The Path to New Therapies for Schizophrenia and Bipolar Illness.
Schizophrenia and bipolar illness are two of the most serious forms of mental illness. Until relatively recently, almost nothing was known about the molecular pathogenesis of either illness. The single largest risk factor that predisposes people to schizophrenia or bipolar illness is genetic risk. Heritability is high, and the incidence is significantly higher in identical twins than in nonidentical twins. Despite decades of work aimed at identifying the genes involved in these two illnesses, virtually no progress had been made until the past decade. With the knowledge and technologies that have been gained from the Human Genome Project, it has been possible to begin to understand the underlying genetics and to use the new information to begin the effort to discover new and better medicines to treat these illnesses. This article will describe the past decade of work toward this goal and articulate both the promise that now exists and what is still needed to bring dramatic and tangible change to patients.-Scolnick, E. M. The path to new therapies for schizophrenia and bipolar illness.


Microleakage of two polyacid-modified resin composites under different conditioning methods in primary teeth.
This study evaluated the effect of different conditioning methods on micro-leakage in primary teeth. Fifty-one cervical cavities were prepared on the twenty-six extracted primary molars and divided randomly into five groups. In Group I and IV phosphoric acid, in group 11 non-rinse conditioner (NRC) was applied. In group III and V no pretreatment was used. Groups I-III were restored with Prime & Bond NT and Dyract AP and Group IV-V restored with Syntac SC and Compoglass F. The restored teeth were stored for 24 hours in distilled water at 37 degrees C, immersed in 0.5 percent basic fuchsin for 24 hours. Dye penetration was determined using a stereomicroscope. The results revealed that although enamel microleakage was not affected by the conditioning method used in both restorative materials, pretreating the cavity with phosphoric acid had a positive effect on reducing the dentin microleakage compared with conditioning by NRC.


Dietary electrolyte balance effects on performance and metabolic characteristics in growing steers.
The effects of dietary electrolyte balance (DEB; mEq of Na + K - Cl/100 g of DM) on performance and acid-base status of growing cattle consuming a corn silage-based diet were established using 120 Angus (n = 60) and Angus crossbred (n = 60) steers (247 +/- 2.4 kg). Treatments consisting of 0, 15, 30, or 45 mEq of DEB/100 g of DM were obtained by varying NH4Cl and NaHCO3. Average daily gain showed a linear increase (P < .05) with increased DEB for the first 28 d and a quadratic response (P < .05) for the remainder of the 84-d study. Average daily feed intake was not affected by DEB the first 28 d. However, feed intake over the entire feeding period showed a linear increase with increasing DEB (P < .01). On d 28, plasma Na, K, and Mg were not affected by DEB, whereas Ca followed a quadratic pattern (P < .10). On d 84, plasma Na and Mg decreased linearly with increasing DEB. Plasma Cl concentrations decreased linearly (P < .01) with increased DEB on d 28 and 84. On d 28 arterial blood pH and HCO3 increased linearly (P < .05) with increased DEB, whereas ionized Ca, pCO2, and pO2 were unchanged. On d 84, arterial blood pH (P < .10), HCO3 (P < .05), and ionized Ca (P < .10) increased quadratically, whereas pO2 and pCO2 were not affected by treatment. Ruminal pH increased linearly (P < .05) with increased DEB on d 28 but showed no differences on d 84. These data indicate that DEB affects performance and systemic values in growing feedlot cattle. A DEB in the range of 15 to 30 mEq seemed to provide normal homeostasis of growing steers fed a corn silage-based diet.


Imipramine N-glucuronidation in human liver microsomes: biphasic kinetics and characterization of UDP-glucuronosyltransferase isoforms.
A method for the direct determination of imipramine N-glucuronidation in human liver microsomes by high-performance liquid chromatography with UV detection was developed. Imipramine was incubated with human liver microsomes and UDP-glucuronic acid. The Eadie-Hofstee plots of imipramine N-glucuronidation in human liver microsomes were biphasic. For the high-affinity component, the K(m) was 97.2 +/- 39.4 microM and the V(max) was 0.29 +/- 0.03 nmol/min/mg of protein. For the low-affinity component, the K(m) was 0.70 +/- 0.29 mM and the V(max) was 0.90 +/- 0.28 nmol/min/mg of protein. The imipramine N-glucuronosyltransferase activities were not detectable in two samples of human jejunum microsomes. Among recombinant UDP-glucuronosyltransferases (UGTs) in baculovirus-infected insect cells (Supersomes or Bacurosomes) or human B-lymphoblastoid cells tested in the present study (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15), only UGT1A4 showed imipramine N-glucuronosyltransferase activity. The activity in UGT1A4 Supersomes was higher than that in recombinant UGT1A4 expressed in human B-lymphoblastoid cells at all imipramine concentration tested. The kinetics of imipramine N-glucuronidation in UGT1A4 Supersomes did not fit the Michaelis-Menten plot, showing a K(m) of >1 mM. In contrast, in UGT1A4 expressed in human B-lymphoblastoid cells, K(m) was 0.71 +/- 0.36 mM and the V(max) was 0.11 +/- 0.03 nmol/min/mg of protein. Interindividual differences in the imipramine N-glucuronidation in liver microsomes from 14 humans were at most 2.5-fold. The imipramine N-glucuronosyltransferase activities in 11 human liver microsomes were significantly (r = 0.817, P < 0.005) correlated with the glucuronosyltransferase activities of trifluoperazine, a typical substrate of UGT1A4. This is the first report of the biphasic kinetics of imipramine N-glucuronide in human liver microsomes.


Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins.
The human cytomegalovirus (HCMV)-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates the retinoblastoma (Rb) tumor suppressor. Here, we identify the other Rb family members p107 and p130 as novel targets of UL97. UL97 phosphorylates p107 and p130 thereby inhibiting their ability to repress the E2F-responsive E2F1 promoter. As with Rb, this phosphorylation, and the rescue of E2F-responsive transcription, is dependent on the L1 LXCXE motif in UL97 and its interacting clefts on p107 and p130. Interestingly, UL97 does not induce the disruption of all p107-E2F or p130-E2F complexes, as it does to Rb-E2F complexes. UL97 strongly interacts with p107 but not Rb or p130. Thus the inhibitory mechanisms of UL97 for Rb family protein-mediated repression of E2F-responsive transcription appear to differ for each of the Rb family proteins. The immediate early 1 (IE1) protein of HCMV also rescues p107- and p130-mediated repression of E2F-responsive gene expression, but it does not induce their phosphorylation and does not disrupt p107-E2F or p130-E2F complexes. The unique regulation of Rb family proteins by HCMV UL97 and IE1 attests to the importance of modulating Rb family protein function in HCMV-infected cells.


Association between extracellular volume control and survival in patients on short daily haemodialysis.
Fluid overload (FO) assessed by bioimpedance spectroscopy (BIS) is associated with higher mortality risk in maintenance haemodialysis (HD). The aim was to assess if a better management of FO through short daily haemodialysis (SDHD) could improve survival. Retrospective analysis of patients who were on HD 3 sessions/week for at least 3 months and shifted to in-centre SDHD (5 or 6 sessions/week, 2 to 3 h/session) between July 2012 and June 2016 at 23 dialysis units in Brazil. The 12-month risk of death was analysed according to the predialysis hydration status measured before and 6 months after initiation of SDHD. Predialysis hydration status was considered adequate when FO ≤15% of extracellular volume. A total of 297 patients on SDHD were included in the analysis. Their median age was 57 (IQR 45-67) years, 62% were males, 44% diabetics, 57% on 6 dialysis sessions/week, with a median session duration of 130 (IQR 120-150) minutes. BIS assessment at initiation of the SDHD regimen was performed in 220 patients and FO > 15% was found in 46.4%. Twelve-month survival rates for those with FO ≤15 and > 15% before initiating SDHD were 87.4 and 88.0%, respectively (P = 0.92). BIS analysis when completing 6 months on SDHD were available for 229 patients, 26.6% with FO > 15%. The survival rates for the next 12 months (from the 6th to the 18th month of follow-up) for those with FO ≤15 and > 15% were 91.0 and 72.0%, respectively (P = 0.0006). In a Cox regression model, after adjustment for demographic, clinical and laboratory variables, FO ≤ 15% persisted associated with a lower mortality risk (hazard ratio 0.34, 95%CI 0.13-0.87). Moving from conventional HD to SDHD was associated with better control of excessive extracellular volume. Patients who reached or maintained predialysis fluid overload ≤15% after initiating SDHD presented a lower risk of death.


HLA-G 3'UTR haplotype analyses in HCV infection and HCV-derived cirrhosis, hepatocellular carcinoma and fibrosis.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune-related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA-G) gene codes for an immunomodulatory protein known to be expressed in the maternal-foetal interface and in immune-privileged tissues. The HLA-G 3' untranslated region (3'UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA-G 3'UTR with susceptibility to viral infections, but other polymorphic variants in the HLA-G 3'UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA-G 3'UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR-1, UTR-2 and UTR-3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA-G expression can be involved in HCV infection susceptibility.


A molecular biology-based approach to resolve the subunit orientation of lipoprotein lipase.
The subunit orientation of a dimeric enzyme influences the mechanism of action and function. To determine the subunit arrangement of lipoprotein lipase (LPL), a molecular biology-based approach was initiated. An eight amino acid linker region was engineered between two LPL monomers and expressed in COS-7 cells. The resultant tandem-repeat molecule (LPLTR) was lipolytically active and had kinetic parameters, salt inhibition, cofactor-dependent activity, heparin-binding characteristics, and a functional unit size very similar to the expressed native human enzyme. By these criteria, LPLTR was the functional equivalent of native LPL. Considering the length of the linker peptide (no more than 24 A), monomers in the tethered molecule were restricted to a head-to-tail subunit arrangement. Since LPLTR demonstrated native enzyme-like properties while constrained to this subunit arrangement, these results provide the first compelling evidence that native LPL monomers are arranged in a head-to-tail subunit orientation within the active dimer. Thus, LPL function in physiology, lipolysis, and binding to cell-surface components must now be addressed with this subunit orientation in mind. The utility of the tandem-repeat approach to resolve the subunit arrangement of an obligate dimer has been demonstrated with LPL and could be generalized for use with other oligomeric enzymes.


