assessment-(ICDAS)-caries-code 5/6 were analyzed. Deep-dentinal sampling and simultaneous assessment of pH were performed. Clinical isolates were speciated using multiplex-PCR and evaluated for their acidogenic and aciduric potential.Results: Surprisingly, a high prevalence of Candida species (72.7%), either singly or in combination, was noted from both the proximal and occlusal cavities. C. tropicalis was the most prevalent species (47%; 34/72), followed by C. krusei (43.1%; 31/72) and C. albicans (40.3%; 29/72), with C. glabrata being the least (9.7%; 7/72). Over 45% low-pH niches (pH <7) of both sites yielded either dual or triple species of Candida. Genotyping revealed three distinct C. albicans genotypes (A, B, and C) with (14/29; 48.3%) of strains belonging to Genotype A. All four evaluated Candida species exhibited acidogenic and aciduric potential, C. tropicalis being the most potent.Conclusion: This, the first report of the high-density, multispecies, yeast colonization of deep-dentinal lesions in S-ECC, suggests that the Candida-biome plays a significant etiologic role in the condition, possibly due to their profound acidogenicity in milieus rich in dietary carbohydrates.


Intermediates in allosteric equilibria of DnaK-ATP interactions with substrate peptides.
Hsp70 molecular chaperones facilitate protein disaggregation and proper folding through iterative cycles of polypeptide binding and release that are allosterically coupled to ATP binding and hydrolysis. Hsp70s are ubiquitous and highly conserved across all of life; they bind ATP at an N-terminal nucleotide-binding domain (NBD) and client peptides in the substrate-binding domain (SBD). The NBD and SBD are connected by a highly conserved linker segment that is integrated into the NBD when ATP is bound but is flexible when the NBD is nucleotide-free or bound with ADP. Allosteric coupling is lost when the linker is flexible, and the freed SBD binds peptide clients with high affinity. It was recently discovered that Hsp70-ATP is in an equilibrium between a restraining state (R) with little affinity for peptides and a low ATPase activity, and a stimulating state (S) that binds peptides efficiently, but with rapid kinetics, and has a relatively high ATPase activity. While attempting to characterize the S state, crystal structures of DnaK-ATP were obtained that demonstrate intrinsic Hsp70 plasticity that affects binding interactions with substrate peptides. These structures provide insights into intermediate states along transition pathways in the Hsp70 chaperone cycle.


Heart failure: living with uncertainty.
Uncertainty has been identified as a significant part of the experience of heart disease and yet no studies have fully explored the experience of uncertainty in persons living with chronic heart failure. The purpose of this study was to describe the uncertainty experienced by men and women with heart failure and to extend the theoretical understanding of uncertainty in chronic illness. Qualitative inquiry was the interpretive approach guiding this study. Data were collected from 22 adults living in urban and rural areas of a rural western state and included audio taped interviews, clinical and demographic information, and scores from the community form of the Mishel Uncertainty in illness Scale (MUIS-C). Three major themes of uncertainty were identified related to symptoms and treatment, attempts to stay well, and quality of life and death. Unique contributions to the uncertainty in illness theory provided by this study include the influence of age related changes on the ability to recognize and respond to symptoms and the presence of cautious trust of health care providers. Nursing implications and recommendations for further study are discussed.


Restoration of mutant cytochrome P450 reductase activity by external flavin.
Cytochrome P450 oxidoreductase (POR) supplies electrons from NADPH to steroid and drug metabolizing reactions catalyzed by the cytochrome P450s located in endoplasmic reticulum. Mutations in human POR cause a wide spectrum of disease ranging from disordered steroidogenesis to sexual differentiation. Previously we and others have shown that POR mutations can lead to reduced activities of steroidogenic P450s CYP17A1, CYP19A1 and CYP21A1. Here we are reporting that mutations in the FMN binding domain of POR may reduce CYP3A4 activity, potentially influencing drug and steroid metabolism; and the loss of CYP3A4 activity may be correlated to the reduction of cytochrome b(5) by POR. Computational molecular docking experiments with a FMN free structural model of POR revealed that an external FMN could be docked in close proximity to the FAD moiety and receive electrons donated by NADPH. Using FMN supplemented assays we have demonstrated restoration of the defective POR activity in vitro.


Stroke survivors' and family members' perspectives of multimodal lifestyle interventions for secondary prevention of stroke and transient ischemic attack: a qualitative review and meta-aggregation.
The incidence of stroke is of global concern, and the rates of recurrence are high. Many risk factors are related to lifestyle behaviours and, as such, are amenable to change. Implementation of effective secondary prevention interventions is essential; however, little is known about influences on participation and adherence. This review and meta-aggregation aimed to improve understanding of stroke survivor and family member perspectives of secondary prevention interventions. We searched 11 databases, e.g. Medline and PsycINFO. We included qualitative studies that focused on adult stroke survivors and family members who had participated in a multimodal stroke secondary prevention intervention. Critical appraisal and data extraction were performed independently by two reviewers. A meta-aggregation of qualitative findings was conducted. Five papers were included. One hundred and three findings were extracted and grouped into 14 categories from which three synthesised findings emerged: feeling supported, acquiring knowledge and gaining confidence. The findings highlight the perceived benefits of participation in secondary prevention group interventions from the perspective of stroke survivors and family members, i.e. feeling supported, by others with shared understanding and by knowledgeable health professionals, acquiring new knowledge and gaining confidence. These findings may be used to inform development of patient-centred interventions and thereby assist in improving health outcomes. Health professionals should consider implementing group-based secondary prevention interventions. The content of group-based secondary prevention interventions should be person-centred, i.e. meaningful and relevant to the individual. Stroke survivors and family members are more likely to comply with advice and information provided by expert and experienced health professionals.


