Corticosteroid nasal irrigation as early treatment of olfactory dysfunction in COVID-19: A prospective randomised controlled trial.
This study aimed to evaluate the efficacy of corticosteroid irrigation compared to saline to no nasal irrigation in COVID-19 patients with olfactory loss. A randomised controlled study was conducted at the Otolaryngology-Head & Neck Surgery Department, Ramathibodi Hospital, Faculty of Medicine, Mahidol University. Two hundred thirty-seven COVID-19 participants with a new-onset smell loss were recruited into the study. Two hundred twenty-two participants met the inclusion criteria and were randomised into three groups: corticosteroid irrigation, saline irrigation and no treatment. The primary outcome was the mean difference in the smell sensation score among the groups after treatment at 1, 2 and 6 weeks. The secondary outcomes measurements included (1) a self-rating quality of life (QOL)-related smell dysfunction score, (2) the change over time in smell sensation score and self-rating QOL-related smell dysfunction score and (3) the median time to complete recovery of smell loss. The mean differences in smell sensation scores among the three groups were not statistically significant at any follow-up period. The mean score of self-rating QOL-related smell dysfunction in the corticosteroid group was significantly better than the other groups at 1 week. The change of outcome scores showed significant improvement over time, regardless of the treatments. The median time to complete smell recovery was similar: 3 weeks. This study emphasised that corticosteroid nasal irrigation is not superior to saline or no nasal irrigation in restoring the sense of smell in COVID-19-associated olfactory loss.


Electrodiagnostic investigation of motor neuron and spinal reflex arch (H-reflex) in spinal cord injury.
Twenty patients with spinal cord injury underwent serial electromyographic examinations. Fibrillation potentials and positive waves were noted in six patients in the spinal shock phase. In another subject, these potentials were found 27 months after injury. Our finding of significant slowing in the NCV of both nerves, indicates that lower motor neurons are indeed affected by upper motor neuron lesions. The H-reflex studies showed an increase in the mean H/M ratio. This may indicate an increase of reflex motor neuron excitability. No clear correlation was found between this increase and the degree of clinical spasticity. With repeat investigations, after a period of physical activity, a trend to reduction of the H/M ratio was noted with no clinical confirmation of reduction in spasticity. These findings emphasise the need for not assigning diagnostic terms to EMC abnormalities, but rather identifying them as neurophysiological changes which must be interpreted in the light of the clinical picture.


Prostaglandin I2 stimulation of granulosa cell cyclic AMP production.
The ability of prostaglandin I2 (PGI2) to stimulate cyclic AMP production by granulosa cells, isolated from intact immature rats, has been demonstrated in vitro. The minimal effective dose was 15 ng/ml, which was comparable to the minimal effective dose for PGE2. However, a concentration of 15 microgram/ml PGI2 was required to stimulate cyclic AMP production maximally, compared to a concentration of 1 microgram/ml PGE2, which produced the maximum response. It therefore appears that PGI2 is not more effective than PGE2 in stimulating cyclic AMP production in granulosa cells, and is possibly less effective. Submaximal concentrations of PGI2 appeared to be able to modify the stimulation of cyclic AMP production by follicle-stimulating hormone (FSH), but whether or not PGI2 plays any role in follicular function remains to be established.


Enterobacter sakazakii: a coliform of increased concern to infant health.
The first cases of neonatal meningitis believed to have been caused by Enterobacter sakazakii were reported in 1961. Prompted by several subsequent outbreaks of E. sakazakii infections in neonates and an increasing number of neonates in intensive care units being fed rehydrated powdered infant formula, considered to be a source of the pathogen, public health authorities and researchers are exploring ways to eliminate the bacterium or control its growth in dry infant formula, processing environments and formula preparation areas in hospitals. Reviewed here are advances in taxonomy and classification of E. sakazakii, methods of detecting, isolating and typing the bacterium, antibiotic resistance, clinical etiology and pathogenicity. Outbreaks of E. sakazakii infections in neonates and adults are summarized. Reports on the presence of E. sakazakii in clinical settings, the environment and foods and food processing facilities are reviewed. Tolerance of the pathogen to environmental stresses, its behavior in powdered and rehydrated infant formulae and hazard analysis and risk management are discussed. Research needs are presented.


Enteropathogenic Escherichia coli-induced macrophage inhibitory cytokine 1 mediates cancer cell survival: an in vitro implication of infection-linked tumor dissemination.
Mucosally adherent Escherichia coli is frequently observed in intestinal surface of patients with colorectal cancer, but rarely in healthy control. Particularly, enteropathogenic Escherichia coli (EPEC) is known to be closely associated with colorectal carcinogenesis in human. In this study, one consequence of EPEC infection in human intestinal cancer cells was induction of macrophage inhibitory cytokine 1 (MIC-1), which is a multifunctional cytokine with biological activities involved in cancer cell growth, differentiation and migration. The present investigation assessed the involvement of MIC-1 protein in EPEC infection-mediated cancer cell survival. The challenge with EPEC induced cancer cell detachment via cytoskeleton rearrangement, which was positively associated with induced MIC-1 expression. Moreover, MIC-1 also mediated RhoA GTPase-linked survival of the detached cancer cells. Blocking of MIC-1 or RhoA activity increased cellular apoptosis of the detached cancer cells. In terms of signaling pathway, MIC-1 triggered transforming growth factorβ-activated kinase 1 (TAK1), which enhanced expression of RhoA GTPase. We conclude that EPEC enhances MIC-1 gene expression in the human intestinal cancer cells, which can be associated with enhanced tumor cell resistance to anchorage-dependent tumor cell death via enhanced TAK1 and RhoA GTPase.


Modified Ghoneim's technique using a single serous-lined extramural tunnel in detubularized orthotopic ileal W-bladder.
We report our preliminary clinical experience with a modification of Ghoneim's original technique involving reimplantation of ureters in a single tunnel on the right part of the neobladder forming a 'W' shape. From 1997 to 1999, we performed radical cystectomy with double 'W' orthotopic neobladder construction and uretero-ileal reimplantation using our modified Ghoneim's technique on 11 male patients, aged 40-74 (mean 65.5) years, affected by invasive bladder cancer. No postoperative complications were observed. After a mean follow-up of 12.5 months all patients are free of recurrences. In our hands the modified Ghoneim's technique seems to reduce the mean operating time required to tailor the uretero-ileal anastomosis and guarantee greater stability of the anastomosis itself.


ROS production and their influence on the cellular antioxidative system in human erythrocytes incubated with daunorubicin and glutaraldehyde.
This study examined the effects of daunorubicin and glutaraldehyde on some parameters of erythrocytes. The aim of the article was to present the results of research aiming to identify the level of glutaraldehyde at which the hemoglobin oxidation, externalization of phosphatidylserine and the changes in the viability (hemolysis) of erythrocytes are not statistically significant and therefore this level of glutaraldehyde can be used for the drug carriers' preparation. Glutaraldehyde was used as a crosslinking agent to enhance the uptake of the drug within red blood cells and to prevent its leakage from the cells. Fluorescence microscopy, flow cytometry and fluorimetric measurements confirmed higher levels of the drug in glutaraldehyde-treated human erythrocytes. Unfortunately, substantial damage to the red blood cells was also noted. DNR increased oxidative processes in the cell, which in turn led to an increase in the reactive oxygen species (ROS) level. When the red blood cells were also treated with glutaraldehyde, ROS production was significantly higher. We also observed loss of both the reduced and the total glutathione. Moreover the decreased activity of glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) was also observed. As hemoglobin, the erythrocytes' main component plays an essential role in the erythrocytes, the level of its oxidized form (metHb) in the erythrocytes and the phosphatidylserine exposure on the erythrocyte surface were also investigated. When higher concentrations of glutaraldehyde (0.0025-0.005%) were used for the uptake of DNR the elevated level of metHb was observed. Only at 0.0005% the level of oxidized form of Hb was within the physiological level and at that level the increase in the exposure of phosphatidylserine at the cell surface was not observed to be statistically significant. Moreover the percent of released hemoglobin was less than 1%. Based on these results it was concluded that glutaraldehyde can be used as a cross-linker between the drug (DNR) and the erythrocytes only at low concentration of about 0.0005%.


Outcome of neurological early rehabilitation patients carrying multi-drug resistant bacteria: results from a German multi-center study.
Colonization or infection with multi-drug resistant (MDR) bacteria is considered detrimental to the outcome of neurological and neurosurgical early rehabilitation patients. In a German multi-center study, 754 neurological early rehabilitation patients were enrolled and and reviewed in respect to MDR status, length of stay (LOS) and the following outcome variables: Barthel Index (BI), Early Rehabilitation Index (ERI), Glasgow Outcome Score Extended (GOSE), Coma Remission Scale (CRS), Functional Ambulation Categories (FAC). The mean age of the study population was 68.0 ± 14.8 years. Upon admission, the following prevalence for MDRs was observed: MRSA (methicillin resistant staphylococcus aureus) 7.0% (53/754), ESBL- (extended spectrum beta-lactamase) producing bacteria strains 12.6% (95/754), VRE (vancomycin resistant enterococci) 2.8% (21/754). Patients colonized or infected with MDR bacteria (MDR+) were significantly more frequently diagnosed with a critical illness polyneuropathy - CIP - than non-colonized (MDR-) patients: 29.0% vs. 14.8%. In addition, they were more frequently mechanically ventilated (MDR+: 55/138, 39.9%; MDR- 137/616, 22.2%). MDR+ patients were referred to rehabilitation earlier, had a longer LOS in early rehabilitation, lower BI on admission and at discharge, lower ERI on admission and lower CRS at discharge than MDR- patients. There was a highly significant correlation of the BI upon admission with the BI at discharge (rs = 0.492, p < 0.001). GOSE at discharge differed significantly between both groups (χ 2-test, p < 0.01). Perhaps of greatest importance, mortality among MDR+ was higher in comparison to MDR- (18.1% vs. 7.6%). The outcome of neurological early rehabilitation patients colonized or infected with MDR bacteria including MRSA or ESBL producing strains is significantly poorer than by non-colonized patients. There is some evidence that the poor outcome could be related to the higher morbidity and lower functional status upon admission.