The calm before the storm? Burnout and compassion fatigue among undergraduate nursing students.
Studies have consistently highlighted the deleterious impact of burnout and compassion fatigue on professional nurses' well-being and willingness to remain in the profession. Yet, as to what extent these noxious conditions are suffered among nursing students is still unclear. In this study 436 undergraduate nursing students completed surveys assessing their experiences of emotional exhaustion, depersonalization, lack of personal accomplishment, burnout, secondary traumatic stress, and compassion satisfaction (factors of burnout and compassion fatigue). There were no significant differences found between 3rd and 4th year students' reports of detrimental conditions and those of the 1st or 2nd year students. Furthermore, 4th year students reported significantly higher levels of personal accomplishment compared to 1st and 2nd year students. Semi-structured in-depth interviews with 3rd and 4th year students revealed that their clinical exposure during these years (especially during the 4th year) may enhance their other-orientation as well as promote role actualization, which may serve as protective features. Students did, however, express concern regarding an inevitable onset of burnout at some point during their professional careers. It is suggested that a key to understanding the onset and experience of burnout and compassion fatigue among nurses is to continue to examine the transition from student to professional nurse and the cultural atmosphere of nursing education compared to professional practice.


Vet the journal before you submit: turnaround times of journals publishing in zoological medicine and related fields.
Many factors influence selection of a target journal for publishing scientific papers, including "fit" within the journal's scope, acceptance rate, readership, open access options, submission and publication costs, journal quality, and timeliness of publication. Timeliness of publication can be a critical factor affecting career development, but many journals are not transparent about turnaround times. Here we evaluated 49 journals publishing papers in zoological medicine and related fields between 2017 and 2022, and aggregated and examined distributions of turnaround time of journals that publicly provided the requisite data, in order to aid authors in selecting target journals that best meet their needs. Of 49 journals evaluated, 39 provided necessary dates for reconstructing turnaround times. Of these, median times to acceptance ranged from 37 to 338 days, and median times to publication ranged from 41 to 403.5 days. The percentage of papers published in greater than 1 year ("slow") ranged from 0 to 57.1%, while the percentage of papers published in under 6 months ("timely") ranged from 0.8 to 99.8%. Acceptance rates and times to first decision were available for only 22% and 20%, respectively, of journals evaluated. Results may prove useful for authors deciding where to submit their works, depending on how they prioritize the many factors involved.


Adenosine A1 Receptor-Mediated Attenuation of Reciprocal Dendro-Dendritic Inhibition in the Mouse Olfactory Bulb.
It is well described that A1 adenosine receptors inhibit synaptic transmission at excitatory synapses in the brain, but the effect of adenosine on reciprocal synapses has not been studied so far. In the olfactory bulb, the majority of synapses are reciprocal dendro-dendritic synapses mediating recurrent inhibition. We studied the effect of A1 receptor activation on recurrent dendro-dendritic inhibition in mitral cells using whole-cell patch-clamp recordings. Adenosine reduced dendro-dendritic inhibition in wild-type, but not in A1 receptor knock-out mice. Both NMDA receptor-mediated and AMPA receptor-mediated dendro-dendritic inhibition were attenuated by adenosine, indicating that reciprocal synapses between mitral cells and granule cells as well as parvalbumin interneurons were targeted by A1 receptors. Adenosine reduced glutamatergic self-excitation and inhibited N-type and P/Q-type calcium currents, but not L-type calcium currents in mitral cells. Attenuated glutamate release, due to A1 receptor-mediated calcium channel inhibition, resulted in impaired dendro-dendritic inhibition. In behavioral tests we tested the ability of wild-type and A1 receptor knock-out mice to find a hidden piece of food. Knock-out mice were significantly faster in locating the food. Our results indicate that A1 adenosine receptors attenuates dendro-dendritic reciprocal inhibition and suggest that they affect odor information processing.


Ran1 is essential for parental macronuclear import of apoptosis-inducing factor and programmed nuclear death in Tetrahymena thermophila.
During programmed nuclear death (PND), apoptosis-inducing factor (AIF) translocates from mitochondria to the parental macronucleus (MAC) in Tetrahymena thermophila. In the degenerating parental MAC, AIF induces chromatin condensation and large-scale DNA fragmentation in a caspase-independent manner. However, the regulation of AIF nuclear translocation and molecular mechanism of PND are less clear. In this study, we demonstrated that the asymmetric distribution of nuclear GDP-bound Ran1-mimetic mutant Ran1T25N and cytoplasmic GTP-bound Ran1-mimetic mutant Ran1Q70L exists across the parental macronuclear-cytoplasmic barrier during PND. Knockdown of RAN1 led to defects in PND progression and failure of parental macronuclear accumulation of AIF. Moreover, AIF parental macronuclear import occurred in Ran1T25N mutants, while it was inhibited in Ran1Q70L mutants. Importantly, artificial accumulation of AIF in the parental MAC rescued PND progression defects in RAN1 knockdown mutants. These data suggest that Ran1 is essential for parental macronuclear import of AIF and PND in T. thermophila.


Ag2S QDs/Si Heterostructure-Based Ultrasensitive SWIR Range Detector.
In the 20th century, microelectronics was revolutionized by silicon-its semiconducting properties finally made it possible to reduce the size of electronic components to a few nanometers. The ability to control the semiconducting properties of Si on the nanometer scale promises a breakthrough in the development of Si-based technologies. In this paper, we present the results of our experimental studies of the photovoltaic effect in Ag2S QD/Si heterostructures in the short-wave infrared range. At room temperature, the Ag2S/Si heterostructures offer a noise-equivalent power of 1.1 × 10-10 W/√Hz. The spectral analysis of the photoresponse of the Ag2S/Si heterostructures has made it possible to identify two main mechanisms behind it: the absorption of IR radiation by defects in the crystalline structure of the Ag2S QDs or by quantum QD-induced surface states in Si. This study has demonstrated an effective and low-cost way to create a sensitive room temperature SWIR photodetector which would be compatible with the Si complementary metal oxide semiconductor technology.


Calorimetric and spectroscopic studies on the interaction of methimazole with bovine serum albumin.
The potential binding interaction(s) of the anti-thyroid drug methimazole (MMZ) with the protein bovine serum albumin (BSA) has been studied using isothermal titration calorimetry (ITC) and UV-Visible, fluorescence and circular dichroism (CD) spectroscopic techniques. The binding of MMZ to BSA has been studied in both the presence and absence of added surfactants. Since, the ITC thermograms show the molar enthalpy of binding of MMZ and BSA to be zero within experimental error, either the enthalpy change of the binding interaction is zero or there is no binding occurring. The CD and the intrinsic fluorescence and life time spectra of BSA were unchanged by the addition of MMZ. This is also indicative of the absence of any significant interaction of MMZ with BSA.


Ambient desorption/ionization mass spectrometry using a liquid sampling-atmospheric glow discharge (LS-APGD) ionization source.
A novel approach to ambient desorption/ionization mass spectrometry (ADI-MS) is described, based on a recently developed liquid sampling-atmospheric pressure glow discharge (LS-APGD) ionization source. The device is essentially unmodified relative to its implementation in elemental mass spectrometry, where the operational space is characterized by low operation power (<10 W) and low solution delivery rates (<50 μL min(-1)). In this implementation, the plasma is produced between a Ni anode and an electrolytic liquid (1 M HNO3) cathode flowing through a glass capillary that is angled towards the sample surface, at a distance of ~2 mm away. Analyte species can be desorbed/ionized from neat solution residues and complex solid samples. The ADI-LS-APGD source is mounted onto the source interface of a Thermo Finnigan LCQ Advantage Max quadrupole ion trap mass spectrometer without modifications to the instrument faceplate or ion optics. Described here is the initial evaluation of the roles of source geometry and working parameters, including electrolytic solution composition and plasma current, on the response of caffeine residues, with preliminary limits of detection based on the relative standard deviation of the spectral background suggested to be on the 10-pg level. Demonstrative spectra are presented for green tea extracts and raw leaves, coffee beans, a dried (raw) tobacco leaf, an analgesic tablet, and paper currency. Versatility is further revealed through the determination of components in common cigarette smoke. In each case, the spectra are characterized by (M + H)(+) species of the expected constituents. The capacity for a single source to perform both in solution and particulate elemental analysis (as shown previously) and ADI of molecular species is unique in the realm of mass spectrometry.


Xanthones of Garcinia cowa.
Five xanthones have been isolated from Garcinia cowa Roxb. (Guttiferae): cowanin (1), cowanol (2), cowaxanthone (3), 1,3,6-trihydroxy-7-methoxy- 2-5-bis(3-methyl-2-butenyl)xanthone (4), and norcowanin (5). The structures were assigned by spectroscopic studies. Xanthones 2 and 3 showed moderate antimicrobial activity against Staphylococcus aureus.


Versatile Self-Assembly and Biosensing Applications of DNA and Carbon Quantum Dots Coordinated Cerium Ions.
Self-assembly exploits noncovalent interactions to offer a facile and effective method for the construction of soft materials with multifunctionalities and diversity. In this work, fluorescence carbon quantum dots coordinated by Ce3+ ions (CQDCe) have been synthesized and exploited as building blocks to generate a series of hierarchical structures through the ionic self-assembly of CQDCe and biomolecules, namely DNA, myoglobin (Mb), and hyaluronic acid (HA). In particular, vesicles can be constructed by the simple mixing of oppositely charged CQDCe and DNA in water. The formation of unusual vesicles can be explained by the self-assembly of CQDCe with a rearranged structure and the rigid DNA biomolecular scaffolds. This facile noncovalent self-assembly method has inspired the innovative use of virgin DNA as a building block to construct vesicles rather than resorting to a sophisticated synthesis. The self-assembly of CQDCe-biopolymers was accompanied by aggregation-induced photoluminescence (PL) quenching. The biosensing platform was designed to detect polypeptides and deoxyribonuclease I through competitive binding of CQDCe and enzymatic hydrolysis of the DNA backbone, respectively. We believe that the integrative self-assembly of CQDCe and DNA will enrich the theoretical study of vesicle formation by DNA molecules and extend the application of fluorescence carbon quantum dots in the biological field.