[Early aseptic loosening of the CF 30 femoral stem].
The CF 30 stem in combination with a cementless acetabulum was used at the First Department of Orthopedic Surgery in Brno in the years 1994 to 1995. From the second year following implantation, aseptic stem loosening was recorded. In order to find explanation of this early loosening, the authors, in cooperation with the Institute of Solid Mechanics, Mechatronics and Biomechanics, carried out the stress-strain analysis in a model system. Eighty patients (31 men and 49 women) received a cemented CF30 femoral component in 1994. Of them, 16 patients underwent revision arthroplasty, three died of causes unrelated to the surgery, and four were lost to follow-up. The final clinical and radiographic check-up was carried out in 2001. The results of a comprehensive examination were available in 57 patients with a CF30 stem. The patients were evaluated on the basis of the Harris hip score and anteroposterior radiographs of the hip. X-ray films obtained immediately after surgery and those taken at regular intervals during follow-up were compared. The following characteristics were noted: translucent lines in individual zones along the stem at the cement-bone interface; osteolysis, i. e., non-linear translucent areas, at least 5 mm long, at the cement-bone interface; and subsidence of the femoral component, i. e., migration of the stem distal to the tip of the greater trochanter. The CF 30 stem survival curve showed that aseptic stem loosening occurred from post-implantation year 2, and increased during the following years. At 6 years and 6 months, a total of 16 patients underwent revision surgery, involving reimplantation in 14 and implant removal in 2 patients. Potential causes of aseptic loosening: Polyethylene wear.However, no acetabular loosening was found in this group, although acetabular components are reported to become loose more often than femoral components. By comparison of the stem survival curves for Poldi and CF 30 stems it appeared that, at 6 years and 6 months, the Poldi stem survival curve showed better results. Matt surface finish of the stem. However, the link between the CF 30 stem and cement was so strong that, in all 16 revised hips, the stem was removed together with nearly a complete cement mantle. The authors therefore dismiss this as a cause. Also, in the remaining cases of CF 30 aseptic loosening, which had not been revised, radiographic evidence suggested loosening between bone and cement. The authors did not find any movement of the CF stem in its cement mantle. The stem always fitted in with the cement mantle. Erroneous surgical technique or cementing was unlikely. The procedures were performed by experienced orthopedic surgeons who used the second-generation cementing technique. In patients with a Poldi stem, the first-generation cementing method was used and the proportion of aseptic loosening at 6 years of follow-up was only 4 %. In contrast, loosening in patients with the CF 30 stem was 20 % at 6 years and 6 months postoperatively. Shape of the CF 30 stem with the intention to find a relationship between stem shape and its early aseptic loosening, the authors started cooperation with the Institute of Solid Mechanics, Mechatronics and Biomechanics at the Faculty of Mechanical Engineering, Brno University of Technology. Using the method of finite elements, they carried out the stressstrain analysis in a model system. Stress at the cement-bone interface in the CF 30 stem was higher than in the Poldi stem, and this difference was statistically significant. The authors believe that the more frequent loosening found in patients with the CF 30 stem can be accounted for by its shape. The survival curve for the CF 30 femoral stem did not show good results, and therefore this stem is not recommended for implantation. The authors suggest that a more frequent early aseptic loosening of CF 30 stems may have been caused by its unsuitable shape.


Simulations of stomatal conductance and ozone uptake to Norway spruce saplings in open-top chambers.
A simulation model was developed to estimate the stomatal conductance and ozone flux to Norway spruce saplings in open-top chambers. The model was parameterized against needle conductance measurements that were made on 4-6-year-old spruce saplings, grown in open-top chambers, in July-September during three different seasons. The spruce saplings were either maintained well watered or subject to a 7-8 week drought period in July-September each year. The simulated conductance showed a good agreement with the measured conductance for the well-watered as well as the drought stress-treated saplings. The simulations were significantly improved when different vapour pressure deficit (VPD) functions were applied for well-watered and drought-stressed spruce saplings. The cumulated ozone uptake which was calculated from the conductance simulations showed less variation between years, compared to the cumulative ozone exposure index AOT40 (accumulated exposure over a threshold of 40 ppb or nl l(-1)) for the corresponding time periods. Measurements in May 1995 demonstrated the occurrence of long-term 'memory-effects' from the drought stress treatments on the conductance. Memory-effects need to be considered when simulation models for stomatal conductance are to be applied to long-lived forest trees under a multiple stress situation.


Cognitive Function Associated with Gut Microbial Abundance in Sucrose and S-Adenosyl-L-Methionine (SAMe) Metabolic Pathways.
Differential abundance of gut microbiota has found to be associated with Alzheimer's disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied. We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI. Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches. We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes), Anaerotruncus colihominis (Firmicutes), and Gordonibacter pamelaeae (Actinobacteria). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores. Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline.


The challenge of multidisciplinary research: improving diabetic pregnancy together.
Improving diabetic pregnancy outcome is a goal shared by many involved specialists. Despite proper glucose control, the incidence of maternal and perinatal complications is very high, including a high risk for pre-eclampsia, congenital malformations, perinatal mortality and macrosomia. To improve outcome, not only collaborating in the doctor's office is required but also participation in critical evaluation of our treatment strategies by means of randomised clinical trials.