Protective effects of maslinic acid on high fat diet-induced liver injury in mice.
Due to the prevalence of high-fat diets and lack of exercise, diseases related to nutrient metabolism such as nonalcoholic fatty liver disease (NAFLD) have become one of the reasons causes endangering human liver health. Maslinic acid (MA) is a pentacyclic triterpenoid acid that is abundant in fruits such as hawthorn and jujube. In this study, we investigated the effect of MA on NAFLD to inform the development of dietary supplements for the treatment and prevention of NAFLD. The NAFLD model was established by feeding mice a high-fat diet (HFD). HEPG2 cells were treated with oleic acid and used as a cell culture model. Testing kits, haematoxylin and eosin staining, oil red O staining, western blotting, and immunofluorescence were performed with in vivo and in vitro experiments. The current study revealed that MA significantly reduced liver weight, body weight and serum lipid levels, and protected against liver steatosis and injury induced by a HFD. MA increased the expression of Beclin1, ATG1, and Bcl-2 mRNA and protein while decreasing the expression of TNF-α and IL-1β, caspase-3 and Bax mRNA and protein. Beclin1, and ATG1 were obviously increased, and the mRNA and protein expression of TNF-α and IL-1β were obviously reduced, the mRNA and protein expression of Caspase-3 and Bax were obviously reduced, and the mRNA and protein expression of Bax were obviously increased by MA. MA reduces the content of fat in the liver cells of NAFLD mice through lipophagy activitiy and reduces inflammation and apoptosis injury.


The study of the quercetin action on human erythrocyte membranes.
Quercetin is a naturally occurring flavonoid that exerts multiple pharmacological effects. In our previous study, we showed that quercetin greatly affects the lipid membrane. In this report, a study of quercetin on human erythrocyte membrane has been performed to determine the influence of this flavonoid on the fluidity and the conformational changes of membrane proteins. An additional aim of the study was to find how quercetin presence affects the resistance of membrane to haemolytic agents. The results showed that incorporation of quercetin into the erythrocyte membranes caused the changes of the partition coefficient of the Tempo spin label between the water and polar head group phases. In the studies, the W/S ratio has been used as a monitor of changes in protein conformation and in the environment within the membrane. It was observed that quercetin caused an increase in protein-protein interactions in human erythrocyte membranes. Haemolytic action of quercetin in the dark was also investigated. This compound showed protective effect against hypotonic haemolysis. However, in the heat-induced haemolysis quercetin caused acceleration of haemolysis. Dark reaction of erythrocyte with quercetin resulted in a shrinkage of the cells and alteration of their shapes. From the results we have concluded that modification of erythrocyte membrane by quercetin proceeds via reaction with membrane lipids and proteins.


Serotonin 7 Receptor Variants Are Not Associated with Response to Second-Generation Antipsychotics in Japanese Schizophrenia Patients.
Individual differences in serotonin 7 receptor (5-HT7R) may result in variable response to antipsychotics with 5-HT7R antagonism. This study investigated the relationship between single nucleotide polymorphisms (SNPs) in the 5-HT7R gene (HTR7) and the efficacy of second-generation antipsychotic drugs with a high affinity for this receptor in Japanese schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. All patients were genotyped for three candidate SNPs (rs12412496, rs7916403, and rs1935349). Patient improvement on the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks was assessed as the primary outcome. PANSS 5-factor scores were investigated as the secondary outcome. Improvement on the PANSS total score and genetic polymorphisms showed no correlation. The rs12412496-rs7916403-rs1935349 A-T-A haplotype was correlated with worse improvement in the cognition score (haplotype frequency: 0.285, p = 0.046, permuted p = 0.043). Our results show that HTR7 variants are not related to the overall improvement in schizophrenia symptoms.


Does salinity induce early ageing of pea root tissue?
The effect of salinity on ageing of pea roots was studied. The distance from the apex at which differentiation of xylem elements occurred and the relative increase in the function of pentose phosphate pathways were taken as parameters for maturation or ageing.Pea seeds (Pisum stivum L.) of the varieties Alaska and Dan were used in these experiments. The seeds were germinated and grown in vermiculite moistened with Hoagland's solution or Hoagland's solution containing either 96 or 120 mM NaCl. In Alaska roots salinity induced differentiation in a lower section of the root than in controls, and the increase in the function of the pentose phosphate pathway paralleled the advance of maturation. Salinity apparently induces earlier ageing in Alaska roots. This is not the case in Dan roots which tolerate slightly higher salinity levels than Alaska.


Profiling the approach to the investigation of viral infections in cases of sudden unexpected death in infancy in the Western Cape Province, South Africa.
Sudden unexpected death in infancy is one of the main contributory factors to high infant mortality rates world-wide. Several risk factors, including viral infection, have been implicated in SUDI cases, but no single factor has been confirmed as the main cause of death. At the Tygerberg Medico-legal Laboratory, Cape Town, South Africa, investigation of lung tissue for viral infection forms part of an institutional protocol for the examination of cases of sudden unexpected death in infancy. Lung tissue from 82 cases of sudden unexpected death in infancy was collected over a 10 month period. Routine shell vial cultures and histological examination of the tissue were performed according to the standard institutional protocol on fresh and formalin-fixed tissue, respectively. In addition, real-time polymerase chain reactions and immunohistochemical staining for adenovirus, cytomegalovirus and respiratory syncytial virus were done on fresh and formalin-fixed lung tissue, respectively. Huge variation was found in the number of positive cases confirmed by shell vial culture, real-time polymerase chain reaction and immunohistochemistry (0, 2 and 0 for adenovirus; 3, 29 and 2 for cytomegalovirus; and 0, 0 and 4 for respiratory syncytial virus, respectively). In the absence of a National Protocol for investigation of sudden unexpected death in infancy, we conclude that the selection of viruses and routine diagnostic technique included in the institutional investigation protocol might be suboptimal and should be re-evaluated.


MyoD-dependent regulation of NF-κB activity couples cell-cycle withdrawal to myogenic differentiation.
Mice lacking MyoD exhibit delayed skeletal muscle regeneration and markedly enhanced numbers of satellite cells. Myoblasts isolated from MyoD-/- myoblasts proliferate more rapidly than wild type myoblasts, display a dramatic delay in differentiation, and continue to incorporate BrdU after serum withdrawal. Primary myoblasts isolated from wild type and MyoD-/- mutant mice were examined by microarray analysis and further characterized by cell and molecular experiments in cell culture. We found that NF-κB, a key regulator of cell-cycle withdrawal and differentiation, aberrantly maintains nuclear localization and transcriptional activity in MyoD-/- myoblasts. As a result, expression of cyclin D is maintained during serum withdrawal, inhibiting expression of muscle-specific genes and progression through the differentiation program. Sustained nuclear localization of cyclin E, and a concomitant increase in cdk2 activity maintains S-phase entry in MyoD-/- myoblasts even in the absence of mitogens. Importantly, this deficit was rescued by forced expression of IκBαSR, a non-degradable mutant of IκBα, indicating that inhibition of NF-κB is sufficient to induce terminal myogenic differentiation in the absence of MyoD. MyoD-induced cytoplasmic relocalization of NF-κB is an essential step in linking cell-cycle withdrawal to the terminal differentiation of skeletal myoblasts. These results provide important insight into the unique functions of MyoD in regulating the switch from progenitor proliferation to terminal differentiation.


Evaluation of leakage resistance improvement in transconjunctival sutureless vitrectomy sclerotomies closed with adhesives. an experimental study.
The purpose of this paper is to study the utility of adhesives (artificial-cyanoacrylate and biological-fibrin glue) for improving transconjunctival sutureless vitrectomy (TSV) sclerotomy closure competency. Experimental and observer-masked study in which after performing TSV in cadaveric pig eyes, different adhesives were tested on sclerotomy entrances in order to determine if they improved closure competency in face of progressive intraocular pressure increase. In 76 eyes cyanoacrylate-treated sclerotomies were compared with sclerotomies in which no additional manoeuvre to aid closing was performed; in 76 eyes fibrin glue with no manoeuvre; and in the last 76 eyes, cyanoacrylate-treated sclerotomies were compared with fibrin glue-treated sclerotomies. A total of 228 eyes had a 23-gauge TSV performed. Both cyanoacrylate and fibrin glue treated sclerotomies achieved higher mean opening pressures when compared with nontreated sclerotomies in the same eye (p < 0.002). When cyanoacrylate was compared with biological adhesive in the same eye, no statistically significant differences were obtained (p = 0.216). This experimental study provides support for the possible role of adhesives in improving TSV sclerotomy closure competency in clinical practice.