Mathematical approach to nonlocal interactions using a reaction-diffusion system.
In recent years, spatial long range interactions during developmental processes have been introduced as a result of the integration of microscopic information, such as molecular events and signaling networks. They are often called nonlocal interactions. If the profile of a nonlocal interaction is determined by experiments, we can easily investigate how patterns generate by numerical simulations without detailed microscopic events. Thus, nonlocal interactions are useful tools to understand complex biosystems. However, nonlocal interactions are often inconvenient for observing specific mechanisms because of the integration of information. Accordingly, we proposed a new method that could convert nonlocal interactions into a reaction-diffusion system with auxiliary unknown variables. In this review, by introducing biological and mathematical studies related to nonlocal interactions, we will present the heuristic understanding of nonlocal interactions using a reaction-diffusion system.


Transforming psychotherapy in order to succeed with adolescent boys: male-friendly practices.
The purpose of this article is to describe a "male-friendly" therapeutic process with troubled adolescent boys. A male-friendly process is one in which the therapist employs a wide variety of strategies and activities that are likely to appeal to male youth and that facilitate the establishment and maintenance of rapport. The nuances of practicing a male-friendly approach are highlighted and then applied in a case study of psychotherapy with a depressed adolescent boy. The implications of this approach for redefining professional conceptions about boundaries in the client-therapist relationship and reexamining inaccurate stereotypes about the emotional lives of boys are discussed.


Use of high performance liquid chromatography in defining the abnormalities in the free amino acid patterns in the cerebrospinal fluid of patients with aseptic meningitis.
Free amino acids were quantitatively determined in cerebrospinal fluid (CSF) and plasma samples from patients with aseptic meningitis by a newly developed high performance liquid chromatographic (HPLC) method. The method of analysis was based on precolumn derivatization of orthophthaladehyde in the presence of 2-mercaptoethanol and detection was made at Eex = 340 nm and Eem = 450 nm. The method was sensitive and the limit for detection was less than 1 pmol for most of the amino acids. It took 45 min to separate 26 amino acids with highly reproducible results, giving a coefficient of variance for retention times and integrated areas less than 0.4% and 2%, respectively, after five replicate runs. The results accumulated in 10 patients were compared statistically with 11 age-matched healthy controls. Among the amino acids almost all the neurotransmitter candidates, such as aspartic acid, glutamic acid, glutamine, glycine, tyrosine, phenylalanine and gamma-aminobutyric acid (GABA), were significantly increased in the patients' CSF, whereas arginine and threonine were low. No change was observed in plasma amino acids in patients as compared to healthy controls. The higher levels of most of the neurotransmitters, especially GABA, aspartic acid and glutamic acid, could be used diagnostically in assessing the progression and remission in aseptic meningitis.


Casein kinases I of the silkworm, Bombyx mori: their possible roles in circadian timing and developmental determination.
Doubletime (DBT), a homolog of casein kinase Iepsilon (CKIepsilon), is an essential circadian clock component and developmental regulator in Drosophila melanogaster. The authors cloned a dbt homolog from the silkworm, Bombyx mori(Bmdbt), and examined its spatial and temporal expression in comparison to a CKI[alpha] homolog (BmCKIalpha). Four Bmdbt splice variants and 2 BmCKIalpha splice variants were detected, and their expression patterns varied in different tissues. The level of Bmdbt transcript in the brain was constant under LD 12:12 while those of BmCKIalpha transcripts fluctuated with a decrease at ZT12. In situ hybridization showed presumably identical distribution of dbt, CKIalpha, and per transcripts in the putative clock neurons of the head ganglia, as well as in the retina, where CKI-and PER-like immunoreactivities were colocalized, suggesting a possible involvement of both CKIs in the B. mori circadian system. Signals were detected at 4 Ia(1) neurons in each dorsolateral protocerebrum, 6 to 8 cells in the pars intercerebralis, about 6 cells in the suboesophageal ganglion, 2 neurons in the frontal ganglion, and most of the photoreceptors. All these cells contained dbt, CKIalpha, and per antisense transcripts. The Northern analysis of dbtand CKIalpha transcripts at different developmental stages showed that both genes were expressed at relatively high levels during early embryogenesis and in the ovary. The levels of CKIalpha transcripts were also high in the late larval stages until the mid-fifth instar and then suddenly disappeared before larval-pupal ecdysis. In contrast, the transcriptional activity of both genes was low in diapausing eggs.


Abnormal long-range spatial interactions in amblyopia.
Neural interactions between widely separated stimuli were explored with psychophysical and visual evoked potential (VEP) measures in normal and amblyopic observers. Contrast detection thresholds were measured psychophysically for small foveally viewed Gabor patches presented in isolation and in the presence of similar, but laterally displaced flanks. The amplitude and phase of VEPs elicited by similar targets were also measured. The presence of neural interaction between the target and flank responses was assessed by comparing the unflanked threshold to the flanked threshold in the psychophysical experiments and by comparing the response predicted by the algebraic sum of test and flank responses to that measured when test and flanks were presented simultaneously. In normal observers simultaneous presentation of test and flank targets produces a VEP response that is up to a factor of two larger than the linear prediction (facilitation). Psychophysical threshold is also facilitated by a comparable factor. Facilitation was found mainly for configurations in which local (carrier) and global (patch) orientations resulted in collinearity, independent of global orientation (meridian). Amblyopic observers showed several deviations from the normal pattern. The facilitation for the collinear configurations was either markedly lower than normal or was replaced by inhibition. The normal pattern of spatial interaction may facilitate the grouping of collinear line segments into smooth curves. In contrast, abnormal long-range spatial interactions may underlie the grouping disorders and perceptual distortions found in amblyopia.


Biomechanics and biocompatibility of woven spider silk meshes during remodeling in a rodent fascia replacement model.
The aim of this study was to investigate biomechanical and immunogenic properties of spider silk meshes implanted as fascia replacement in a rat in vivo model. Meshes for hernia repair require optimal characteristics with regard to strength, elasticity, and cytocompatibility. Spider silk as a biomaterial with outstanding mechanical properties is potentially suitable for this application. Commercially available meshes used for hernia repair (Surgisis and Ultrapro) were compared with handwoven meshes manufactured from native dragline silk of Nephila spp. All meshes were tied onto the paravertebral fascia, whereas sham-operated rats were sutured without mesh implantation. After 4 or 14 days, 4 weeks, and 4 or 8 months, tissue samples were analyzed concerning inflammation and biointegration both by histological and biochemical methods and by biomechanical stability tests. Histological sections revealed rapid cell migration into the spider silk meshes with increased numbers of giant cells compared with controls with initial decomposition of silk fibers after 4 weeks. Four months postoperatively, spider silk was completely degraded with the formation of a stable scar verified by constant tensile strength values. Surgisis elicited excessive stability loss from day 4 to day 14 (P < 0.001), with distinct inflammatory reaction demonstrated by lymphocyte and neutrophil invasion. Ultrapro also showed decreasing strength and poor elongation behavior, whereas spider silk samples had the highest relative elongation (P < 0.05). Hand-manufactured spider silk meshes with good biocompatibility and beneficial mechanical properties seem superior to standard biological and synthetic meshes, implying an innovative alternative to currently used meshes for hernia repair.


Interaction of human PD-L1 and B7-1.
Numerous studies have pointed to the role of programmed death-1 ligand 1 (PD-L1) in regulating tolerance, chronic infection, and tumor immunity. Recently, we have identified murine B7-1 as a new binding partner for murine PD-L1. Human and mouse B7-1 share only 46% identity, leading us to question whether human B7-1 and PD-L1 can participate in a similar interaction. Here we show that human B7-1 can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. We characterize a series of anti-human PD-L1 monoclonal antibodies and identify antibodies that can block interactions of PD-L1 with B7-1, PD-1, or both. Since PD-L1 and CD28 on T cells may compete for B7-1 as a binding partner and CD8 T cells may express high or low levels of CD28, we examined when PD-L1 and CD28 are co-expressed on CD8 T cells. We compared the time-course and extent of PD-L1 induction on CD8 CD28high versus CD28low T cells following stimulation with anti-CD3. We show that PD-L1 is induced to a higher level on CD28high T cells than on CD28low T cells upon activation. These results suggest that PD-L1 may play an important and undervalued role on human T cells.


[Preparation and characterization of the mAb against Vibrio harveyi].
To prepare the mAb against Vibrio harveyi and analyse their biological properties. 8-week-old female BALB/c mice were immunized with pathogenic V.harveyi GYC1108-1, which was isolated from the diseased great yellow croaker in Zhejiang China in 2003. Spleen cells collected from the immunized mice after the fifth immunization were fused with Sp2/0-Ag-14 myeloma cells. ELISA was used to screen hybridoma cells and identify the specificity and sensitivity of mAbs. Limited dilution method was used to subclone the positive clones. After three cycles of subcloning, 5 mAbs against GYC1108-1 were obtained and were proved to have high titer of ELISA. The test of specificity suggested that 1B7 reacted on V.harveyi, V.alginolyticus and V.parahaemolyticus but did not react on V.mimicus, V.anguillarum, Aeromonas hydrophila and the other isolates among the 14 bacterium species tested. 1B7 was used to detect V.harveyi at the concentration of 10(4) CFU/mL by indirect ELISA. The obtained mAbs could be used to diagnosis and prevent of V.harveyi in aquaculture rapidly.