Selectable and unselectable sets of neurons in recurrent neural networks with saturated piecewise linear transfer function.
The concepts of selectable and unselectable sets are proposed to describe some interesting dynamical properties of a class of recurrent neural networks (RNNs) with saturated piecewise linear transfer function. A set of neurons is said to be selectable if it can be co-unsaturated at a stable equilibrium point by some external input. A set of neurons is said to be unselectable if it is not selectable, i.e., such set of neurons can never be co-unsaturated at any stable equilibrium point regardless of what the input is. The importance of such concepts is that they enable a new perspective of the memory in RNNs. Necessary and sufficient conditions for the existence of selectable and unselectable sets of neurons are obtained. As an application, the problem of group selection is discussed by using such concepts. It shows that, under some conditions, each group is a selectable set, and each selectable set is contained in some group. Thus, groups are indicated by selectable sets of the RNNs and can be selected by external inputs. Simulations are carried out to further illustrate the theory.


An in vivo expression technology screen for Vibrio cholerae genes expressed in human volunteers.
In vivo expression technology (IVET) has been widely used to study gene expression of human bacterial pathogens in animal models, but has heretofore not been used in humans to our knowledge. As part of ongoing efforts to understand Vibrio cholerae pathogenesis and develop improved V. cholerae vaccines, we have performed an IVET screen in humans for genes that are preferentially expressed by V. cholerae during infection. A library of 8,734 nontoxigenic V. cholerae strains carrying transcriptional fusions of genomic DNA to a resolvase gene was ingested by five healthy adult volunteers. Transcription of the fusion leads to resolvase-dependent excision of a sacB-containing cassette and thus the selectable phenotype of sucrose resistance (Suc(R)). A total of approximately 20,000 Suc(R) isolates, those carrying putative in vivo-induced fusions, were recovered from volunteer stool samples. Analysis of the fusion junctions from >7,000 Suc(R) isolates from multiple samples from multiple volunteers identified 217 candidate genes for preferential expression during human infection. Of genes or operons induced in three or more volunteers, the majority of those tested (65%) were induced in an infant mouse model. VC0201 (fhuC), which encodes the ATPase of a ferrichrome ABC transporter, is one of the identified in vivo-induced genes and is required for virulence in the mouse model.


In Vivo Ibogaine Blockade and In Vitro PKC Action of Cocainea.
Ibogaine may have antiaddiction potential against alcohol, psychostimulant and opiate abuse, but its mechanism of action is unclear. Ibogaine, however, has been demonstrated in numerous studies to have effects in multiple central nervous system (CNS) neurotransmitters systems. We are using in vitro and in vivo systems to study the effects of cocaine and whether these effects can be blocked by ibogaine. For the In Vivo studies, we first determined the acute and subacute effects of ibogaine (1-5.0 mg/kg) in mice using the plus-maze test. Acutely increasing doses of ibogaine produced a reduced aversion to the open arms. The subacute administration provoked a variable response which was characterized by fluctuations in aversive and antiaversive behavior of the animals to the open arms of the plus-maze during the 14-day treatment period. A separate group of mice received 1.0 mg/kg cocaine for 14 days, and upon abrupt cessation from cocaine treatment, ibogaine 2.5 mg/kg was administered to a subgroup of these mice. Ibogaine reversed the withdrawal aversions produced by the abrupt cessation from cocaine administration. For the in vitro studies, the expression and activity of protein kinase C (PKC) isoforms and Ca2+ levels were examined following the incubation of PC 12 cells with cocaine. This is because PKC plays a key role in a number of cellular and neuronal functions. We report that cocaine disrupts signal transduction in PC 12 cells by altering the expression and activity of PKC isoforms and Ca2+ levels. The data obtained suggest (1) that the PC 12 cells may be useful in studying the neurobiology of abused drugs, like cocaine in vitro, (2) that if anxiety is a factor in drug dependency, then the antiaddictive property of ibogaine In Vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety. It remains to be determined whether the signaling involving PKC is important in the antiaddictive properties of ibogaine.


Treatment of right-sided aortic arch aneurysms with aberrant left subclavian artery with Kommerell's diverticulum using the frozen elephant trunk technique.
The ideal treatment for aneuryms of aberrant left subclavian arteries with Kommerell's diverticulum arising from right aortic arches remains open. Between January 2015 and December 2020, five patients with aneurysms from a right-sided aortic arch with aberrant left subclavian artery and Kommerell's diverticulum underwent repair by using the frozen elephant trunk (FET) technique in three aortic centers. Patients' characteristics were retrospectively reviewed and the surgical procedure and outcomes are presented. The median age of the 2 male and 3 female patients was 59 (range from 49 to 63) years. Median operative times were as follow: surgery 405 min (range from 335 to 534), cardiopulmonary bypass time 244 min (range from 208 to 280), aortic clamp time 120 min (from 71 to 184). The mean core temperature was 25,94 °C (from 24 to 28). The intensive care unit stay was 4 days (range from 1 to 8) and the in-hospital stay 21 days (from 16 to 34). All patients were discharged and we observed no stroke or spinal cord ischaemia postoperatively. During the median follow-up time of 1003 days (range from 450 to 2306), three patients required subsequent thoracic endovascular distal stent graft extension. The FET technique is a good treatment option for patients with aneuryms of an aberrant left subclavian artery with Kommerell's diverticulum arising from right aortic arches. Secondary stent graft extension is a frequently needed component of the treatment concept.