Mutation rate of bacteriophage ΦX174 modified through changes in GATC sequence context.
Bacteriophage ΦX174 has a relatively high mutation rate of 10⁻⁶ substitutions per nucleotide per strand copying. A thirty-fold reduction in the mutation rate was achieved by introducing seven GATC sequences in its genome. This motif allows for methyl-directed mismatch repair and is strongly avoided in nature by ΦX174 and other phages.


Characterization of degradation signals at protein C-termini.
Protein termini are critical for protein functions. They are often more accessible than internal regions and thus are frequently subjected to various modifications that affect protein function. Protein termini also contribute to regulating protein lifespan. Recent studies have revealed a series of degradation signals located at protein C-termini, termed C-degrons or C-end degrons. C-degrons have been implicated as underlying a protein quality surveillance system that eliminates truncated, cleaved and mislocalized proteins. Despite the importance of C-degrons, our knowledge of them remains sparse. Here, we describe an established framework for the characterization of C-degrons by Global Protein Stability (GPS) profiling assay, a fluorescence-based reporter system for measuring protein stability in cellulo. Furthermore, we apply an approach that couples GPS with random peptide libraries for unbiased and context-independent characterization of C-degron motifs. Our methodology provides a robust and efficient platform for analyzing the degron potencies of C-terminal peptides, which can significantly accelerate our understanding of C-degrons.


Lack of detectable nuclease activity in highly purified preparations of murine fibroblast interferon.
The size distribution of radiolabeled mouse C-243 cell poly-A containing RNA, and SV40 DNA was analyzed electrophoretically before and after incubation with high concentrations of electrophoretically pure murine fibroblast interferon. Using this sensitive assay, no evidence for any nuclease activity directly associated with interferon could be found, under a wide variety of incubation conditions.


Imaging of Abdominal Postoperative Complications.
We present a case-based review of abdominal postoperative complications, organized by organ system affected, including wound/superficial, hepatobiliary, pancreatic, gastrointestinal, genitourinary, and vascular complications. Both general complications and specific considerations for certain types of operations are described, as well as potential pitfalls that can be confused with complications. Representative cases are shown using all relevant imaging modalities, including CT, fluoroscopy, ultrasound, MRI, and nuclear medicine. Management options are also described, highlighting those that require radiologist input or intervention.


Critical Roles of STAT3 in β-Adrenergic Functions in the Heart.
β-Adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR, protein kinase A, and T-type Ca(2+) channels. Our data demonstrate for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodeling, and heart failure.


Creating Virtual Presence During a Pandemic.
This article describes ways in which telemedicine has reshaped the doctor-patient relationship, and how we may face the challenge of maintaining a clinician's presence in the virtual environment.


Research Progress on Exosomes and MicroRNAs in the Microenvironment of Postoperative Neurocognitive Disorders.
Postoperative neurocognitive disorder (PND) is a disease that frequently develops in older patients during the perioperative period. It seriously affects the quality of life of the affected patients. Despite advancements in understanding PND, this disorder's mechanisms remain unclear, including pathophysiological processes such as central synaptic plasticity and function, neuroinflammation, excitotoxicity, and neurotrophic support. Growing evidence suggests that microenvironmental changes are major factors for PND induction in older individuals. Exosomes are carriers for transporting different bioactive molecules between nerve cells in the microenvironment and maintaining intercellular communication and tissue homeostasis. Studies have shown that exosomes and microRNAs (miRNAs) are involved in various physiological and pathological processes, including neural processes related to PND, such as neurogenesis and cell death, neuroprotection, and neurotrophy. This article reviews the effects of exosomes and miRNAs on the brain microenvironment in PND and has important implications to improve PND diagnosis, as well as to develop targeted therapy of this disorder.


Radiomics Analysis Based on Multiparametric MRI for Predicting Early Recurrence in Hepatocellular Carcinoma After Partial Hepatectomy.
Preoperative prediction of early recurrence (ER) of hepatocellular carcinoma (HCC) plays a critical role in individualized risk stratification and further treatment guidance. To investigate the role of radiomics analysis based on multiparametric MRI (mpMRI) for predicting ER in HCC after partial hepatectomy. Retrospective. In all, 113 HCC patients (ER, n = 58 vs. non-ER, n = 55), divided into training (n = 78) and validation (n = 35) cohorts. 1.5T or 3.0T, gradient-recalled-echo in-phase T1 -weighted imaging (I-T1 WI) and opposed-phase T1 WI (O-T1 WI), fast spin-echo T2 -weighted imaging (T2 WI), spin-echo planar diffusion-weighted imaging (DWI), and gradient-recalled-echo contrast-enhanced MRI (CE-MRI). In all, 1146 radiomics features were extracted from each image sequence, and radiomics models based on each sequence and their combination were established via multivariate logistic regression analysis. The clinicopathologic-radiologic (CPR) model and the combined model integrating the radiomics score with the CPR risk factors were constructed. A nomogram based on the combined model was established. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative performance of each model. The potential clinical usefulness was evaluated by decision curve analysis (DCA). The radiomics model based on I-T1 WI, O-T1 WI, T2 WI, and CE-MRI sequences presented the best performance among all radiomics models with an area under the ROC curve (AUC) of 0.771 (95% confidence interval (CI): 0.598-0.894) in the validation cohort. The combined nomogram (AUC: 0.873; 95% CI: 0.756-0.989) outperformed the radiomics model and the CPR model (AUC: 0.742; 95% CI: 0.577-0.907). DCA demonstrated that the combined nomogram was clinically useful. The mpMRI-based radiomics analysis has potential to predict ER of HCC patients after hepatectomy, which could enhance risk stratification and provide support for individualized treatment planning. 4. Stage 4.


The Impact of COVID-19 on Food Stockpiling Behavior over Time in China.
Studying the impact of COVID-19 on consumer food stockpiling behavior is timely and imperative. It can provide important information and help to understand whether consumers permanently change their behavior or return to their old habits in the long run. This study analyzed Chinese consumers' food stockpiling behavior using six rounds of nationwide surveys in China from December 2020 to July 2021. The results show that the scale of food reserves extended from 3.03 to 10.01 days after the outbreak of COVID-19, then dropped to a "new normal" plateau and kept fluctuating with the tide of the COVID-19 pandemic. Consumers who stockpile food for "Avoiding shortage" and "Pursuing ease" are going to stockpile food on a larger scale, implying a supply shock may affect the demand side. Those who perceive a higher level of severity of the pandemic are less likely to return to their old habits. Finally, although consumers' food stockpiling behavior fluctuates with the tide of COVID-19 pandemic, it gradually returns to old habits over time.


Phototherapy in Skin of Color.
Phototherapy in skin of color requires special consideration. Pigmented skin is an efficient ultraviolet filter. Hence, higher doses of ultraviolet radiation are generally more effective and well tolerated in skin of color. An objective and practical system has not yet been established to determine optimal phototherapy dosing in skin of color. The authors recommend obtaining a detailed history of each individual patient's response to sun exposure before prescribing a phototherapy dosing regimen. In addition, providers should consider the role of socioeconomic factors and their impact on phototherapy-related outcomes, including barriers to access and compliance.


1H, 23Na and 35Cl Imaging in Cementitious Materials with NMR.
A set-up especially designed for semi-simultaneous measurements of 1H, 23Na and 35Cl in ordinary cementitious materials using nuclear magnetic resonance was built. This setup makes use of the main field of a whole body magnetic resonance imaging system (Philips Intera), which has allowed us to combine two measurement setups into one, i.e., a 23Na/35Cl and a 1H insert. This 1.5 T field was chosen as a compromise between the signal-to-noise ratio of the spin-echo signal, which increases at higher frequencies, and the line broadening due to the presence of magnetic impurities of these materials, which leads to a decrease of the resolution at higher magnetic fields. The preliminary experiments show that this setup can be used to the study the interaction of different types of ions with cementitious materials. One-dimensional profiles of the moisture and dissolved ions can be measured with a spatial resolution of about 2 mm for 1H, 6 mm for 23Na and 9 mm for 35Cl.


Silica exposure activates non-canonical inflammasome complex in intratracheal instilled rat model.
Inhalation of silica crystals in occupational settings is a main cause of silicosis, a chronic irreversible pulmonary disorder. Our prior studies demonstrated the activation of inflammasome sensors AIM2 and NLRP3, effector protein caspase-1, and significant increase in IL-1β in silica exposed rats, suggesting that the canonical inflammasome activation may be associated with silica-induced tissue damage and inflammation. In our current study using the same animal model system, we further evaluated the components of non-canonical inflammasome, including NEK7, caspase-11, and GSDMD following silica exposure. We demonstrated sustained NEK7 elevation in the rat lung epithelial cells and macrophages following 1- and 3-day exposure. Enhanced NEK7 expression was also detected in lung homogenate by western blot. Similarly, caspase-11 expression was induced by silica exposure in lung sections and homogenate. Elevated GSDMD was observed both in lung sections by immunohistochemical staining and in lung tissue homogenate by western blot. In summary, our current study demonstrated increase in NEK7, caspase-11, and GSDMD in silica exposed rats, indicating activation of non-canonical inflammasome complex, thereby providing a broad inflammasome activation pathway caused by silica exposure.