Ultrasound Hepatic Vein Ratios Are Associated With the Development of Acute Kidney Injury After Cardiac Surgery.
The authors investigated the use of hepatic venous and right-heart ultrasound parameters in predicting cardiac surgery-associated acute kidney injury (AKI). This was a prospective, contextual, descriptive two-center study. Blood tests,clinical and ultrasound data were obtained preoperatively, and postoperative day one, and day four. The hepatic vein, inferior vena cava, and right-heart Doppler ultrasound parameters were obtained and analyzed. The sites of the study were Johannesburg, South Africa, and Aarhus, Denmark. Adult patients who satisfied inclusion criteria, between August 2019 and January 2020, were included, with a total of 152 participants. None. The median (interquartile range) age of patients was 68 (55-73) years, predominantly male, and the majority were hypertensive. Of 152 patients analyzed, 54 (35%) patients developed AKI. Among these, 37 (69%) were classified as Kidney Disease: Improving Global Outcomes (KDIGO) stage I, 11 (20%) as stage II, while six (11%) were stage III. Age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.00-1.10 p = 0.031), The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (AOR 1.43, 95% CI 1.14-1.80, p = 0.005], and preoperative serum creatinine (AOR 1.04, 95% CI 1.01-1.08, p = 0.013) were predictive of AKI. Those who developed AKI had experienced longer cardiopulmonary bypass (CPB) times (p < 0.001). Preoperatively, hepatic vein S-wave measurements were significantly higher in patients with AKI (p < 0.05). On postoperative day one (D1), the hepatic vein flow ratios of patients with AKI were significantly decreased, driven by low S waves and high D waves, and accompanied by significantly elevated central venous pressure (CVP) levels. CVP levels on D1 postoperatively were predictive of AKI (AOR 1.31, 95% CI 1.11-1.55, p = 0.001). Measurements of right ventricular (RV) base, tricuspid annular plane excursion (TAPSE), and inferior vena cava were not associated with the development of AKI (p > 0.05). There was an association between the development of AKI and a decrease in hepatic flow ratios on D1, driven by low S-wave and high D-wave velocities. The presence of venous congestion was reflected by significantly elevated CVP values, which were independently associated with AKI on D1. RV base and TAPSE measurements were, however, not associated with AKI. These parameters may reflect perioperative circumstances, including prolonged CPB times and potential fluid management, which can be modified in this period.


Skin microbiome alterations in seborrheic dermatitis and dandruff: A systematic review.
Seborrheic dermatitis (SD) and dandruff (DF) are common chronic inflammatory skin diseases characterized by recurrent greasy scales, sometimes with erythema and itchiness. Although the exact pathophysiology of the disease is still unclear, current theories highlight the role of microbes on the skin surface in the pathogenesis of SD. Here, we conducted a systematic review to investigate the skin microbiome alterations in patients with SD/DF. We searched Medline/PubMed, Embase and Web of Science for research studies published in English between 1 January 2000 and 31 December 2020. A total of 12 studies with 706 SD/DF samples and 379 healthy samples were included in this study. The scalp and face were predominated by the fungi of Ascomycota and Basidiomycota and the bacteria of Actinobacteria and Firmicutes. In general, the included studies demonstrated an increased Malassezia restricta/Malassezia globosa ratio and a reduction in the Cutibaterium/Staphylococcus ratio in the setting of SD/DF. Staphylococcus was associated with epidermal barrier damage, including elevated levels of trans-epidermal water loss and pH, while Cutibacterium had a positive correlation with water content. Malassezia was also found to be related to an increased itching score and disease severity. Further studies focusing on the interactions between various microbes and the host and microbes can help us to better understand the pathogenesis of SD/DF.


Spontaneous aberrant right subclavian arterio-oesophageal fistula in a previously healthy child.
An aberrant right subclavian artery arising from a left aortic arch is the most frequently described congenital aortic arch anomaly, occurring in 0.5 to 2.3% of the general population. Despite the retro-oesophageal course of the aberrant subclavian artery, an arterio-oesophageal fistula is an uncommon finding, only previously reported as a very rare complication in critically ill patients with oesophageal instrumentation or foreign body ingestion. We describe a unique case of a spontaneous aberrant right subclavian arterio-oesophageal fistula without an inciting event in a 17-month-child.


Transmission of ATLV (HTLV-I) through blood transfusion.
In a follow-up of blood recipients, antibodies against adult T-cell leukemia antigen (anti-ATLA) were found in those who had received blood preparations containing cells. Detection of lymphocytes carrying viral antigen of ATLV (human T-cell leukemia virus type I (HTLV-I) ) in seroconverted recipients and the appearance of the viral antigen in cord blood lymphocytes co-cultured with a T-cell clone of a seroconverted recipient strongly suggested that the virus was transmitted through blood transfusion. Screening of blood donors by testing their antibodies against the virus is necessary to prevent future transmission through transfusion, and should be done even if such transmission does not result in the development of adult T-cell leukemia.


The positive and negative regulation of Tn10 transposition by IHF is mediated by structurally asymmetric transposon arms.
The Tn10 transpososome has symmetrical components on either side: there are two transposon ends each of which has binding sites for a monomer of transposase and an IHF heterodimer. The DNA bending activity of IHF stimulates assembly of an intermediate with tightly folded transposon ends in which transposase has additional 'subterminal' DNA contacts, located distal to the IHF site. These subterminal contacts are required to activate later steps in the reaction. Quantitative hydroxyl radical footprinting and gel retardation unfolding experiments show that the transpososome is fundamentally asymmetric, despite having identical components on either side. Major differences between the transposon ends define alpha and beta sides of the complex. IHF can dissociate from the transposon arm on the beta side of the complex in the absence of metal ion. However, IHF is locked onto the alpha side of the complex, probably by the subterminal transposase contacts, until released by a metal ion-dependent conformational change. Later in the reaction, IHF inhibits target interactions. Using a very short transposon arm, target interactions are demonstrated at a saturating IHF concentration. This suggests that inhibition of target interactions is due to steric hindrance of the target binding site by a single IHF-folded transposon arm.


Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies.
Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease whose incidence has risen worldwide in recent years. Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of IBD. This review highlights the generation of reactive oxygen species (ROS) and antioxidant defense mechanisms in the gastrointestinal (GI) tract, the involvement of oxidative stress signaling in the initiation and progression of IBD and its relationships with genetic susceptibility and the mucosal immune response. In addition, potential therapeutic strategies for IBD that target oxidative stress signaling are reviewed and discussed. Though substantial progress has been made in understanding the role of oxidative stress in IBD in humans and experimental animals, the underlying mechanisms are still not well defined. Thus, further studies are needed to validate how oxidative stress signaling is involved in and contributes to the development of IBD.


Effect of desferrioxamine on aluminum kinetics during hemodialysis.
The effects of desferrioxamine administration on aluminum kinetics during hemodialysis were studied. Desferrioxamine leads to an increase of plasma aluminum levels in patients on chronic hemodialysis which could be attributed to mobilization of tissue aluminum. The in vivo protein binding of aluminum was found to be 70% after administration of desferrioxamine vs. 80% without a premedication with desferrioxamine, thus greatly enhancing the concentration gradient between free diffusible plasma aluminum and dialysate aluminum. Desferrioxamine therefore leads to increased aluminum removal during hemodialysis and should be considered in the therapy of aluminum toxicity syndromes.


Assessment of mandibular bone mineral density in patients with type 2 diabetes mellitus.
To assess mandibular bone mineral density in patients with type 2 diabetes mellitus using panoramic radiographs. Nineteen patients with type 2 diabetes mellitus and 17 control subjects participated in the study. Bone mineral density measurements were performed on the panoramic radiographs with the help of a five-step copper stepwedge phantom, attached to each film cassette, which was calibrated before hand by dual energy X-ray absorptiometry (DXA). The analysis was performed on digitized images by dedicated software (Scion Image). The accuracy of the measurement technique was also evaluated by cross-calibration with a DXA phantom. Mean mandibular bone mineral density (g cm(-2)) was 1.53+/-0.27 in women and 1.52+/-0.29 in men with type 2 diabetes. In age and gender matched control subjects the values were 1.56+/-0.28 and 1.46+/-0.23 in women and in men, respectively. No statistically significant difference was observed between groups in mandibular bone mineral density. The present study showed that bone mineral density of the mandible does not seem to be affected in patients with type 2 diabetes mellitus. We also observed that a panoramic radiograph could serve for accurate mandibular bone density determination, when calibrated well with the DXA method.


Extensive craniofacial subcutaneous emphysema after evacuation of a chronic subdural haematoma.
An unusual complication of craniofacial subcutaneous emphysema after evacuation of a chronic subdural haematoma is reported. The emphysema caused massive swelling and deformity of the patient's head and face, as well as the occlusion of both eyes, and it resolved spontaneously. The possible mechanisms of development of emphysema are discussed.


Nivolumab-induced tumour-like gastritis: A case report.
Immune checkpoint inhibitors are one of the modern treatment methods for advanced malignancies. However, this group of medications is also associated with various immune-related adverse events, such as colitis or pneumonitis. Immune checkpoint inhibitor-induced gastritis is a less common adverse event. We describe a 64-year-old woman presenting with diarrhea, nausea, and discomfort in the upper abdominal region. The patient had a history of metastatic lung cancer, which was treated with nivolumab. During the first endoscopy, an infiltrating gastric tumour was suspected. Later, based on endoscopic, histological and radiological findings, nivolumab-induced gastritis was diagnosed. The patient was successfully treated with three courses of omeprazole. As a consequence of the increased use of immune checkpoint inhibitors, a growing number of reported immune-related adverse events could be expected. The diagnosis of immune checkpoint inhibitor-induced gastritis should be considered when assessing a patient treated with nivolumab with upper gastrointestinal distress.


Maternal anemia during pregnancy is an independent risk factor for low birthweight and preterm delivery.
The present study was designed to investigate the outcome of pregnancy and delivery in patients with anemia. A retrospective population-based study comparing all singleton pregnancies of patients with and without anemia was performed. Deliveries occurred during the years 1988-2002 in the Soroka University Medical Center. Maternal anemia was defined as hemoglobin concentration lower than 10 g/dl during pregnancy. Patients with hemoglobinopathies such as thalassemia were excluded from the analysis. Multiple logistic regression models were performed to control for confounders. During the study period there were 153,396 deliveries, of which 13,204 (8.6%) occurred in patients with anemia. In a multivariable analysis, the following conditions were significantly associated with maternal anemia: placental abruption, placenta previa, labor induction, previous cesarean section (CS), non-vertex presentation and Bedouin ethnicity. Higher rates of preterm deliveries (<37 weeks gestation) and low birthweight (<2500 g) were found among patients with anemia as compared to the non-anemic women (10.7% versus 9.0%, p < 0.001 and 10.5% versus 9.4%, p < 0.001; respectively). Higher rates of CS were found among anemic women (20.4% versus 10.3%; p < 0.001). The significant association between anemia and low birthweight persisted after adjusting for gender, ethnicity and gestational age, using a multivariable analysis (OR = 1.1; 95% CI 1.0-1.2, p = 0.02). Two multivariable logistic regression models, with preterm delivery (<37 weeks gestation) and low birthweight (<2500 g) as the outcome variables, were constructed in order to control for possible confounders such as ethnicity, maternal age, placental problems, mode of delivery and non-vertex presentation. Maternal anemia was an independent risk factor for both, preterm delivery (OR = 1.2; 95% CI 1.1-1.2, p < 0.001) and low birthweight (OR = 1.1; 95% CI 1.1-1.2, p = 0.001). Maternal anemia influences birthweight and preterm delivery, but in our population, is not associated with adverse perinatal outcome.