Construction of core-shell CoSe2/ZnIn2S4 heterostructures for efficient visible-light-driven photocatalytic hydrogen evolution.
The use of photocatalysts based on semiconductor heterostructures for hydrogen evolution is a prospective tactic for converting solar energy. Herein, visible-light-responsive three-dimensional core-shell CoSe2/ZnIn2S4 heterostructures were successfully fabricated via in situ growth of ZnIn2S4 ultrathin nanosheets on spherical CoSe2. Without any noble metal co-catalysts, the as-prepared CoSe2/ZnIn2S4 composite achieved attractive photocatalytic hydrogen evolution activity under visible light illumination. Optimal CoSe2/ZnIn2S4 achieved a hydrogen evolution rate of 2199 μmol g-1 h-1, which was 7 times higher than that of pristine ZnIn2S4 and even exceeded that of ZnIn2S4 loaded with platinum. In this distinctive core-shell heterostructure, the presence of CoSe2 could considerably improve the ability to harvest light, quicken the charge transfer kinetics, and avoid the agglomeration of ZnIn2S4 nanosheets. Meanwhile, the experimental results demonstrated that the strong interaction between CoSe2 and ZnIn2S4 at the compact interface could appropriately boost the photogenerated electron-hole pair migration and relieve charge recombination, thus improving photocatalytic hydrogen evolution activity. This work has bright prospects in constructing noble-metal-free core-shell heterostructures for solar energy conversion.


Phenylalanine hydroxylase: absolute configuration and source of oxygen of the 4a-hydroxytetrahydropterin species.
The formation of tyrosine from phenylalanine catalyzed by rat liver phenylalanine hydroxylase is coupled to the generation of a 4a-hydroxy adduct from the requisite tetrahydropterin cofactor. As indicated by its circular dichroism (CD) spectrum, the optical activity of the adduct generated from racemic 6-methyltetrahydropterin requires stereoselectivity of the oxygenation. The absolute configuration of this new stereocenter is 4a(S)-hydroxy-6(RS)-methyltetrahydropterin by analogy to the CD spectrum of one of the four stereoisomers of 5-deaza-4a-hydroxy-6-methyltetrahydropterin. The source of the 4a-hydroxy oxygen is O2, as demonstrated by the observation of a 18O-induced 13C shift in the 13C NMR spectrum of the adduct when generated from [4a-13C]-6-methyltetrahydropterin and 18O2.


Interacting chemokine signals regulate dendritic cells in acute brain injury.
Brain trauma is known to activate inflammatory cells via various chemokine signals although their interactions remain to be characterized. Mice deficient in Ccl3, Ccr2 or Cxcl10 were compared with wildtype mice after controlled cortical impact injury. Expression of Ccl3 in wildtypes was rapidly upregulated in resident, regularly spaced reactive microglia. Ccl3-deficiency enhanced endothelial expression of platelet selectin and invasion of peripheral inflammatory cells. Appearance of Ccr2 transcripts, encoding the Ccl2 receptor, reflected invasion of lysozyme 2-expressing phagocytes and classical antigen-presenting dendritic cells expressing major histocompatibility complex class II. Ccr2 also directed clustered plasmacytoid dendritic cells positive for the T-cell attracting chemokine Cxcl10. A reduction in Ccr2 and dendritic cells was found in injured wildtype cortex after cyclophosphamide treatment resembling effects of Ccr2-deficiency. The findings demonstrate the feasibility to control inflammation in the injured brain by regulating chemokine-dependent pathways.


Ammonia-lowering activities and carbamoyl phosphate synthetase 1 (Cps1) induction mechanism of a natural flavonoid.
Ammonia detoxification is essential for physiological well-being, and the urea cycle in liver plays a predominant role in ammonia disposal. Nobiletin (NOB), a natural dietary flavonoid, is known to exhibit various physiological efficacies. In the current study, we investigated a potential role of NOB in ammonia control and the underlying cellular mechanism. C57BL/6 mice were fed with regular chow (RC), high-fat (HFD) or high-protein diet (HPD) and treated with either vehicle or NOB. Serum and/or urine levels of ammonia and urea were measured. Liver expression of genes encoding urea cycle enzymes and C/EBP transcription factors was determined over the circadian cycle. Luciferase reporter assays were carried out to investigate function of CCAAT consensus elements on the carbamoyl phosphate synthetase (Cps1) gene promoter. A circadian clock-deficient mouse mutant, Clock (Δ19/Δ19) , was utilized to examine a requisite role of the circadian clock in mediating NOB induction of Cps1. NOB was able to lower serum ammonia levels in mice fed with RC, HFD or HPD. Compared with RC, HFD repressed the mRNA and protein expression of Cps1, encoding the rate-limiting enzyme of the urea cycle. Interestingly, NOB rescued CPS1 protein levels under the HFD condition via induction of the transcription factors C/EBPα and C/EBPβ. Expression of other urea cycle genes was also decreased by HFD relative to RC and again restored by NOB to varying degrees, which, in conjunction with Cps1 promoter reporter analysis, suggested a C/EBP-dependent mechanism for the co-induction of urea cycle genes by NOB. In comparison, HPD markedly increased CPS1 levels relative to RC, yet NOB did not further enrich CPS1 to a significant extent. Using the circadian mouse mutant Clock (Δ19/Δ19) , we also showed that a functional circadian clock, known to modulate C/EBP and CPS1 expression, was required for NOB induction of CPS1 under the HFD condition. NOB, a dietary flavonoid, exhibits a broad activity in ammonia control across varying diets, and regulates urea cycle function via C/EBP-and clock-dependent regulatory mechanisms.