Efficient Cu-catalyzed base-free C-S coupling under conventional and microwave heating. A simple access to S-heterocycles and sulfides.
S-aryl thioacetates can be prepared by reaction of inexpensive potassium thioacetate with both electron-rich and electron-poor aryl iodides under a base-free copper/ligand catalytic system. CuI as copper source affords S-aryl thioacetates in good to excellent yields, by using 1,10-phenanthroline as a ligand in toluene at 100 °C after 24 h. Under microwave irradiation the time was drastically reduced to 2 h. Both procedures are simple and involve a low-cost catalytic system. This methodology was also applied to the "one-pot" synthesis of target heterocycles, such as 3H-benzo[c][1,2]dithiol-3-one and 2-methylbenzothiazole, alkyl aryl sulfides, diaryl disulfides and asymmetric diaryl sulfides in good yields.


Primary Signet Ring Cell Adenocarcinoma of the Urinary Bladder: A Report of 2 Cases.
Primary signet ring cell carcinoma of the urinary bladder is a rare and aggressive histologic subtype of adenocarcinoma. In general, this tumor occurs in the middle age, and clinical presentation does not differ from transitional cell carcinomas. The prognosis is often poor, given the advanced stage at diagnosis. To our knowledge, <100 cases of signet ring cell adenocarcinoma of the urinary bladder have been reported. We report 2 cases with bladder linitis plastica primitive, and we draw attention to its pathologic, anatomoclinical, and evolution specificity to optimize its therapeutic management.


Pattern of urolithiasis in a general hospital. A prospective study.
Judging from the abundance of papers published in the medical journals there appears to be a global increase in the incidence of urolithiasis. Urinary excretion of various stone-forming salts in a 24-hour urine specimen is the mainstay of the metabolic workup done in stone-formers. According to the findings patients have been classified into neat categories depending on whether they were hypercalciuric, hyperuricosuric, etc. As a group their excretion of calcium, oxalate, and urate was not different from the controls. However, they excreted significantly more phosphate and had lower 24-hour urine volumes than the controls.


Evidence for sequential degeneration of the neurons in the intermediate zone of the spinal cord in amyotrophic lateral sclerosis: a topographic and quantitative investigation.
To elucidate the degenerating mechanism of the neurons in the intermediate zone of the spinal cord in classical amyotrophic lateral sclerosis (ALS), the spinal neurons in a patient with ALS, whose muscular strength was fairly well preserved up to death, were examined quantitatively and topographically, and compared with the data of advanced ALS patients and age-matched control subjects reported previously. In advanced ALS patients, anterior horn cells completely disappeared and the medium-sized (nuclear area; 71-150 microns 2) and large (nuclear area; greater than 151 microns 2) neurons in the intermediate zone were severely reduced. In the present case, however, the loss of anterior horn cells was severe but the degree was not equal to that of advanced ALS patients, and the neurons in the intermediate zone were quite well preserved. The finding indicates that the primary degeneration may occur in the anterior horn cells and the neurons in the intermediate zone degenerate sequentially in the spinal gray matter in ALS.


Asbestos, dental X-rays, tobacco, and alcohol in the epidemiology of laryngeal cancer.
A case-control study of 47 laryngeal cancers in males of three counties of Washington State was conducted. Personal interview was used to obtain information on smoking, alcohol use, exposure to asbestos, and other substances, and x-rays of the head and neck area. Smoking and alcohol consumption were found to increase risk of laryngeal cancer independently, with a clear dose-response relationship. Neither asbestos exposure nor exposure to other substances was found to significantly increase the risk of laryngeal cancer, although the relative risk with asbestos exposure was 1.75. Lifetime history of exposure to dental x-rays on five or more occasions was associated with significantly increased risk of laryngeal cancer among heavy smokers but not among light smokers. The importance of tobacco and alcohol in the epidemiology of laryngeal cancer was re-affirmed, the importance of asbestos exposure was brought into question, and a possible relationship of laryngeal cancer with exposure to dental x-rays among heavy smokers was demonstrated.


A qualitative examination of the content validity of the EQ-5D-5L in patients with type 2 diabetes.
The EQ-5D is frequently used to derive utilities for patients with type 2 diabetes (T2D). Despite widely available quantitative psychometric data on the EQ-5D, little is known about content validity in this population. Thus, the purpose of this qualitative study was to examine content validity of the EQ-5D in patients with T2D. Patients with T2D in the UK completed concept elicitation interviews, followed by administration of the EQ-5D-5L and cognitive interviewing focused on the instrument's relevance, clarity, and comprehensiveness. A total of 25 participants completed interviews (52.0 % male; mean age = 53.5 years). Approximately half (52 %) reported that the EQ-5D-5L was relevant to their experience with T2D. When asked if each individual item was relevant to their experience with T2D, responses varied widely (24.0 % said the self-care item was relevant; 68.0 % said the anxiety/depression item was relevant). Participants frequently said items were not relevant to themselves, but could be relevant to patients with more severe diabetes. Most participants (92.0 %) reported that T2D and/or its treatment/monitoring requirements had an impact on their quality of life that was not captured by the EQ-5D-5L. Common missing concepts included food awareness/restriction (n = 13, 52.0 %); activities (n = 11, 44.0 %); emotional functioning other than depression/anxiety (n = 8, 32.0 %); and social/relationship functioning (n = 8, 32.0 %). The results highlight strengths and potential limitations of the EQ-5D-5L, including missing content that could be important for some patients with T2D. Suggestions for addressing limitations are provided.


When and where to practice: social influences on the development of nut-cracking in bearded capuchins (Sapajus libidinosus).
The habitual use of tools by wild capuchin monkeys presents a unique opportunity to study the maintenance and transmission of traditions. Young capuchins spend several years interacting with nuts before cracking them efficiently with stone tools. Using a two-observer method, we quantified the magnitude of the social influences that sustain this long period of practice. During five collection periods (over 26 months), one observer recorded the behavior of 16 immature monkeys, and another observer concurrently recorded behavior of group members in the focal monkey's vicinity. The two-observer method provides a means to quantify distinct social influences. Data show that immatures match the behavior of the adults in time and especially in space. The rate of manipulation of nuts by the immatures quadrupled when others in the group cracked and ate nuts, and immatures were ten times more likely to handle nuts and 40 times more likely to strike a nut with a stone when they themselves were near the anvils. Moreover, immature monkeys were three times more likely to be near an anvil when others were cracking. We suggest a model for social influence on nut-cracking development, based on two related processes: (1) social facilitation from observing group members engaged in nut-cracking, and (2) opportunity for practice provided by the anvils, hammer stones and nut shells available on and around the anvils. Nut-cracking activities by others support learning by drawing immatures to the anvils, where extended practice can take place, and by providing materials for practice at these places.


Polypharmacy, benzodiazepines, and antidepressants, but not antipsychotics, are associated with increased falls risk in UK care home residents: a prospective multi-centre study.
Falls and polypharmacy are both common in care home residents. Deprescribing of medications in residents with increased falls risk is encouraged. Psychotropic medications are known to increase falls risk in older adults. These drugs are often used in care home residents for depression, anxiety, and behavioural and psychological symptoms of dementia. However, a few studies have explored the link between polypharmacy, psychotropic medications, and falls risk in care home residents. This was a prospective cohort study of residents from 84 UK care homes. Data were collected from residents' care records and medication administration records. Age, diagnoses, gender, number of medications, and number of psychotropic medications were collected at baseline and residents were monitored over three months for occurrence of falls. Logistic regression models were used to assess the effect of multiple medications and psychotropic medication on falls whilst adjusting for confounders. Of the 1655 participants, mean age 85 (SD 8.9) years, 67.9% female, 519 (31%) fell in 3 months. Both the total number of regular drugs prescribed and taking ≥ 1 regular psychotropic medication were independent risk factors for falling (adjusted odds ratio (OR) 1.06 (95% CI 1.03-1.09, p < 0.01) and 1.39 (95% CI 1.10-1.76, p < 0.01), respectively). The risk of falls was higher in those taking antidepressants (p < 0.01) and benzodiazepines (p < 0.01) but not antipsychotics (p > 0.05). In UK care homes, number of medications and psychotropic medications (particularly antidepressants and benzodiazepines) predicted falls. This information can be used to inform prescribing and deprescribing decisions.


Production of biodegradable pots from cattle manure and wood waste: effects of natural binders on mechanical performances and biodegradability.
The present study seeks to investigate the use of husbandry waste and sawdust in the construction of degradable pots as a suitable alternative to plastic pots. Six mixture ratios of cattle manure and sawdust (85:15, 80:20, 75:25, 70:30, 65:35, and 60:40) were used along with three types of natural binders (sheep's wool, cornstarch, and sheep's wool:cornstarch) in phase I of the project. Phase I was replicated in triplicate to identify the best composition for each binding agent. International standards dictate that evaluations of biological pots include investigations into thickness swelling, internal bonding, and water absorption. Mean comparison of the resultant factorial data using the Tukey and TOPSIS methods indicated that production of bio-pots with a mixture of 80% manure and 20% sawdust may provide the best results for all three pot types. Phase II of the project involved using field experiments and cultivation of tomato plants in direct comparison to a commercial sample pot. The optimal pots for each binding agent in phase I were used in the evaluation. Field tests showed pots produced with 80% manure and 20% sawdust using cornstarch for binding adhesion performed best in terms of degradability and physical and mechanical properties.


Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories.
To describe characteristics of dosing history in patients prescribed a once a day antihypertensive medication. Longitudinal database study. Clinical studies archived in database for 1989-2006. Patients who participated in the studies whose dosing histories were available through electronic monitoring. Persistence with prescribed antihypertensive treatment and execution of their once a day drug dosing regimens. The database contained dosing histories of 4783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n=2088), calcium channel blockers (n=937), angiotensin converting enzyme inhibitors (n=665), beta blockers (n=195), and diuretics (n=155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day's dose, whereas 43% were part of a sequence of several days (three or more days-that is, drug "holidays"). Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen. Early discontinuation of treatment and suboptimal daily execution of the prescribed regimens are the most common facets of poor adherence with once a day antihypertensive drug treatments. The shortfalls in drug exposure that these dosing errors create might be a common cause of low rates of blood pressure control and high variability in responses to prescribed antihypertensive drugs.


Resource heterogeneity and community structure: A case study inHeliconia imbricata Phytotelmata.
Complex or non-additive differences in the distribution and abundance of arthropod species inhabiting the water-filled bracts ofHeliconia imbricata can be created by simple manipulations of resource levels. The primary resources for these assemblages are the corollas of the flowers that accumulate in the bracts. Removing or adding corollas to individual bracts changes the pattern in the abundance of arthropod species within each bract such that bracts with different treatments ultimately differ in composition and numerical associations among species. These results suggest that direct and indirect resource-mediated factors can structure or significantly affect the distribution and abundance of species in these and perhaps other assemblages. Thus, in natural communities, if resources are heterogeneous among patches (such as among the bracts in this study) structure in a given patch may be a function of the resource level of that patch and can differ significantly from neighboring patches that provide different resource levels.


Effects of exogenous glycosaminoglycans on the histological structure of the rat bladder in experimental cystitis.
The protective effects of a complex glycosaminoglycan preparation in doses of 50 and 100 mg/kg were studied in experimental cystitis induced in rats by administration of 9% acetic acid. Daily glycosaminoglycan intake for 2 weeks before intrabladder injection of acetic acid resulted in a less severe injury to the bladder mucosa in comparison with controls receiving no glycosaminoglycans.


Isolates identification and characteristics of microorganisms in biotrickling filter and biofilter system treating H2S and NH3.
A combination system of biotrickling filter (BTF) and biofilter (BF), adopting surfactant-modified clinoptilolite and surfactant-modified wood chip as the media respectively, was applied to treat H2S and NH3 simultaneously. The identification and sole carbon sources utilization patterns of isolates in the combination system were studied by Biolog system. The isolates were identified as Bacillus sphaericus, Geobacillus themoglucosidasius (55 degrees C) and Micrococcus luteus (ATCC 9341) in BTF, and Aspergillus sydowii (Bainier & Sartory) Thorm & Church in BF. Among 95 substrate classes supplied by Biolog system, the carboxylic acids and methyl esters had the highest utilization extent for the four species, followed by the amino acids and peptides. The descending sequence of carbon sources utilization capability of isolates was A. sydowii (52.6%), M. luteus (39.5%), B. sphaericus (21.6%), and G. thermoglucosidasius (17.7%).


Drugs and alcohol Use patterns among those seeking care in urban rehabilitation centres before and during early months of COVID-19 in Uganda.
There is a rise in alcohol and other drug (AOD) abuse in the country but details of the practice are scanty. This paper provides characteristics of clients in the rehabilitation centres, their AOD related practices before and early months of COVID-19, and correlates of repeat treatment. The study was conducted in 10 rehabilitation centres in Kampala Metropolitan area. Characterization of AOD clients involved descriptive analysis while comparison of AOD related practices pre-and during COVID-19 lockdown was carried out using interrupted time series analysis. Modified Poisson regression model was used to analyse the repeat treatment. The clients were mostly male (85%), single (57%) and had attained secondary education (84%). Nearly a third of them (29%) were unemployed while 68% were aged between 15-34 years. The commonest substances used were alcohol (52%), cannabis (19%), cocaine (13%) and opioids (8%). The commonest sources of substances were street dealers (52%) and friends (37%). COVID-19 did not change the pattern of AOD use except for Opioids. Repeat treatment was associated with being male, seeking care in private facilities, being casual labourer/self-employed. Intervention programs should target the educated, the unemployed, young men, their friends, street drug dealers and AOD hotspots.


Cholecystokinetic cholecystography.
A prospective clinical trial of 100 patients receiving either intramuscular ceruletide or a fatty meal to contract the gallbladder after oral cholecystography is described. The percentage reduction of the gallbladder area after 30 min of stimulation was not significantly greater with ceruletide (49%) than with a fatty meal (44%) (t-test: p greater than 0.3). Ceruletide caused significantly more adverse reactions than a fatty meal (Fisher test, p less than 0.01). The diagnostic value of routine cholecystokinetic stimulation is doubtful, since the diagnosis changed after the contraction in only 1 patient.


2-DE Gel Analysis: The Spot Detection.
The abundance of different proteins on a 2-DE gel is reflected by the shape, size, and intensity of the corresponding spots. Protein quantitation requires the conversion of an analog gel image into digital data, resulting into a catalog of individual spots listed as x, y positions, shape parameters, and quantitative values. So, it is possible to carry out objective comparisons of equivalent spots on different gels, determining whether a particular protein is more or less abundant in one sample compared with another. Unfortunately, spots on protein gels are not uniform in shape, size, or density, and detection, quantitation, and comparison can be challenging without intervention. Once a processed image is available, a number of different algorithms can be applied to detect and quantitate individual spots.


Physiological characterization and genetic engineering of Pseudomonas corrugata for medium-chain-length polyhydroxyalkanoates synthesis from triacylglycerols.
Pseudomonas belonging to the rRNA-DNA homology group I produce medium-chain-length (mcl)-polyhydroxyalkanoates (PHA). We show that P. corrugata, a member of this group, accumulates 0.5-1.0 g of mcl-PHA/L of culture when grown on glucose (Gl) or oleic acid (Ol). The predominant monomers of Gl-PHA and Ol-PHA are beta-hydroxydecanoate and beta-hydroxyoctanoate, respectively. The molecular masses and polydispersity of P. corrugata PHAs are higher than those typically found with other Pseudomonas. We electrotransformed P. corrugata with a plasmid pCN51lip-1 carrying Pseudomonas lipase genes to generate strain III111-1. The recombinant strain grew on intact triacylglycerols (TAGs) to 1.9-2.7 g of cell-dry-weight/L of culture. The yields and the predominant repeat-units of PHAs obtained from the lard- and tallow-grown III111-1 were similar to those of Ol-PHA from wild-type cells. In contrast to other Pseudomonas species, P. corrugata III111-1 grown on TAGs at temperatures up to 36 degrees C was not significantly affected with regard to cell yields, amounts of PHA produced, and the repeat unit compositions of the polymer.


A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1.
The 2.9 A crystal structure of the core SRPK1:ASF/SF2 complex reveals that the N-terminal half of the basic RS domain of ASF/SF2, which is destined to be phosphorylated, is bound to an acidic docking groove of SRPK1 distal to the active site. Phosphorylation of ASF/SF2 at a single site in the C-terminal end of the RS domain generates a primed phosphoserine that binds to a basic site in the kinase. Biochemical experiments support a directional sliding of the RS peptide through the docking groove to the active site during phosphorylation, which ends with the unfolding of a beta strand of the RRM domain and binding of the unfolded region to the docking groove. We further suggest that the priming of the first serine facilitates directional substrate translocation and efficient phosphorylation.


Neurobehavioral actions of coumestrol and related isoflavonoids in rodents.
Isoflavonoids are plant estrogens that are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. As weak estrogen agonists/antagonists with a range of other enzymatic activities, the isoflavonoids provide a useful model for the actions of endocrine disruptors. This paper reviews the responses of rodents to diets containing coumestrol or an isoflavone supplement in comparison to animals fed the phytoestrogen-free AIN76A diet. Neural mechanisms were investigated by examining isoflavonoid effects on ER(alpha)-dependent (regulation of oxytocin receptor [OTR] binding in the ventromedial nucleus of the hypothalamus [VMN]) and ERbeta-dependent (regulation of ERbeta mRNA in the paraventricular nucleus [PVN]) endpoints. Activational as well as organizational effects on sexual behavior and gonadotropin secretion were observed for coumestrol. Treatment of rat dams with a 100-ppm coumestrol diet from birth to postnatal day (PND) 21 induced premature anovulation in female offspring, and treatment from birth to PND 10 suppressed sexual behavior in male offspring. One-week treatment of ovariectomized (OVX) female rats with the same coumestrol diet increased ERbeta mRNA expression in the PVN, an effect opposite to that of estradiol. Ten days of treatment with a 200-ppm coumestrol diet increased LH secretion in OVX wild-type mice, an effect opposite to the normal negative feedback effects of estradiol. No effects were observed in ER(alpha) knockout (ER(alpha)KO)-OVX females, indicating that coumestrol's action on LH was mediated through ER(alpha). Similar activational effects were observed for the isoflavone diet. The lordotic response to estrogen was significantly reduced by 2 days of treatment of OVX adult females with an isoflavone diet providing 13 ppm genistein and 33 ppm daidzein. One week of treatment with the same isoflavone diet produced an effect opposite to that of estradiol in the PVN, increasing ERbeta mRNA expression above control levels. These investigations show that, in spite of their preferential affinity for ERbeta, isoflavonoids act through both ER(alpha) and ERbeta. Moreover, their neurobehavioral actions were antiestrogenic, either antagonizing or producing an action in opposition to that of estradiol. This work demonstrates that even small, physiologically relevant exposure levels can alter estrogen-dependent gene expression in the brain and complex behavior.