Shikonin inhibits proliferation, migration, invasion and promotes apoptosis in NCI-N87 cells via inhibition of PI3K/AKT signal pathway.
Shikonin has been testified to wield the anti-tumor action in multiple cancers. But, the clout of Shikonin for gastric cancer (GC) is still inconclusive. The contemplation of this research undertook to disclose the impacts of Shikonin on GC progress meanwhile to uncover the conceivable mechanism. NCI-N87 cells were disposed by Shikonin at diverse concentration points. The trials of CCK-8, colony formation, flow cytometry and Transwell assays were executed for detecting the functions of Shikonin in NCI-N87 cells. The impacts of miR-195 on Shikonin-regulated PI3K/AKT pathway were estimated via western blot. The in vivo trial was detected by xenografts model assay. We found that Shikonin suppressed cell survival and triggered apoptosis in NCI-N87 cells. Additionally, Shikonin restrained cell migration, invasion and down-regulated MMP2, RhoA, ROCK1 and Vimentin expression in NCI-N87 cells. Furthermore, Shikonin notably inhibited PI3K/AKT signal pathway, but the restraining functions were repealed by miR-195 inhibition in NCI-N87 cells. The in vivo trial results revealed that Shikonin determinately impeded tumor formation. In conclusion, these results demonstrated that Shikonin prohibited NCI-N87 cells proliferation, migration, invasion, and accelerated apoptosis by inactivation of PI3K/AKT pathway. The findings maybe provide a fresh opinion for healing GC.


Late results of optical urethrotomy.
Of 46 patients who underwent optical urethrotomy for differing strictures of the urethra, 41 (89.1%) remained free of stricture symptoms at follow up 6 years later. The initial effectiveness of this procedure in improving stricture symptoms is sustained in the long term.


Silica-based nanoparticles: a versatile tool for the development of efficient imaging agents.
This review describes the recent advances in the development of imaging agents based on silica nanoparticles. Different techniques (magnetic resonance imaging, optical imaging, positron emission tomography, X-ray computed tomography, and ultrasound imaging) are described as well as the possibility of combining together different imaging techniques in the same nanoplatform and simultaneously performing imaging and therapy.


Pulmonary recovery after COVID-19 - a review.
COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). As the respiratory tract is the primary site of infection and host-mediated inflammatory responses, pathologies and dysfunction of the respiratory system characterize the severe disease and are typically associated with the need for oxygen supply or even ventilator support. In survivors of severe COVID-19, computed tomography follow-up frequently reveals structural lung abnormalities, and one-third of individuals who were hospitalized during acute COVID-19 demonstrate persisting lung abnormalities for at least 12 months after disease onset. This review summarizes current evidence on pulmonary recovery after COVID-19, focusing on adult patients who suffered from COVID-19 pneumonia. Severe COVID-19 is associated with a high frequency of persisting lung abnormalities at follow-up. The long-term consequences of these findings remain elusive and urge further evaluation to identify individuals at risk for COVID-19 long-term consequences.


Erythropoietin in patients undergoing coronary artery bypass graft surgery.
Recombinant human erythropoietin (rHuEPO) has proved to be a useful drug that can aid in protecting patients from possible hazards of homologous blood. Use of rHuEPO for patients scheduled for coronary artery bypass graft (CABG) surgery can enhance the benefit of a preoperative autologous blood donation program while simultaneously minimizing its risks. The main objective are to decrease homologous transfusion requirements by increasing the amount of collected autologous blood and to maximize safety by ameliorating a pre- or postoperative anemia. The goal of this review is to assess the possible benefits of perioperative use of rHuEPO during CABG surgery. Furthermore, we evaluate its ability to augment the quality of collected blood and to lower the risk of autologous blood donation. Side effects, dosages, manner of administration, concomitant iron therapy and suggestions for special patient groups will be discussed.


Predictive position computations mediated by parietal areas: TMS evidence.
When objects move or the eyes move, the visual system can predict the consequence and generate a percept of the target at its new position. This predictive localization may depend on eye movement control in the frontal eye fields (FEF) and the intraparietal sulcus (IPS) and on motion analysis in the medial temporal area (MT). Across two experiments we examined whether repetitive transcranial magnetic stimulation (rTMS) over right FEF, right IPS, right MT, and a control site, peripheral V1/V2, diminished participants' perception of two cases of predictive position perception: trans-saccadic fusion, and the flash grab illusion, both presented in the contralateral visual field. In trans-saccadic fusion trials, participants saccade toward a stimulus that is replaced with another stimulus during the saccade. Frequently, predictive position mechanisms lead to a fused percept of pre- and post-saccade stimuli (Paeye et al., 2017). We found that rTMS to IPS significantly decreased the frequency of perceiving trans-saccadic fusion within the first 10min after stimulation. In the flash grab illusion, a target is flashed on a moving background leading to the percept that the target has shifted in the direction of the motion after the flash (Cavanagh and Anstis, 2013). In the first experiment, the reduction in the flash grab illusion after rTMS to IPS and FEF did not reach significance. In the second experiment, using a stronger version of the flash grab, the illusory shift did decrease significantly after rTMS to IPS although not after rTMS to FEF or to MT. These findings suggest that right IPS contributes to predictive position perception during saccades and motion processing in the contralateral visual field.


Establishment of the early-life microbiome: a DOHaD perspective.
The human microbiome plays a number of critical roles in host physiology. Evidence from longitudinal cohort studies and animal models strongly supports the theory that maldevelopment of the microbiome in early life can programme later-life disease. The early-life microbiome develops in a clear stepwise manner over the first 3 years of life. During this highly dynamic time, insults such as antibiotic use and formula feeding can adversely affect the composition and temporal development of the microbiome. Such experiences predispose infants for the development of chronic health conditions later in life. This review highlights key factors that disrupt the early-life microbiome and highlights major non-communicable diseases which are underpinned by early-life dysbiosis.


Isolation of an adenovirus antigenically distinct from equine adenovirus type 1 from diarrheic foal feces.
Adenovirus was isolated in equine fetal kidney cell cultures from the feces of 2 foals with diarrhea that also had large numbers (greater than 10(6)/g) of rotavirus particles in their feces. Unlike equine adenovirus type 1 (EAdV1), the fecal EAdV did not hemagglutinate human O, rhesus macaque, or equine RBC. By serum neutralization, the fecal viruses were identical with each other, but showed no relationship to EAdV1. Antiserum prepared against the fecal viruses did not contain hemagglutination-inhibiting antibody to EAdV1. It is proposed that the fecal viruses be considered prototypic of EAdV2. The frequency of neutralizing antibody to EAdV2 in 339 equine serum samples was 77%. Neither EAdV1 nor EAdV2 is related by serum neutralization to any of 30 human adenovirus serotypes.


Lunasin ameliorates glucose utilization in C2C12 myotubes and metabolites profile in diet-induced obese mice benefiting metabolic disorders.
Obesity is the main cause of low-grade inflammation and oxidation, resulting in insulin resistance. This study aimed to investigate the effects of a seed peptide lunasin on glucose utilization in C2C12 myotubes and the metabolite profiles in obese mice. C2C12 myotubes were challenged by palmitic acid (PA) to mimic the obese microenvironment and inflammation, cell vitality, and glucose utilization were determined. C57BL6/j mice were divided into low-fat diet (LF), high-fat diet (HF), and HF with intraperitoneally injected lunasin (HFL) groups. Glucose intolerance and metabolite profiles of the tissues were analyzed. In vitro, C2C12 myotubes treated with lunasin showed decreased proinflammatory cytokines and increased cell vitality under palmitic acid conditions. Lunasin improved glucose uptake and glucose transporter 4 expression by activating insulin receptor substrate-1 and AKT phosphorylation. Next-generation sequencing revealed that lunasin regulates genes expression by promoting insulin secretion and decreasing oxidative stress. In vivo, HF mice showed increased tricarboxylic acid cycle and uric acid metabolites but decreased bile acids metabolites and specific amino acids. Lunasin intervention improved glucose intolerance and modulated metabolites associated with increased insulin sensitivity and decreased metabolic disorders. This study is the first to reveal that lunasin is a promising regulator of anti-inflammation, anti-oxidation, and glucose utilization in myotubes and ameliorating glucose uptake and metabolite profiles in obese mice, contributing to glucose homeostasis and benefiting metabolic disorders.


Benefits of the Mediterranean diet: Epidemiological and molecular aspects.
More than 50 years after the Seven Countries Study, a large number of epidemiological studies have explored the relationship between the Mediterranean diet (MD) and health, through observational, case-control, some longitudinal and a few experimental studies. The overall results show strong evidence suggesting a protective effect of the MD mainly on the risk of cardiovascular disease (CVD) and certain types of cancer. The beneficial effects have been attributed to the types of food consumed, total dietary pattern, components in the food, cooking techniques, eating behaviors and lifestyle behaviors, among others. The aim of this article is to review and summarize the knowledge derived from the literature focusing on the benefits of the MD on health, including those that have been extensively investigated (CVD, cancer) along with more recent issues such as mental health, immunity, quality of life, etc. The review begins with a brief description of the MD and its components. Then we present a review of studies evaluating metabolic biomarkers and genotypes in relation to the MD. Other sections are dedicated to observation and intervention studies for various pathologies. Finally, some insights into the relationship between the MD and sustainability are explored. In conclusion, the research undertaken on metabolomics approaches has identified potential markers for certain MD components and patterns, but more investigation is needed to obtain valid measures. Further evaluation of gene-MD interactions are also required to better understand the mechanisms by which the MD diet exerts its beneficial effects on health. Observation and intervention studies, particularly PREDIMED, have provided invaluable data on the benefits of the MD for a wide range of chronic diseases. However further research is needed to explore the effects of other lifestyle components associated with Mediterranean populations, its environmental impact, as well as the MD extrapolation to non-Mediterranean contexts.