Asymmetric fan transmission CT on SPECT systems.
For proper attenuation correction of SPECT images, a set of 3D attenuation maps specific to the imaging slices is needed. Among the many different approaches for deriving the attenuation maps, fan beam transmission CT (FBTCT), performed on the same SPECT system as emission imaging, has many promising and clinically practical features. The major problem of FBTCT is that the current SPECT systems do not have a large enough field of view (FOV) to cover the typical cross-sectional size of patients. To address this problem, we have developed a novel asymmetric fan (AsF) sampling scheme to extend the FOV to practical sizes for clinical TCT imaging on existing SPECT systems. This AsF scheme samples only half of the intended FOV in each projection; the other half would be sampled in an opposing projection after detector rotation. We have implemented the AsF sampling on a three-head SPECT system through a specially designed source-collimator assembly. We have modified the conventional convolution backprojection algorithm to facilitate simple and fast image reconstruction. The feasibility of the approach is confirmed by the quality of the derived TCT images of various phantoms and human subjects. The AsF sampling scheme could also have applications in other general transmission CT systems.


Feasibility of HPV self-sampling pathway in Kathmandu Valley, Nepal using a human-centred design approach.
Cervical cancer is preventable and curable yet causes almost 2000 deaths in Nepali women each year. The present study aims to explore the feasibility and acceptability of a self-sampling-based approach for cervical cancer screening in urban and peri-urban Nepal and develop pathways for self-sampling using a co-design methodology. An iterative design approach was applied. Semi-structured in-depth interviews were conducted with 30 healthy women and four women who had had a prior cancer diagnosis on topics which included: sexual and reproductive health knowledge and human papillomavirus (HPV); use of the internet/social media platforms; their views regarding acceptability and usability of the self-sampling kit and the proposed user journey. Data collection was done between December 2020 and January 2021. Seven medical experts were also interviewed to explore the current service configuration for cervical cancer screening in Nepal. Knowledge regarding HPV and its association with cervical cancer was absent for the majority of participants. Although 70% (n = 21/30) had purchased items online previously, there was a general lack of trust in online shopping. Half of the women (n = 17/30; 56.7%) expressed a willingness to self-sample and provided recommendations to improve the clarity of the instructions. The proposed user journey was considered feasible in the urban area. There is a clear unmet need for information about HPV and alternative cervical screening options in Nepal. An online pathway for self-sampling service delivery to urban women is feasible but will need to be optimally designed to address barriers such as confidence in self-sampling and trust in online purchasing.


Growing as slow as a turtle: Unexpected maturational differences in a small, long-lived species.
Turtle body size is associated with demographic and other traits like mating success, reproductive output, maturity, and survival. As such, growth analyses are valuable for testing life history theory, demographic modeling, and conservation planning. Two important but unsettled research areas relate to growth after maturity and growth rate variation. If individuals exhibit indeterminate growth after maturity, older adults may have an advantage in fecundity, survival, or both over younger/smaller adults. Similarly, depending on how growth varies, a portion of the population may mature earlier, grow larger, or both. We used 23-years of capture-mark-recapture data to study growth and maturity in the Spotted Turtle (Clemmys guttata), a species suffering severe population declines and for which demographic data are needed for development of effective conservation and management strategies. There was strong support for models incorporating sex as a factor, with the interval growth model reparametrized for capture-mark-recapture data producing later mean maturation estimates than the age-based growth model. We found most individuals (94%) continued growing after maturity, but the instantaneous relative annual plastral growth rate was low. We recommend future studies examine the possible contribution of such slow, continued adult growth to fecundity and survival. Even seemingly negligible amounts of annual adult growth can have demographic consequences affecting the population vital rates for long-lived species.


Experiencing financial toxicity associated with cancer in publicly funded healthcare systems: a systematic review of qualitative studies.
Understanding how patients and families experience, respond to, and cope with the financial burden associated with cancer could assist in identifying future research priorities and developing relevant interventions to assist patients and families facing financial hardship. This systematic review offers a synthesis of the qualitative evidence on cancer-related financial toxicity from the perspective of patients and/or informal caregivers in publicly funded healthcare systems where it might be expected that financial protection would be strongest. Articles published between January 1, 2005, and March 7, 2019, describing financial burden experienced by cancer patients and/or informal caregivers were identified using OVID MEDLINE Embase and PsychInfo, CINAHL, Business Source Complete, and EconLit databases. English language, peer-reviewed qualitative papers describing studies conducted in countries with predominantly publicly funded healthcare systems were eligible. Quality appraisal was conducted using CASP Quality Appraisal Checklist. Narrative synthesis was completed with extracted data and themes identified inductively by all team members. Twelve articles were identified as eligible. Articles reported on 10 studies conducted in Australia (n = 2), Canada (n = 2), England (n = 3), and Ireland (n = 3). The papers illustrate the complexity and multifaceted nature of experiencing financial hardship following a cancer diagnosis. Each contributes to the whole picture, providing different viewpoints regarding various and diverse forms of financial hardship, the process of confronting financial challenges, working to overcome difficulties, and coping with the resulting impacts. Synthesis of the studies suggested five themes: household and medical costs are increased, financial resources are reduced, financial change and financial hardship vary, financial hardship has many consequences, various mitigation strategies are used. Cancer patients and their families can experience a broad range of impacts when they are facing and coping with financial toxicity. Consistent gaps in support highlight that strategies to mitigate financial effects related to travel, accommodation, medications, family support, and income replacement are needed for many patients and families even in the context of publicly funded healthcare systems. Survivors need to be informed early in their cancer experience about the potential financial burden associated with cancer treatment and its impact on survivors and their family members.