Hybrid electrospun chitosan-phospholipids nanofibers for transdermal drug delivery.
Chitosan (Ch) polysaccharide was mixed with phospholipids (P) to generate electrospun hybrid nanofibers intended to be used as platforms for transdermal drug delivery. Ch/P nanofibers exibithed average diameters ranging from 248±94nm to 600±201nm, depending on the amount of phospholipids used. Fourier Transformed Infra-Red (FTIR) spectroscopy and Dynamic Light Scattering (DLS) data suggested the occurrence of electrostatic interactions between amine groups of chitosan with the phospholipid counterparts. The nanofibers were shown to be stable for at least 7days in Phosphate Buffer Saline (PBS) solution. Cytotoxicity studies (WST-1 and LDH assays) demonstrated that the hybrid nanofibers have suitable biocompatibility. Fluorescence microscopy, also suggested that L929 cells seeded on top of the CH/P hybrid have similar metabolic activity comparatively to the cells seeded on tissue culture plate (control). The release of curcumin, diclofenac and vitamin B12, as model drugs, from Ch/P hybrid nanofibers was investigated, demonstrating their potential utilization as a transdermal drug delivery system.


Inhibition of horseradish peroxidase activity by specific antibody: determinant specificity of anticatalytic antibodies.
Rabbit antisera specific for horseradish peroxidase inhibit the catalytic activity of the enzyme. All antibodies prepared against the holoenzyme react with the peroxidase apoenzyme. However, only a minority (30-45%) of the total antiperoxidase pool cross react with reduced and alkylated apoenzymes. The antibodies inhibiting peroxidase activity do not bind to S-carboxymethyl of S-carboxamidomethylated apoenzyme derivatives as measured by absorption and competition of inhibition experiments. Glycopeptides derived from horseradish peroxidase also failed to bind anticatalytic antibodies. Antibodies that inhibit enzyme activity have specificity for noncarbohydrate conformation dependent antigenic determinants of horseradish peroxidase. Additional experiments probed the mechanism by which inhibitory antibody decreases the catalytic activity of horseradish peroxidase. Absorption spectra of horseradish peroxidase that has bound Fab fragments sufficient to cause 90% inhibition of the enzyme activity determined that the enzyme retained the ability to bind hydrogen peroxide. Thus, anticatalytic antibodies do not prevent the formation of the first enzyme-substrate intermediate but mediate their inhibitory effects by disrupting a later step in the reaction mechanism.


Quantification of EEG changes following electroconvulsive therapy in depression.
Frequency analysis of EEG was made during electroconvulsive therapy (ECT) in patients with depression. Acute effects were quantified by calculating differences of EEG power from before to after the induced seizure, and were found to correlate with the duration of the seizure but not with the time lapse following the seizure. Increases in delta power were much more pronounced at the end of the treatment series than at the beginning. Non-acute effects were quantified as the differences from before the first treatment to the pre-ECT EEG later in the series. Increases in delta power correlated with the accumulated seizure duration and positively with the time lapse from the previous seizure, suggesting that it takes considerable time for this effect to develop. The concept of two different sources of EEG slowing during the ECT series is supported by different correlations between acute and non-acute EEG slowing on the one hand and on the other symptoms of depression, anxiety, cognitive disturbances, and cerebral blood flow as presented elsewhere.


Chronic illness, reproductive health and moral work: women's experiences of epilepsy.
The impact of chronic illness on families has long been noted in the literature, but in such studies families appear as ready-formed entities. This exploratory qualitative study addresses the largely unacknowledged work involved in the production of families and the maintenance of reproductive health by women with epilepsy, a condition whose symptoms and treatment have serious implications for all aspects of reproductive health. Qualitative in-depth interviews were conducted with a sample of 15 women aged 20-40 years diagnosed with epilepsy and recruited from across the UK. The women had a range of neurological symptoms and hence different diagnostic categories; most had been diagnosed during childhood or adolescence. Ten women had at least one child. Women's experiences of healthcare services for key phases of reproduction are explored. While some women reported that they had received good healthcare, others reported that they were given inadequate information and that advice was offered too late to enable them to take appropriate action. Management of both epilepsy and reproductive health involves work with a significant moral dimension, the accomplishment of which is contingent on appropriate and timely advice from healthcare practitioners.


Monoclonal autoantibodies: an approach to studying autoimmune disease.
Hybridoma technology has paved the way for new insights into mechanisms of autoimmunity and autoimmune disease. Autoantibodies and autoantigens can now be studied at the level of the individual molecule. The specificity of the autoimmune reaction, as well as its pathogenetic role in disease, may be more accurately assessed. Monoclonal autoantibodies which bind to red blood cells, IgG, DNA, RNA and ribonucleoprotein complexes have been prepared by several groups of investigators. The initial molecular and functional characterization of these immunoglobulins and their corresponding antigens is described.


[Combined hepatocellular-cholangiocarcinoma (cholangiolocellular type) with stem-cell features: a clinicopathologic analysis of 26 cases].
To study the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (cholangiolocellular type, CLC type) with stem cell features and its relationship to hepatic progenitor cells (HPCs). Clinical and histologic features of 26 cases of combined hepatocellular-cholangiocarcinoma (CLC type) were reviewed. Histochemistry was performed to confirm the type of mucin and immunohistochemical study was carried out for hepatocytic markers (Hep Par-1 and AFP) and biliary/HPCs markers (CK7, CK9, EMA, EpCAM, NCAM, CKIT). The age of patients ranged from 51 to 82 years (mean 64 years). All 26 cases contained CLC and hepatocellular carcinoma components. CLC area was composed of mixtures of small monotonous glands with abundant fibrous stroma and lymphocytic infiltrate. Tumor cells were cuboidal, smaller in size than normal hepatocytes, with basophilic cytoplasm and round nuclei. All cases, especially at the tumor boundary, showed HCC-like trabecular areas characterized by mildly atypical tumor cells with abundant eosinophilic cytoplasm and little stroma. Out of 26 cases, 21 showed definite glandular formation with mucin production, representing intrahepatic cholangiocarcinoma areas. The three distinct areas showed transitional zones merging with each other. The surrounding liver tissue showed cirrhosis and chronic hepatitis with varying degrees of fibrosis and periportal ductular reaction. Immunohistochemistry showed that biliary/HPC markers (CK7, CK9, EMA, EpCAM, NCAM and CKIT) were strongly positive in CLC area in almost all cases, similar to the staining pattern of ductular reaction. In HCC-like areas, CK7 and CK19 were positive in all cases and the expression rates of EMA, EpCAM, NCAM, CKIT, AFP, Hep Par-1 were 80.8% (21/26), 88.5% (23/26), 84.6% (22/26), 88.5% (23/26), 46.2% (12/26) and 53.8% (14/26) respectively, similar to the staining pattern of intermediate hepatocytes. In ICC areas, CK7, CK9, EMA and EpCAM were positive in all cases without the expression of NCAM and CKIT. The clinicopathologic findings and immunohistochemical results in this study highly suggest a hepatic progenitor cell origin of combined hepatocellular-cholangiocarcinoma (CLC type).


COVID-19 detection in cough, breath and speech using deep transfer learning and bottleneck features.
We present an experimental investigation into the effectiveness of transfer learning and bottleneck feature extraction in detecting COVID-19 from audio recordings of cough, breath and speech. This type of screening is non-contact, does not require specialist medical expertise or laboratory facilities and can be deployed on inexpensive consumer hardware such as a smartphone. We use datasets that contain cough, sneeze, speech and other noises, but do not contain COVID-19 labels, to pre-train three deep neural networks: a CNN, an LSTM and a Resnet50. These pre-trained networks are subsequently either fine-tuned using smaller datasets of coughing with COVID-19 labels in the process of transfer learning, or are used as bottleneck feature extractors. Results show that a Resnet50 classifier trained by this transfer learning process delivers optimal or near-optimal performance across all datasets achieving areas under the receiver operating characteristic (ROC AUC) of 0.98, 0.94 and 0.92 respectively for all three sound classes: coughs, breaths and speech. This indicates that coughs carry the strongest COVID-19 signature, followed by breath and speech. Our results also show that applying transfer learning and extracting bottleneck features using the larger datasets without COVID-19 labels led not only to improved performance, but also to a marked reduction in the standard deviation of the classifier AUCs measured over the outer folds during nested cross-validation, indicating better generalisation. We conclude that deep transfer learning and bottleneck feature extraction can improve COVID-19 cough, breath and speech audio classification, yielding automatic COVID-19 detection with a better and more consistent overall performance.