Coherence resonance versus synchronization in a periodically forced self-sustained system.
A fundamental relationship between coherence resonance (CR) and phase synchronization in a self-sustained system in the presence of noise is addressed. A Van der Pol system synchronized by external forcing is taken as an example. It is shown that, in breaking down synchronization, applied noise creates a new ordered motion whose coherence depends resonantly on its intensity, i.e., CR occurs. The same is true for both types of synchronization, via phase locking and via suppression: only the mechanisms of CR differ. The result is valid for any order n:m of synchronization.


Impairment of skin capillary recruitment precedes chronic complications in patients with type 1 diabetes.
Microvascular function in patients with type 1 diabetes without chronic complications was assessed using skin capillary recruitment during post-occlusive reactive hyperemia (PORH). Structural (maximal) capillary density was evaluated during venous occlusion. The study included 48 consecutive outpatients aged 26.3 +/- 10.8 years with type 1 diabetes (duration of 9.5 years) without chronic complications and 34 control subjects. Intravital capillary video-microscopy was used in the dynamic study of skin capillaries in the dorsum of the fingers and toes. Capillary recruitment during PORH (% increase in mean capillary density, MCD) was significantly higher in the controls than the patients in both the fingers (p < 0.001) and toes (p < 0.001). During venous occlusion, MCD increase was also higher in the controls than the patients in both the fingers (p < 0.05) and toes (p < 0.0001). In patients, no difference was found between MCD at baseline and after venous occlusion in the fingers but a decrease was observed in the toes (p < 0.001). It is concluded that skin capillary function is significantly impaired in both fingers and toes of patients with type 1 diabetes without chronic complications. Moreover, capillary density during venous occlusion did not increase in either extremity in the patients, suggesting that their capillaries at rest are already maximally recruited.


[A Case of Central-Type Disc Herniation at the C7/T1 Level Presenting with Myelopathy].
In contrast to other levels of upper disc spaces, the Luschka joints are usually absent at the C7/T1 disc space. Therefore, it has been reported that the C7/T1 disc herniation is prone to herniate laterally rather than centrally. In this manuscript, we describe an extremely rare central-type disc herniation at the C7/T1 level presented with myelopathy. A 76-year-old man presented with a 20-day history of progressive gait disturbance. Physical examination revealed bilateral lower extremity hyperreflexia and mild foot numbness with no upper extremity motor weakness or sensory disturbance. Cervical magnetic resonance imaging(MRI)revealed severe spinal cord compression at the C7/T1 level caused by a central-type disc herniation. We removed the herniated disc and performed anterior fusion with a titanium box cage. Lower extremity numbness and weakness diminished rapidly. Three weeks later, cervical MRI showed a well-decompressed spinal cord and almost normal gait. We reevaluated the preoperative computed tomography of this patient and confirmed the absence of Luschka joints at the C7/T1 level. Although the condition is rare, clinicians should consider the possibility of C7/T1 disc herniation in patients with leg weakness or numbness but no or few hand-related symptoms.


Transarterial chemoembolization combined with recombinant human adenovirus type 5 H101 prolongs overall survival of patients with intermediate to advanced hepatocellular carcinoma: a prognostic nomogram study.
Patients with intermediate to advanced hepatocellular carcinoma (HCC) are most commonly treated with transarterial chemoembolization (TACE). Previous studies showed that TACE combined with recombinant human adenovirus type 5 (H101) may provide a clinical survival benefit. In the present study, we aimed to determine the survival benefit of TACE with or without H101 for patients with intermediate to advanced HCC and to develop an effective nomogram for predicting individual survival outcomes of these patients. We retrospectively collected data from 590 patients with intermediate to advanced HCC who were treated at Sun Yat-sen University Cancer Center between January 2007 and July 2015. After propensity score matching, 238 patients who received TACE with H101 (TACE with H101 group) and 238 patients who received TACE without H101 (TACE group) were analyzed. Overall survival (OS) was evaluated using the Kaplan-Meier method; the nomogram was developed based on Cox regression analysis. Discrimination and calibration were measured using the concordance index (c-index) and calibration plots. Clinical and radiologic features were similar between the two groups. OS rates were significantly lower in the TACE group than in the TACE with H101 group (1-year OS rate, 53.8% vs. 61.3%; 2-year OS rate, 33.4% vs. 44.2%; 3-year OS rate, 22.4% vs. 40.5%; all P < 0.05). Multivariate Cox regression analysis for the entire cohort showed that alpha-fetoprotein level, alkaline phosphatase level, tumor size, metastasis, vascular invasion, and TACE with or without H101 were independent factors for OS, all of which were included in the nomogram. Calibration curves showed good agreement between nomogram-predicted survival and observed survival. The c-index of the nomogram for predicting OS was 0.716 (95% confidence interval 0.686-0.746). TACE plus H101 extends the survival of patients with intermediate to advanced HCC. Our proposed nomogram provides individual survival prediction and stratification for patients with intermediate to advanced HCC who receive TACE with or without H101.


Sequencing and expression of the CD3 gamma/delta mRNA in Pleurodeles waltl (urodele amphibian).
The CD3 complex is an essential component of the T-cell receptor (TCR) implicated in T-cell maturation and activation. This TCR has been identified in both cartilaginous and bony vertebrates. In different studies where the CD3 chains were cloned and sequenced, it appeared that the CD3 complex is composed of several chains, all susceptible to phosphorylation and able to transduce signals. Here, by an approach combining degenerative oligonucleotide primers and RACE-PCR, we report the cloning and sequencing of a CD3 cDNA from the salamander Pleurodeles waltl, highly homologous to the Xenopus and chicken CD3 gamma/delta cDNAs. Using semi-quantitative PCR and Northern blot analysis, we found the highest CD3 gamma/delta mRNA expression in the thymus; weaker expression was observed in the spleen and blood, followed by the intestine, therefore confirming the tissue and lymphoid specificities of this mRNA. The signals in the spleen, blood and intestine represented 55%, 33% and 16%, respectively, of the signal detected in the thymus. During the embryonic and larval stages of Pleurodeles waltl development, CD3 gamma/delta mRNA expression begins early at the neurula stage (stage 15, 69 h after laying), increases up to stage 33 (9 days after laying) and afterwards remains stable, at least until the larval stage 42 (28 days after laying). As the thymus primordium appears much later, the question of the formation and maturation of the first T-cell precursors outside this organ is posed.


Diagnostic Dilemma in Fatal Paraquat Poisoning: An Autopsy Case Report.
Paraquat is a highly toxic agent used as an herbicide worldwide. Despite its easy and widespread availability, data regarding cases of paraquat poisoning in India is limited. Diagnosis often becomes difficult without a clear history, owing to its rather nonspecific and varying presentation. In the present case, a 22-year-old man was brought with a history of high-grade fever, sore throat, and oral ulcers for around a week. He was symptomatically treated at multiple hospitals and was worked up for suspected diagnoses like diphtheria and influenza (H1N1). Later during treatment, it was revealed that "Paraxzone" was procured online by the patient himself two weeks before the onset of his symptoms. Thence, the treatment regimen was modified following suspicion of paraquat poisoning. However, the delay in diagnosis led to the worsening his condition, and the patient succumbed to death due to pulmonary and renal complications after 16 days of survival. The postmortem examination, supplemented with histopathological evaluation, supported the diagnosis of paraquat poisoning. Paraquat poisoning can mimic a myriad of clinical conditions. Thorough history taking, a high degree of suspicion, and collaborative work with the investigating agency are of paramount importance while dealing with cases of suspected paraquat poisoning in hospital settings.


Revisiting the role of erythropoietin for treatment of ocular disorders.
Erythropoietin (EPO) is a glycoprotein hormone conventionally thought to be responsible only in producing red blood cells in our body. However, with the discovery of the presence of EPO and EPO receptors in the retinal layers, the EPO seems to have physiological roles in the eye. In this review, we revisit the role of EPO in the eye. We look into the biological role of EPO in the development of the eye and the physiologic roles that it has. Apart from that, we seek to understand the mechanisms and pathways of EPO that contributes to the therapeutic and pathological conditions of the various ocular disorders such as diabetic retinopathy, retinopathy of prematurity, glaucoma, age-related macular degeneration, optic neuritis, and retinal detachment. With these understandings, we discuss the clinical applications of EPO for treatment of ocular disorders, modes of administration, EPO formulations, current clinical trials, and its future directions.


General mechanism for RecA protein binding to duplex DNA.
RecA protein binding to duplex DNA occurs by a multi-step process. The tau analysis, originally developed to examine the binding of RNA polymerase to promoter DNA, is adapted here to study two kinetically distinguishable reaction segments of RecA-double stranded (ds) DNA complex formation in greater detail. One, which is probably a rapid preequilibrium in which RecA protein binds weakly to native dsDNA, is found to have the following properties: (1) a sensitivity to pH, involving a net release of approximately one proton; (2) a sensitivity to salts; (3) little or no dependence on temperature; (4) little or no dependence on DNA length. The second reaction segment, the rate-limiting nucleation of nucleoprotein filament formation accompanied by partial DNA unwinding, is found to have the following properties: (1) a sensitivity to pH, involving a net uptake of approximately three protons; (2) a sensitivity to salts; (3) a relatively large dependence on temperature, with an Arrhenius activation energy of 39 kcal mol(-1); (4) a sensitivity to DNA topology; (5) a dependence on DNA length. These results contribute to a general mechanism for RecA protein binding to duplex DNA, which can provide a rationale for the apparent preferential binding to altered DNA structures such as pyrimidine dimers and Z-DNA.