A Novel 4H-Chromen-4-One Derivative from Marine Streptomyces ovatisporus S4702T as Potential Antibacterial and Anti-Cancer Agent.
Marine actinomycetes are among indispensable sources of natural bioactive compounds with unique antimicrobial and anti-cancer activities. Herein, it was aimed to elucidate the bioactive potential of a marine-derived Streptomyces ovatisporus S4702T, isolated previously. Streptomyces ovatisporus S4702T was cultured in N-Z Amine broth, and extraction was carried out using different organic solvents. Bioassay-guided purification was followed by chemical characterization using NMR and LC-MS/MS. The compound was then evaluated for its antibacterial, antioxidant and cytotoxic activities. Etyl acetate extracts gave the highest antibacterial activity, and chemical characterization of this extract indicated the formula as C15H29O5N3 and the corresponding possible molecular structure as 4H-chromen-4-one derivative. It was found highly potent against Bacillus subtilis ATCC 6633 (MIC: 0.25 μg ml-1) and Micrococcus luteus ATCC 9341 (MBC: 0.5 μg ml-1). It has no remarkable antioxidant activity, but a higher EC50 value and less cytotoxicity against normal cells. The EC50 values of this chromen derivative were found as 9.68 μg ml-1 for human colon carcinoma, 9.93 μg ml-1 for human prostate adenocarcinoma and 25.5 μg ml-1 for human embryonic kidney cells. Overall, the presented 4H-chromen-4-one derivative is a remarkable bioactive compound with potent antibacterial and cytotoxic activity. With its high bioactive potential, it is proposed as a good candidate in medicine.


Moral Psychopharmacology Needs Moral Inquiry: The Case of Psychedelics.
The revival of psychedelic research coincided and more recently conjoined with psychopharmacological research on how drugs affect moral judgments and behaviors. This article makes the case for a moral psychopharmacology of psychedelics that examines whether psychedelics serve as non-specific amplifiers that enable subjects to (re-)connect with their values, or whether they promote specific moral-political orientations such as liberal and anti-authoritarian views, as recent psychopharmacological studies suggest. This question gains urgency from the fact that the return of psychedelics from counterculture and underground laboratories to mainstream science and society has been accompanied by a diversification of their users and uses. We propose bringing the pharmacological and neuroscientific literature into a conversation with historical and anthropological scholarship documenting the full spectrum of moral and political views associated with the uses of psychedelics. This paper sheds new light on the cultural plasticity of drug action and has implications for the design of psychedelic pharmacopsychotherapies. It also raises the question of whether other classes of psychoactive drugs have an equally rich moral and political life.


Direct induction of human neural stem cells from peripheral blood hematopoietic progenitor cells.
Human disease specific neuronal cultures are essential for generating in vitro models for human neurological diseases. However, the lack of access to primary human adult neural cultures raises unique challenges. Recent developments in induced pluripotent stem cells (iPSC) provides an alternative approach to derive neural cultures from skin fibroblasts through patient specific iPSC, but this process is labor intensive, requires special expertise and large amounts of resources, and can take several months. This prevents the wide application of this technology to the study of neurological diseases. To overcome some of these issues, we have developed a method to derive neural stem cells directly from human adult peripheral blood, bypassing the iPSC derivation process. Hematopoietic progenitor cells enriched from human adult peripheral blood were cultured in vitro and transfected with Sendai virus vectors containing transcriptional factors Sox2, Oct3/4, Klf4, and c-Myc. The transfection results in morphological changes in the cells which are further selected by using human neural progenitor medium containing basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). The resulting cells are characterized by the expression for neural stem cell markers, such as nestin and SOX2. These neural stem cells could be further differentiated to neurons, astroglia and oligodendrocytes in specified differentiation media. Using easily accessible human peripheral blood samples, this method could be used to derive neural stem cells for further differentiation to neural cells for in vitro modeling of neurological disorders and may advance studies related to the pathogenesis and treatment of those diseases.


Do Prolactin and its Receptor Play a Role in Alopecia Areata?
Studying the link between prolactin and autoimmunity has gained much ground over the past years. Its role played in alopecia areata (AA) is not clear yet, as previous reports yielded controversial results. This study aimed to measure the serum level of prolactin and to detect the expression of its receptor in AA, in an attempt to highlight its possible role in the pathogenesis of this disease. A case-control study of 30 AA patients and 20 controls from outpatient clinic were undertaken. Every patient was subjected to history taking and clinical examination to determine the severity of alopecia tool (SALT) score. Blood samples were taken from patients and controls to determine the serum prolactin level. Scalp biopsies were obtained from the lesional skin of patients and normal skin of controls for assessment of the prolactin receptor. Depending upon the type of data, t-test, analysis of variance test, Chi-square, receiver operator characteristic curve were undertaken. On comparing the serum prolactin level between patients and controls, no significant difference was found, while the mean tissue level of prolactin receptor was significantly higher in patients than in controls. In patients, a significant positive correlation was found between the prolactin receptor and the SALT score. Prolactin plays a role in AA, and this role is probably through the prolactin receptors rather than the serum prolactin level.


A controlled genetic algorithm by fuzzy logic and belief functions for job-shop scheduling.
Most scheduling problems are highly complex combinatorial problems. However, stochastic methods such as genetic algorithm yield good solutions. In this paper, we present a controlled genetic algorithm (CGA) based on fuzzy logic and belief functions to solve job-shop scheduling problems. For better performance, we propose an efficient representational scheme, heuristic rules for creating the initial population, and a new methodology for mixing and computing genetic operator probabilities.