Role of Spectralis HRA+OCT spectral domain optical coherence tomography in the diagnosis and management of fungal choroidal granuloma.
To report the usefulness of inverted scan technique using Spectral domain Optical Coherence Tomography (OCT) in inflammatory fungal chorioretinitis. Case Report-Interventional. We present a 53 year old female with sudden painful blurring of vision in left eye. Ocular examination revealed retinochoroiditis.OCT using the inverted scan technique showed a choroidal mass lesion. Polymerase chain reaction was positive for panfungal genome. She was treated with systemic fluconazole. Symptoms improved and the choroidal mass was diminished in size after one week of therapy. Inverted OCT scan technique is useful in the diagnosis and management of choroidal inflammatory mass lesion.


Renal cell carcinoma in patients with a personal or family history of hematologic malignancies.
A little-appreciated association between renal cell carcinoma (RCC) and hematologic malignancies (HMs) has been reported for at least 20 years. The HM characteristically occurs first in patients with both neoplasms, and the large majority (94%) of these HMs are of B-cell origin. Furthermore, the majority of patients with RCC and an HM are male. Recently, we have noted an increased incidence of HMs in families of patients with RCC and are exploring this observation further. Here, we summarize our reports on the association between these neoplasms in individual patients and review the relevant literature.


Effects of dietary iron deficiency and tungsten supplementation on 59Fe absorption and gastric retention from 59Fe compounds in rats.
1. In vivo 59Fe absorption from intrinsically labelled Fe-containing fractions of liver and blood were measured in rats by intragastric dosing. All rats were fed on a low-Fe diet for 3 d before dosing in order to standardize the Fe status of the intestinal mucosal cells. 2. An increase in digestion time from 2 to 12 h increased 59Fe absorption (P less than 0.01) from all fractions except ferritin. 3. Fe-deficient rats when compared with essentially Fe-replete rats showed decreased gastric retention for all fractions, but increased 59Fe absorption over 2 h only from ferritin. Ferritin showed several unusual absorption characteristics. 4. Dietary tungsten supplementation of Fe-deficient rats reduced the ferroxidase activity of intestinal mucosal xanthine oxidase. In addition, gastric retention and 59Fe absorption (P less than 0.05) from all fractions were increased.


The relationship between the serotonin 2A receptor gene -1438A/G and 102T/C polymorphisms and citalopram/sertraline-induced nausea in major depressed patients.
The aim of the present study was to determine the relationship between the polymorphisms of -1438A/G and 102T/C in the 5-HT2A receptor (HTR2A) gene and nausea/vomiting as a side effect induced by sertraline (SERT) or citalopram (CIT) in patients with major depressive disorder. A total of 128 patients were enrolled, 63 patients received CIT, whereas 65 patients were treated with SERT. Nausea/vomiting were assessed with the UKU Side-effects Rating Scale at baseline and at the end of the second and fourth weeks. Polymerase chain reaction-restriction fragment length polymorphism technique was employed to determine genetic differences. We have found that, in the patients treated with CIT, there was a nominally significant difference in the genotypic distribution associated with -1438A/G polymorphism between patients with and without nausea (X2 = 6.15, p = 0.041). Moreover, logistic regression analysis revealed a significant association between nausea/vomiting as a side effect and -1438A/G polymorphism. That is, patients with the G allele were at a higher risk for developing nausea/vomiting (p = 0.044, odds ratio = 2.213). The 102T/C polymorphism in the HTR2A gene had no significant effect on the nausea/vomiting as a side effect among participants treated with either CIT or SERT. The present study suggests the association of the HTR2A gene -1438A/G polymorphism with nausea/vomiting as a side effect related to CIT treatment.


The hemoglobin derived peptide LVV-hemorphin-7 evokes behavioral effects mediated by oxytocin receptors.
LVV-hemorphin-7 (LVV-h7) is bioactive peptide resulting from degradation of hemoglobin β-globin chain. LVV-h7 is a specific agonist of angiotensin IV receptor. This receptor belongs to the class of insulin-regulated aminopeptidases (IRAP), which displays oxytocinase activity. Herein, our aims were to assess whether: i) LVV-h7 modifies centrally organized behavior and cardiovascular responses to stress and ii) mechanisms underlying LVV-h7 effects involve activation of oxytocin (OT) receptors, probably as result of reduction of IRAP proteolytic activity upon OT. Adult male Wistar rats (270-370g) received (i.p.) injections of LVV-h7 (153nmol/kg), or vehicle (0.1ml). Different protocols were used: i) open field (OP) test for locomotor/exploratory activities; ii) Elevated Plus Maze (EPM) for anxiety-like behavior; iii) forced swimming test (FST) test for depression-like behavior and iv) air jet for cardiovascular reactivity to acute stress exposure. Diazepam (2mg/kg) and imipramine (15mg/kg) were used as positive control for EPM and FST, respectively. The antagonist of OT receptors (OTr), atosiban (1 and 0,1mg/kg), was used to determine the involvement of oxytocinergic paths. We found that LVV-h7: i) increased the number of entries and the time spent in open arms of the maze, an indicative of anxiolysis; ii) provoked antidepressant effect in the FS test; and iii) increased the exploration and locomotion; iv) did not change the cardiovascular reactivity and neuroendocrine responses to acute stress. Also, increases in locomotion and the antidepressant effects evoked by LVV-h7 were reverted by OTr antagonist. We conclude that LVV-h7 modulates behavior, displays antidepressant and anxiolytic effects that are mediated in part by oxytocin receptors.


Evaluation of the implementation progress through key performance indicators in a new multimorbidity patient-centered care model in Chile.
Complex health interventions involve deep organizational, structural, and cultural changes that challenge health teams and decision-makers. The explosion of chronic diseases has made the multimorbidity approach a global priority. The Centro de Innovación en Salud ANCORA UC implemented a Multimorbidity Patient-Centered Care Model in the Chilean public health system. This study aims to evaluate the progress of the implementation of the Multimorbidity Patient-Centered Care Model in seven primary care centers through key performance indicators. a set of indicators was designed to evaluate change management, operations, installation of new roles, and services and activities of the intervention strategy of the model. Key performance indicators were identified to monitor the implementation progress on minimal components for the model's sustainability. Each item was assigned against an expected minimum score of 67% of progress from the overall score. They were monitored twice in seven primary health centers in 2019 and 2020, which intervened 22,642 patients with the intervention. The results showed that six of the seven primary care centers reached the minimum implementation threshold. The main advances were in operational conditions, and those with minor progress in implementation were the clinical services. Population size, organization, coordination of the health care teams, additional training, and decision-makers support were key factors that determined the degree of progress in a complex intervention. It was possible to measure the progression of the implementation of a complex intervention through key performance indicators delivering relevant information for decision-makers that pursue a successful and faithful implementation. This study provides a valuable tool for the national scale-up of a similar model started in Chile by the Ministry of Health and other countries.


Genome characterization, phylogenomic assessment and spatio-temporal dynamics study of highly mutated BA variants from India.
The emergence of highly mutated and transmissible BA variants has caused an unprecedented surge in COVID-19 infections worldwide. Thorough analysis of its genome structure and phylogenomic evolutionary details will serve as scientific reference for future research. Here, we have analyzed the BA variants from India using whole-genome sequencing, spike protein mutation study, spatio-temporal surveillance, phylogenomic assessment and epitope mapping. The predominance of BA.2/BA.2-like was observed in India during COVID-19 third wave. Genome analysis and mutation study highlighted the existence of 2128 amino acid changes within BA as compared to NC_045512.2. Presence of 23 unknown mutation sites (spanning region 61-831) were observed among the Indian BA variants as compared to the global BA strains. Unassigned probable Omicron showed the highest number of mutations (370) followed by BA.1 (104), BA.2.3 (56), and BA.2 (27). Presence of mutations 'Q493R + Q498R + N501Y', and 'K417 N + E484A + N501Y' remained exclusive to BA.2 as well as unassigned probable Omicron. The time-tree and phylogenomic network assessed the evolutionary relationship of the BA variants. Existence of 424 segregating sites and 113 parsimony informative sites within BA genomes were observed through haplotype network analysis. Epitope mapping depicted the presence of unique antigenic sites within the receptor binding domain of the BA variants that could be exploited for robust vaccine development. These findings provide important scientific insights about the nature, diversity, and evolution of Indian BA variants. The study further divulges in the avenues of therapeutic upgradation for better management and eventual eradication of COVID-19.


Electromyographic analysis of muscle function after latissimus dorsi tendon transfer.
The latissimus dorsi transfer is an established method for irreparable tears of the rotator cuff. The original task of the muscle is to move the arm downward and to rotate it internally. After the transfer, it has to perform the completely new function of elevating the arm. We used surface electromyography to calculate the mean values of the activity pattern in relation to the Constant score in 45 patients. We assessed patients after 6 weeks and at 6, 9, and 19 months. After the operation, most patients showed a typical activity pattern of the latissimus dorsi on electromyography, which improved in the course of the study. We also found a strong correlation between the activity pattern on electromyography and the Constant score in different areas. We conclude that the functional improvement is due to an active muscle contraction as shown on electromyography and is not just an interposition or tenodesis effect.