Identification and visualization of cage-shaped proteins.
Cage-shaped protein, with its special structure, may have potential applications in biomedicine and nanotechnology. We developed a program CSPro (Cage-Shaped Protein) for efficient identification of cage-shaped proteins based on quaternary structure. CSPro is capable of revealing the corresponding cage-shaped feature more clearly and quickly than traditional visualization tools. Using CSPro, we have searched the full set of PDB (protein data bank) and three types of proteins are retrieved with notably large central cavities inside. CSPro can be used to validate if the quaternary structure of a protein is cage shaped in molecular simulation. http://www.cad.zju.edu.cn/home/humin


Predicting outcomes following open revascularization for aortoiliac occlusive disease using machine learning.
Open surgical treatment options for aortoiliac occlusive disease carry significant perioperative risks; however, outcome prediction tools remain limited. Using machine learning (ML), we developed automated algorithms that predict 30-day outcomes following open aortoiliac revascularization. The National Surgical Quality Improvement Program (NSQIP) targeted vascular database was used to identify patients who underwent open aortoiliac revascularization for atherosclerotic disease between 2011 and 2021. Input features included 38 preoperative demographic/clinical variables. The primary outcome was 30-day major adverse limb event (MALE; composite of untreated loss of patency, major reintervention, or major amputation) or death. The 30-day secondary outcomes were individual components of the primary outcome, major adverse cardiovascular event (MACE; composite of myocardial infarction, stroke, or death), individual components of MACE, wound complication, bleeding, other morbidity, non-home discharge, and unplanned readmission. Our data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, we trained six ML models using preoperative features. The primary model evaluation metric was area under the receiver operating characteristic curve (AUROC). Model robustness was evaluated with calibration plot and Brier score. Variable importance scores were calculated to determine the top 10 predictive features. Performance was assessed on subgroups based on age, sex, race, ethnicity, symptom status, procedure type, and urgency. Overall, 9649 patients were included. The primary outcome of 30-day MALE or death occurred in 1021 patients (10.6%). Our best performing prediction model for 30-day MALE or death was XGBoost, achieving an AUROC of 0.95 (95% confidence interval [CI], 0.94-0.96). In comparison, logistic regression had an AUROC of 0.79 (95% CI, 0.77-0.81). For 30-day secondary outcomes, XGBoost achieved AUROCs between 0.87 and 0.97 (untreated loss of patency [0.95], major reintervention [0.88], major amputation [0.96], death [0.97], MACE [0.95], myocardial infarction [0.88], stroke [0.93], wound complication [0.94], bleeding [0.87], other morbidity [0.96], non-home discharge [0.90], and unplanned readmission [0.91]). The calibration plot showed good agreement between predicted and observed event probabilities with a Brier score of 0.05. The strongest predictive feature in our algorithm was chronic limb-threatening ischemia. Model performance remained robust on all subgroup analyses of specific demographic/clinical populations. Our ML models accurately predict 30-day outcomes following open aortoiliac revascularization using preoperative data, performing better than logistic regression. They have potential for important utility in guiding risk-mitigation strategies for patients being considered for open aortoiliac revascularization to improve outcomes.


The calcium antagonists PY 108-068 and verapamil diminish the effects of angiotensin II: sites of interaction in the peripheral circulation of anaesthetized cats.
The sites of interaction between the vasoconstrictor angiotensin II (A II) and the calcium antagonists PY 108-068 (PY) (a dihydropyridine derivative) or verapamil (V) in different peripheral vascular beds were investigated using the microsphere method in chloralose-urethane anaesthetized open-chested cats. A II was infused intravenously into 27 cats at a rate of 0.15 microgram kg-1 min-1. Systemic haemodynamic variables and regional blood flow were measured immediately before and 10 min after the start of the infusion. While the infusion of A II continued, PY (3 micrograms kg-1 min-1), V (30 micrograms kg-1 min-1) or the vehicle was infused for 10 min into 9 cats each and the effects of this combined infusion were again measured at the end of the 10 min period. A II increased mean arterial blood pressure but decreased peripheral conductance and, to a smaller but still significant degree, cardiac output and peak acceleration of blood in the aorta (an ejection phase parameter of myocardial contractility). The calcium antagonists reversed these effects. Cardiac output and total peripheral conductance were increased even beyond the pre-A II level by PY. A II constricted the vascular beds of the kidney, small intestine, liver and skin. Arterio-venous shunt flow decreased. Vasoconstriction was also found in the stomach, spleen and in different parts of the heart with the exception of the subendocardial layer of the left ventricle, where blood flow increased and conductance remained unchanged. A II did not decrease conductance in different parts of the brain or in skeletal muscle. The vasoconstrictor effects of A II persisted or tended to be increased in most of the vascular beds of placebo treated animals. PY 108-068 and verapamil abolished the vasoconstrictor effects of A II in most of the vascular beds with the exception of the liver, the spleen, the skin and the arterio-venous shunts and caused vasodilatation in the heart. PY also induced vasodilatation in the brain and skeletal muscle, where A II had not induced vasoconstriction. The pattern of attenuation of A II effects was different from the pattern of vasodilatation induced by these and other calcium antagonists in the same cat preparation not treated with a vasoconstrictor. The sites of action of this dihydropyridine derivative (PY) on the peripheral circulation thus, appear to depend not only on the vascular bed but also on the presence of a vasoconstrictor influence at the time of investigation.


Analysis of femtosecond laser assisted capsulotomy cutting edges and manual capsulorhexis using environmental scanning electron microscopy.
Purpose. To investigate the structure and irregularity of the capsulotomy cutting edges created by two femtosecond (FS) laser platforms in comparison with manual continuous circular capsulorhexis (CCC) using environmental scanning electron microscopy (eSEM). Methods. Ten anterior capsulotomies were obtained using two different FS laser cataract platforms (LenSx, n = 5, and Victus, n = 5). In addition, five manual CCC (n = 5) were obtained using a rhexis forceps. The specimens were imaged by eSEM (FEI Quanta 400, OR, USA). Objective metrics, which included the arithmetic mean deviation of the surface (Sa) and the root-mean-square deviation of the surface (Sq), were used to evaluate the irregularity of both the FS laser capsulotomies and the manual CCC cutting edges. Results. Several microirregularities were shown across the FS laser capsulotomy cutting edges. The edges of manually torn capsules were shown, by comparison of Sa and Sq values, to be smoother (P < 0.05) than the FS laser capsulotomy edges. Conclusions. Work is needed to understand whether the FS laser capsulotomy edge microirregularities, not seen in manual CCC, may act as focal points for the concentration of stress that would increase the risk of capsular tear during phacoemulsification as recently reported in the literature.


A multicentre point prevalence survey (PPS) of antimicrobial use amongst admitted patients in tertiary care centres in India.
Data from point prevalence surveys (PPSs) in India are scarce. Conducting PPSs is especially challenging in the absence of electronic medical records, a lack of dedicated resources and a high patient load in resource-poor settings. This multicentre survey was conducted to provide background data for planning and strengthening antimicrobial stewardship programmes across the country. This inpatient PPS was conducted over 2 weeks in May 2019 simultaneously across five study centres in India. Data about patient characteristics, indications for antimicrobials use and details of each antimicrobial prescribed including supportive investigation reports were collected in predesigned forms. A total of 3473 admitted patients in wards and ICUs were covered across five study centres. Of these, 1747 (50.3%) patients were on antimicrobials, with 46.9% patients being on two or more antimicrobials. Out of the total antimicrobials prescribed, 40.2% of the antimicrobials were prescribed for community-acquired infection requiring hospitalization followed by surgical prophylaxis (32.6%). Third-generation cephalosporins and drugs from the 'Watch' category were prescribed most commonly. Only 22.8% of the antimicrobials were based on microbiology reports. The survey demonstrated a high use of antimicrobials in admitted patients with a considerable proportion of drugs from the 'Watch' category. The targets for interventions that emerged from the survey were: improving surgical prophylaxis, decreasing double anaerobic cover, initiating culture of sending cultures and de-escalation with targeted therapy.


Effect of Antibiotics and Diet on Enterolactone Concentration and Metabolome Studied by Targeted and Nontargeted LC-MS Metabolomics.
High plant lignan intake is associated with a number of health benefits, possibly induced by the lignan metabolite enterolactone (ENL). The gut microbiota plays a crucial role in converting dietary lignans into ENL, and epidemiological studies have shown that use of antibiotics is associated with lower levels of ENL. Here we investigate the link between antibiotic use and lignan metabolism in pigs using LC-MS/MS. The effect of lignan intake and antibiotic use on the gut microbial community and the pig metabolome is studied by 16S rRNA sequencing and nontargeted LC-MS. Treatment with antibiotics resulted in substantially lower concentrations of ENL compared with concentrations detected in untreated animals, whereas the plasma concentrations of plant lignans were unchanged. Both diet and antibiotic treatment affected the clustering of urinary metabolites and significantly altered the proportions of taxa in the gut microbiota. Diet, but not antibiotic treatment, affected the plasma lipid profile, and a lower concentration of LDL cholesterol was observed in the pigs fed a high lignan diet. This study provides solid support for the associations between ENL concentrations and use of antibiotics found in humans and indicates that the lower ENL concentration may be a consequence of the ecological changes in the microbiota.


Orientation of ECM protein deposition, fibroblast cytoskeleton, and attachment complex components on silicone microgrooved surfaces.
The microfilaments and vinculin-containing attachment complexes of rat dermal fibroblasts (RDF) incubated on microtextured surfaces were investigated with confocal laser scanning microscopy (CLSM) and digital image analysis (DIA). In addition, depositions of bovine and endogenous fibronectin and vitronectin were studied. Smooth and microtextured silicone substrata were produced that possessed parallel surface grooves with a groove and ridge width of 2.0, 5.0, and 10.0 microns. The groove depth was approximately 0.5 micron. CLSM and DIA make it possible to visualize and analyze intracellular and extracellular proteins and the underlying surface simultaneously. It was observed that the microfilaments and vinculin aggregates of the RDFs on the 2.0 microns grooved substrata were oriented along the surface grooves after 1, 3, 5, and 7 days of incubation while these proteins were significantly less oriented on the 5.0 and 10.0 microns grooved surfaces. Vinculin was located mainly on the surface ridges on all textured surfaces. In contrast, bovine and endogenous fibronectin and vitronectin were oriented along the surface grooves on all textured surfaces. These proteins did not seem to be hindered by the surface grooves since many groove-spanning filaments were found on all the microgrooved surfaces. In conclusion, it can be said that microtextured surfaces influence the orientation of intracellular and extracellular proteins. Although results corroborate three earlier published hypotheses, they do not justify a specific choice of any one of these hypotheses.