The dependence of timing jitter of superconducting nanowire single-photon detectors on the multi-layer sample design and slew rate.
We investigated the timing jitter of superconducting nanowire single-photon detectors (SNSPDs) and found a strong dependence on the detector response. By varying the multi-layer structure, we observed changes in pulse shape which are attributed to capacitive behaviour affecting the pulse heights, rise times and consequently timing jitter. Moreover, we developed a technique to predict the timing jitter of a single device within certain limits by capturing only a single detector pulse, eliminating the need for detailed jitter measurement using a pulsed laser when a rough estimate of the timing jitter is sufficient.


The side-to-side differences of bone mass at proximal femur in female rhythmic sports gymnasts.
This cross-sectional study examined the side-to-side differences of the bone mineral density (BMD) at proximal femora in female rhythmic sports gymnasts (RSGs). The hypothesis on which the study is based is that gymnasts use a different leg in take-off (left leg) and in landing (right leg) and therefore differ in the loading for the left and right legs. The gymnasts made up two groups: the regular group, which consisted of 15 regular players who had trained for about 28 h/week, and the substitutes group, which consisted of 8 substitute players who had trained for about 12 h/week. The control group consisted of 10 nonathletic college women who had not participated in any kind of regular sports activity. BMD (g/cm2) was measured in three hip sites using the XR-26 dual-energy X-ray absorptiometer scanner. Muscle strength at knee extensors (EXT) and flexors (FLX) was examined using an isokinetic dynamometer (CYBEX6000), and the vertical ground reaction force was determined with a force platform during take-off and landing movements. In the regular players, the BMDs of the left leg were significantly higher than those of the right leg at the femoral necks, greater trochanters, and Ward's triangles (p < 0.01 to approximately 0.005). The side-to-side differences were 4.7 to approximately 9.6%. Regarding the strength parameters, the left side was greater than the right side significantly at EXT 60 degrees/s (p < 0.01), although the overall side-to-side difference was small. In the substitutes, the BMDs at the three sites mentioned above were also higher in the left leg than the right, but the side-to-side difference was statistically significant only at Ward's triangles (93%, p < 0.05). The side-to-side difference of strength was not significant. In the controls, there were small left-to-right differences of the BMDs, ranging from -1.8 to 0.5%, which was significantly lower than in the regular players at each site. The overall average strength measurements were larger in the right leg than in the left except at the 120 degrees/s. The side-to-side difference was statistically significant at EXT 30 degrees/s and 60 degrees/s (p < 0.05). The peak force was greater in take-off than in landing, and the unit time force during take-off was significantly greater than that during landing (p < 0.001). In conclusion, regarding the side-to-side difference of the BMD at proximal femora, our results demonstrate: that the left leg for take-off had higher measurements than the right leg for landing in both gymnasts' groups, which accounts for the vertical ground reaction force during take-off being greater than that during landing; that the difference in the regular players group was greater than that in the substitute group, which can be explained because the regular players practiced much more than the substitutes did; and that there was no difference in the control group.


Carbohydrate metabolism of malarial parasites.
The evidence for the pathways involved in the metabolism of carbohydrates by malarial parasites is critically reviewed. In all species studied, glucose is catabolized mainly by glycolysis with little participation of the pentose-phosphate pathway. It has not been proved conclusively that there is a functioning citric acid cycle in the intraerythrocytic stages of avian plasmodia, nor is it certain that these stages of any malarial parasites use oxygen.


SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages.
Phagocytosis is a pivotal process by which macrophages eliminate microorganisms after recognition by pathogen sensors. Here we unexpectedly found that the self ligand and cell surface receptor SLAM functioned not only as a costimulatory molecule but also as a microbial sensor that controlled the killing of gram-negative bacteria by macrophages. SLAM regulated activity of the NADPH oxidase NOX2 complex and phagolysosomal maturation after entering the phagosome, following interaction with the bacterial outer membrane proteins OmpC and OmpF. SLAM recruited a complex containing the intracellular class III phosphatidylinositol kinase Vps34, its regulatory protein kinase Vps15 and the autophagy-associated molecule beclin-1 to the phagosome, which was responsible for inducing the accumulation of phosphatidylinositol-3-phosphate, a regulator of both NOX2 function and phagosomal or endosomal fusion. Thus, SLAM connects the gram-negative bacterial phagosome to ubiquitous cellular machinery responsible for the control of bacterial killing.


ZnO-Nanowires-Coated Smart Surface Mesh with Reversible Wettability for Efficient On-Demand Oil/Water Separation.
The rapid industrial growth has led to the large production of oily wastewater. Treatment of oily wastewater is an inevitable challenge to manage the greater demand of clean water for the rapidly growing population and economy. In the present work, we have developed a smart surface mesh with reversible wetting properties via a simple, ecofriendly, and scalable approach for on-demand oil-water separation. ZnO nanowires (NWs) obtained from the chemical vapor deposition method were coated on a stainless steel (SS) mesh. The as-synthesized ZnO-NWs-coated mesh shows superhydrophilic/underwater superoleophobic behavior. This mesh works in "water-removing" mode, where the superhydrophilic as well as underwater superoleophobic nature allows the water to permeate easily through the mesh while preventing oil. The wetting property of ZnO-NWs-coated mesh can be switched easily from superhydrophilic to superhydrophobic state and vice versa by simply annealing it at 300 °C alternatively under hydrogen and oxygen environment. The separation is solely driven by gravity. Thus, the reversible wettability of ZnO NWs provides a smart surface mesh which can be switched between "oil-removing" and "water-removing" modes. It was found that for more than 10 cycles of mesh reutilization in both modes alternatively, the separation efficiency of 99.9% stayed relatively invariant, indicating a prolonged antifouling property and excellent recyclability. This work provides a simple, fast, cost-effective, and on-demand solution for oily wastewater treatment and opens up new perspectives in the field of controllable oil-water separation.


Capability for change at community health centers serving Asian Pacific Islanders: an exploratory study of a cancer screening evidence-based intervention.
Understanding and enhancing change capabilities, including Practice Adaptive Reserve (PAR), of Community Health Centers (CHCs) may mitigate cancer-related health disparities. Using stratified random sampling, we recruited 232 staff from seven CHCs serving Asian Pacific Islander communities to complete a self-administered survey. We performed multilevel regression analyses to examine PAR composite scores by CHC, position type, and number of years worked at their clinic. The mean PAR score was 0.7 (s.d. 0.14). Higher scores were associated with a greater perceived likelihood that clinic staff would participate in an evidence-based intervention (EBI). Constructs such as communication, clinic flow, sensemaking, change valence, and resource availability were positively associated with EBI implementation or trended toward significance. PAR scores are positively associated with perceived likelihood of clinic staff participation in cancer screening EBI. Future research is needed to determine PAR levels most conducive to implementing change and to developing interventions that enhance Adaptive Reserve.


Finding the SNARC Instead of Hunting It: A 20∗20 Monte Carlo Investigation.
The Spatial Numerical Association of Response Codes (SNARC) effect describes a stimulus-response association of left with small magnitude and right with large magnitude. Usually, it is estimated by means of regression slopes, where the independent variable only has a limited number of levels. Inspection of the literature reveals that it is not difficult to detect a SNARC effect within a group, but it has been quite unusual to find group differences. Is the SNARC effect as it is usually estimated using regression slopes largely insensitive to group differences, and are there design parameters necessary to increase sensitivity in group comparison analyses? Using numerical simulations, we provide evidence that both sample size and the number of stimulus repetitions, as well as intra-individual variability, contribute in a substantial way to the probability of detecting an existing SNARC effect. Our results show that the adequate choice of either sample size or number of repetitions per experimental cell does not fully compensate for a poor choice of the other parameter. Moreover, repeated failures to find significant group differences in the SNARC effect can be explained by insufficient power. Fortunately, increasing the number of repetitions to about 20 and testing at least 20 participants provides in most cases sufficient sensitivity to reliably detect the SNARC effect as well as group differences. Power plots are provided, which may help to improve both the economy and sensitivity of experimental design in future SNARC experiments, or, more generally when regression slopes are estimated intra-individually.


Dispersed-nanoparticle loading synthesis for monodisperse Au-titania composite particles and their crystallization for highly active UV and visible photocatalysts.
Submicrometer-sized amorphous titania spheres incorporating Au nanoparticles (NPs) were prepared in a one-pot synthesis consisting of a sol-gel reaction of titanium(IV) isopropoxide in the presence of chloroauric acid and a successive reduction with sodium borohydride in a mixed solvent of ethanol/acetonitrile. The synthesis was allowed to prepare monodisperse titania spheres that homogeneously incorporated Au NPs with sizes of ca. 7 nm. The Au NP-loaded titania spheres underwent different crystallization processes, including 500 °C calcination in air, high-temperature hydrothermal treatment (HHT), and/or low-temperature hydrothermal treatment (LHT). Photocatalytic experiments were conducted with the Au NP-loaded crystalline titania spheres under irradiation of UV and visible light. A combined process of LHT at 80 °C followed by calcination at 500 °C could effectively crystallize titania spheres maintaining the dispersion state of Au NPs, which led to photocatalytic activity higher than that of commercial P25 under UV irradiation. Under visible light irradiation, the Au NP-titania spheres prepared with a crystallization process of LHT at 80 °C for 6 h showed photocatalytic activity much higher than a commercial product of visible light photocatalyst. Structure analysis of the visible light photocatalysts indicates the importance of prevention of the Au NPs aggregation in the crystallization processes for enhancement of photocatalytic activity.


Immunogenic properties of Streptococcus agalactiae FbsA fragments.
Several species of Gram-positive bacteria can avidly bind soluble and surface-associated fibrinogen (Fng), a property that is considered important in the pathogenesis of human infections. To gain insights into the mechanism by which group B Streptococcus (GBS), a frequent neonatal pathogen, interacts with Fng, we have screened two phage displayed genomic GBS libraries. All of the Fng-binding phage clones contained inserts encoding fragments of FbsA, a protein displaying multiple repeats. Since the functional role of this protein is only partially understood, representative fragments were recombinantly expressed and analyzed for Fng binding affinity and ability to induce immune protection against GBS infection. Maternal immunization with 6pGST, a fragment containing five repeats, significantly protected mouse pups against lethal GBS challenge and these protective effects could be recapitulated by administration of anti-6pGST serum from adult animals. Notably, a monoclonal antibody that was capable of neutralizing Fng binding by 6pGST, but not a non-neutralizing antibody, could significantly protect pups against lethal GBS challenge. These data suggest that FbsA-Fng interaction promotes GBS pathogenesis and that blocking such interaction is a viable strategy to prevent or treat GBS infections.