Mesenchymal stem cells ameliorate H9N2-induced acute lung injury by inhibiting caspase-3-GSDME-mediated pyroptosis of lung alveolar epithelial cells.
Influenza A virus infection mediates the host's excessive immune response, wherein caspase-3-GSDME-mediated pyroptosis of lung alveolar epithelial cells can contribute to inducing cytokine storm, leading to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Numerous studies have shown that mesenchymal stem cells (MSCs) possess potent immunomodulatory abilities and can mitigate virus-induced cytokine storm and lung injury. However, the role of MSCs in lung pyroptosis remains poorly understood. In this study, we established an ALI model using a mouse-adapted strain of avian influenza virus H9N2 (MA01) and intervened by injecting appropriate bone marrow-derived mesenchymal stem cells (BMMSCs) into the mouse's trachea. The results obtained from animal experiments demonstrated that BMMSCs prevented and ameliorated ALI by inhibiting Caspase-3-GSDME-mediated pyroptosis of lung epithelial cells as well as hypercytokinemia. Similarly, corresponding results were observed in vitro, where BMMSCs and the lung epithelial cell line MLE-12 cells were co-cultured in a transwell compartment. Additionally, the caspase-3 inhibitor Z-DEVD-FMK could block MA01-induced GSDME activation. Furthermore, by combining RNA-Seq data with in vitro and in vivo results, we also discovered that MA01-induced pyroptosis is associated with the BAK/BAX-dependent mitochondrial apoptosis pathway. Notably, BMMSCs exhibit the ability to interfere with this signaling pathway. In conclusion, this study provides novel theoretical support for the utilization of BMMSCs in the treatment of ALI induced by influenza.


Morphological adjustment of senescent cells by modulating caveolin-1 status.
Morphological change is one of the cardinal features of the senescent phenotype; for example, senescent human diploid cells have a flat large shape. However, the mechanisms underlying such senescence-related morphological alterations have not been well studied. To investigate this situation, we characterized the senescence-dependent changes of cellular structural determinants in terms of their levels and activities. These determinants included integrins, focal adhesion complexes, and small Rho GTPases, and special emphasis was placed on their relationships with caveolin-1 status. We observed that the expression integrin beta(1) and focal adhesion kinase (FAK) were increased and that the phosphorylations of FAK and paxillin, hallmarks of focal adhesion formation, were also increased in senescent human diploid fibroblast cells. Moreover, the Rho GTPases Rac1 and Cdc42 were found to be highly activated in senescent cells. In addition, focal adhesion complexes and Rho GTPases were up-regulated in the caveolin-rich membrane domain in the senescent cells. Activated Rac1 and Cdc42 directly interacted with caveolin-1 in senescent cells. Interestingly, caveolin-1 knock-out senescent cells, achieved by using small interfering RNA and antisense oligonucleotide, showed disrupted focal adhesion formation and actin stress fibers via the inactivation of FAK, which resulted in morphological adjustment to the young cell-like small spindle shape. Based on the results obtained, we propose that caveolin-1 plays an important role in senescence-associated morphological changes by regulating focal adhesion kinase activity and actin stress fiber formation in the senescent cells.


A unique case of anti-GBM disease with concomitant anti-PLA2R positivity.
Concomitant occurrence of anti-GBM disease and anti-PLA2R positive membranous nephropathy have been previously described. However, to the best of our knowledge, this is the first case report that documents the co-occurrence of the diseases proven by both serologic and histologic methods. A 51-year-old woman presented to hospital with nausea, bilateral lower extremity edema, dyspnea, dark urine, and then anuria. Symptoms developed one month after an upper respiratory tract infection. Laboratory results showed acute kidney injury, and hypoalbuminemia. Immunologic examination revealed both anti-GBM and anti-PLA2R positivity. Kidney biopsy demonstrated the histological features of Goodpasture's disease and anti-PLA2R positive membranous nephropathy. Steroid, cyclophosphamide, and plasmapheresis were commenced. Despite the combined immunosuppressive, the patient remained on renal replacement therapy. Microbial kidney injury can trigger multiple autoimmune diseases. The simultaneous occurrence of anti-glomerular basement (anti-GBM) disease and membranous nephropathy is extremely rare. Delayed recognition leads to delayed treatment, causing worse renal and patient outcomes, as well as increased financial costs.


Resolution of small molecules by passage through an open capillary.
When a solute passes through an open capillary, in which a laminar flow is established, different peak profiles can be obtained according to its diffusion property under a working condition, i.e., the radius and length of the capillary and the flow rate of the carrier solution. If a solute diffuses over the entire cross section of the capillary before it is eluted, a Gaussian-shaped diffusion peak appears, which has an apex at the travel time of the average flow. Insufficient solute diffusion, which is realized, e.g., by increasing flow rates or capillary radius, produces a new peak having an apex at the travel time of the maximum flow. This implies that two solutes can be resolved simply by passing through a capillary. However, our previous study indicated that the diffusion coefficients of two solutes should be at least one order different for their resolution based on this principle, suggesting that its applicability is highly restricted. In the present paper, this concept has been extended to the resolution between dissolved solutes that have similar intrinsic diffusion properties. The incorporation of molecular aggregates in the carrier makes a solute less diffusive according to the extent of their interaction and allows the resolution of a dissolved molecule from other ones differing in the affinity to the molecular aggregates. Several examples of peak resolution for phenols, aromatic hydrocarbons, and inorganic anions are shown and discussed on the basis of the modification of the diffusion natures due to their interactions with micelles or vesicles.


The effectiveness of bedside handovers: A multilevel, longitudinal study of effects on nurses and patients.
To investigate the effectiveness of bedside handovers. For nurses, effects on nurse-patient communication, individualized care, coordination of the care process, job satisfaction, intention to leave, patient participation and work interruptions were measured. For patients, effects on patient activation, individualized care and quality of care were measured. This is a longitudinal, controlled, multicentred study on 13 nursing wards in five hospitals. The seven interventional wards consisted of two medical rehabilitation, two geriatric and three surgical/medical wards. A questionnaire for patients and nurses at baseline (May-June 2016), 3 (July-August 2017) and 9 months (December 2017-January 2018) after implementation was completed by 799 patients and 165 nurses. Per protocol analysis was used in combination with linear mixed models analysis. With exception for work interruptions and patient participation for nurses, no overall effects could be found for both patients and nurses. For nurses, patient participation increased, and work interruptions decreased in the intervention group. Individualized care remained stable in the intervention group, whereas it decreased in the control group. The results indicate that bedside handover can be regarded as superior to more commonly used handover models as it enhances patient participation and decreases work interruptions. However, the positive image of bedside handovers, mostly based on observational, short-term and single-centred experiences, cannot be confirmed as there were no effects on any of the other measured parameters. As bedside handovers put patient participation on the agenda and negative effects are absent, implementing bedside handovers should be considered a mean for more patient-centeredness instead of a goal itself.


N-Heterocyclic silylenes in coinage metal chemistry: an account of recent advances.
This article intends to highlight and comprehensively summarize the recent developments in the field of silylene-coinage metal chemistry. Recent years have witnessed exponential growth in the utilization of N-heterocyclic silylenes as ligands in transition metal chemistry. Still, silylene-coinage metal complexes have only started to appear very recently. Particular attention is focused on the synthetic approaches to silylene-coinage metal complexes and their unusual properties derived from the spectroscopic and crystallographic data. Recent studies have demonstrated that silylene-coinage metal complexes exhibit catalytic efficiency towards hydrosilylation, copper-catalyzed alkyne azide cycloaddition (CuAAC), and glycosidation reactions. Although the chemistry of silylene-coinage metal complexes has only begun to blossom, these findings justify the need for a review at this stage of development. This article will summarize the previous work on silylene-coinage metal complexes followed by recent advances and conclude with future possibilities.


Effects of the new antiallergic drug epinastine and ketotifen on repeated antigen challenge-induced airway hyperresponsiveness in rats.
Airway hyperresponsiveness (AHR) is a critical component in bronchial asthma, probably associated with airway inflammation. The effects of epinastine (WAL-801 CL, CAS 80012-43-7), a new antiallergic drug, and ketotifen on AHR were investigated with a new AHR model in rats. Male Wistar rats which were actively sensitized with DNP-Ascaris (DNP-Asc) antigen, were challenged by inhaling DNP-Asc 3 times every 48 h. The airway responsiveness to inhaled ACh was determined 24 h after the last antigen challenge by modified Konzett-Rössler method under anesthesia with urethane. Antiallergic drugs were given orally 1 h before each antigen challenge in case of single treatment, and 3 times a day for 5 days in case of chronic treatment. The airway responsiveness to inhaled ACh was significantly increased after the repeated antigen challenge. Single treatments with epinastine and ketotifen did not inhibit AHR induced by repeated antigen challenge. On the other hand, chronic epinastine and ketotifen treatments, significantly inhibited the enhancement of AHR. From the above results, it is suggested that chronic treatments with epinastine and ketotifen are effective even for therapy of AHR.


Predicting the exposure of coastal species to plastic pollution in a complex island archipelago.
Plastic pollution in the marine environment is a pervasive and increasing threat to global biodiversity. Prioritising management actions that target marine plastic pollution require spatial information on the dispersal and settlement of plastics from both local and external sources. However, there is a mismatch between the scale of most plastic dispersal studies (regional, national and global) and the scale relevant to management action (local). We use a fine-resolution hydrodynamic model to predict the potential exposure of coastal habitats and species (mangroves, coral reefs and marine turtles) to plastic pollution at the local scale of a management region (the 1,700 km2 Whitsunday Islands, Queensland, Australia). We assessed the potential exposure of mangroves, coral reefs and marine turtles to plastics during the two dominant wind conditions of the region; the trade wind and monsoon wind seasons. We found that in the trade wind season (April to September) all habitats and species had lower exposure than during the monsoon wind season (October to March). In both wind seasons we found a small proportion of coral reef habitat and large area of turtle habitat were in high potential exposure categories. Unlike coral reefs or marine turtles, mangroves had consistent hotspots of high exposure across wind seasons. Local scale management requires data at fine resolution to capture the variability that occurs at this scale. The outputs of our study can inform the development of conservation resources and local scale management action.