A Mixed-ligand Pb(II)-coordination Polymer: Photocatalytic Performance and Reduction Activity of the Inflammatory Response After Severe Burns by Inhibiting NF-κB Signaling Pathway.
Via the employment of a mixed-ligand method, a novel Pb(II)-coordination polymer with the chemical formula of [Pb(pdc)(bdc)]·2DMF (1, H2bdc = 1,4-benzenedicarboxylic acid and H2pdc = 3,5-pyridinedicarboxylic acid) has been produced via reaction of Pb(NO3)2 with the two organic linkers in a mixed solvent of DMF and water. Complex 1 has high photocatalytic degradation efficiency for methylene blue and rhodamine B under ultraviolet light irradiation. The mechanism of photocatalysis was hypothesized and verified in detail by the r photocatalysis reaction in the existence of the hydroxyl radical scavenger mannitol. Furthermore, the influence of the inflammatory response in the severe burns rats was evaluated. Firstly, the inflammatory response levels were assessed by measuring the content of IL-6 and TNF-α in the plasma after treated with compound. Next, the real time RT-PCR was carried out to determine the signaling pathway of NF-κB relative expression in inflammatory cells.


The lp13.3 genomic region -rs599839- is associated with endothelial dysfunction in patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is an inflammatory disease associated with accelerated atherosclerosis and high risk of cardiovascular (CV) disease. Since genome-wide association studies demonstrated association between rs599839 polymorphism and coronary artery disease, in the present study we assessed the potential association of this polymorphism with endothelial dysfunction, an early step in atherogenesis. A total of 128 RA patients without history of CV events were genotyped for rs599839 A/G polymorphism. The presence of endothelial dysfunction was assessed by brachial ultrasonography (brachial flow-mediated endothelium-dependent (FMD)). Patients carrying the allele G exhibited more severe endothelial dysfunction (FMD%: 4.61 ± 3.94%) than those carrying the wild allele A (FMD%: 6.01 ± 5.15%) (P = 0.08). Adjustment for gender, age at the time of study, follow-up time and classic CV risk factors disclosed a significant association between the rs599839 polymorphism and FMD (G vs. A: P = 0.0062). Our results confirm an association of the rs599839 polymorphism with endothelial dysfunction in RA.


Long-Term Excessive Selenium Supplementation Affects Gene Expression in Esophageal Tissue of Rats.
Esophageal cancer is one of the leading causes of cancer death and the seventh most prevalent cancer worldwide. Considering the positive association of high selenium with the prevalence of esophageal cancer, we have investigated the effect of high doses of selenium on gene expression in the normal esophageal tissue of rats. Twenty male rats were randomly divided into four groups: control group, group 2 mg Se/L, 10 mg Se/L, and 20 mg Se/L rats fed with a basal basic diet and 2, 10, and 20 mg Se/L as sodium selenite in drinking water, respectively, for 20 weeks. Serum malondialdehyde and glutathione peroxidase activity were measured. Moreover, the expression and concentration of the cyclin D1, cyclin E, KRAS, p53, NF-kB, TGF-β, and MGMT in the esophageal tissue were analyzed and compared between the four groups. In normal esophageal tissue, selenium supplementations (2, 10, and 20 mg Se/L) increased the mRNA levels of cyclin D1, P53, KRAS, NF-κB p65, and MGMT and decreased the mRNA level of TGFß1. The concentrations of cyclin D1 and MGMT were also significantly increased by selenium supplementations. Selenium supplementations had no significant effect on serum MDA but significantly increased GPX activity. The present study suggests that selenium supplementation (2, 10, and 20 mg Se/L) affects gene expression related to inflammation, Cell proliferation, and apoptosis in the normal esophageal tissue. However, there were no observed abnormalities other than reduced growth with supplementation of 20 mg/L as Na2SeO3 in rats.


Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1.
Glioblastoma (GBM), the most common primary brain tumor, has a median survival of 15-16 months. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. GBMs express the interferon-gamma (IFN-γ)-responsive immunosuppressive molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1). Extracellular vesicles (EVs) have also been implicated in GBM-mediated immunosuppression, in part through PD-L1. We therefore sought to determine if GBM IFN-γ exposure increased GBM EV-mediated immunosuppression and mechanisms underlying this. Human GBM-derived cells were cultured in the presence/absence of IFN-γ. EVs were harvested. PD-L1, IDO1, and EV-associated protein expression was assessed. GBM EVs (+/-IFN-γ) were cultured with healthy donor monocytes. Immunosuppressive myeloid-derived suppressor cell (MDSC) and nonclassical monocyte (NCM) frequency was determined. Impact of GBM (+/-IFN-γ) EV-treated monocytes on CD3/CD28-mediated T cell proliferation was assessed. The impact of PD-L1 and IDO1 knockdown in GBM EVs in this system was evaluated. IFN-γ exposure increased PD-L1 and IDO1 expression in GBM cells and EVs without altering EV size or frequency. IFN-γ-exposed GBM EVs induced more MDSC and NCM differentiation in monocytes and these monocytes caused more T cell inhibition than IFN-γ-naive GBM EVs. PD-L1 and/or IDO1 knockdown in GBM cells abrogated the immunosuppressive effects of IFN-γ-exposed GBM EVs on monocytes. IFN-γ exposure such as might occur during an antitumor immune response results in superinduction of GBM EVs' baseline immunosuppressive effects on monocytes. These effects are mediated by increased PD-L1 and IDO1 expression in GBM EVs. These data highlight mechanisms of GBM EV-mediated immunosuppression and identify therapeutic targets (PD-L1, IDO1) to reverse these effects.


Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry.
Current prognostic implication of symptomatic patients with aortic stenosis (AS) remains undetermined. This study investigated the current prognostic implications of AS-related symptoms and the effect of aortic valve replacement (AVR) on outcome. We enrolled 586 consecutive patients with severe AS (aortic valve area <1.0cm2) with preserved left ventricular ejection fraction (≥50%). All patients were stratified into the following four groups based on the predominant symptoms: Group 1, asymptomatic (n=316); Group 2, chest pain (n=41); Group 3, heart failure (n=192); or Group 4, syncope (n=37). AS-related symptoms were diagnosed in 270 patients (46.1%), among whom 182 patients (32.2%) received AVR. Thirty-nine patients (6.7%) had cardiac death during the mean follow-up of 16±14 months. AVR was associated with significant reduction in cardiac death in Groups 3 (p<0.001) and 4 (p=0.004) whereas no significant prognostic advantage of AVR was observed in Groups 1 or 2. Cox proportional-hazard multivariate analysis revealed that age, heart failure, and mean pressure gradient (PG) were associated with increased risk of cardiac death in all patients regardless of AVR [hazard ratio (HR): 1.079, 2.090, and 1.008 respectively, all p<0.05]. In the patients without AVR, age, heart failure, syncope, and mean PG were independently associated with cardiac death (HR: 1.130, 3.639, 4.638, and 1.008, all p<0.05). This retrospective study demonstrated the current associations between the types of AS symptoms and prognosis in Japanese patients with severe AS.


In silico prediction of optimal in vivo delivery properties using convolution-based model and clinical trial simulation.
To develop a new strategy for the in silico evaluation of the optimal in vivo delivery properties of a drug, minimizing a cost function defined by the brain receptor occupancy obtained in positron-emission tomography experiments. A convolution-based model was formulated to link in vivo delivery rate to plasma concentrations whereas a second-stage model was used to link plasma concentrations to the pharmacodynamic effect. A feedback control approach was applied to identify the optimal in vivo delivery rate given an appropriate optimality criterion. Finally, clinical trial simulation was used as a supportive tool for decision-making by evaluating different scenarios accounting for pharmacokinetic/pharmacodynamic parameter uncertainty, inter-subject variability. and drug potency. The results revealed that the mean in vivo delivery time significantly affects brain receptor occupancy whereas the fraction of the dose available for the systemic circulation shows the highest influence on brain receptor occupancy for a given in vivo delivery rate. Finally, variability on receptor occupancy seems to be more affected by the inter-individual variability on the disposition PK parameters. The integration of convolution-based model. feedback control approach, and clinical trial simulation offers a unique tool for in ilico improvement of the drug development process by identifying critical issues on drug properties, optimal in vivo delivery rate, and potential problems related to the inter-individual variability.


CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1.
The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy-endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2BIntron5 mutation. In this study, we identify CHMP2B as a modifier of TDP-43-mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2BIntron5 causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation.


Machine Learning and Deep Learning Applications in Multiple Myeloma Diagnosis, Prognosis, and Treatment Selection.
Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ their discoveries to make abreast choice, while deep learning is a field of machine learning basically represented by algorithms inspired by the organization and function of the brain, named artificial neural networks. In this review, we examine the possibility of the artificial intelligence applications in multiple myeloma evaluation, and we report the most significant experimentations with respect to the machine and deep learning procedures in the relevant field. Multiple myeloma is one of the most common haematological malignancies in the world, and among them, it is one of the most difficult ones to cure due to the high occurrence of relapse and chemoresistance. Machine learning- and deep learning-based studies are expected to be among the future strategies to challenge this negative-prognosis tumour via the detection of new markers for their prompt discovery and therapy selection and by a better evaluation of its relapse and survival.


Bleomycin induces delayed instability of interstitial telomeric sequences in Chinese hamster ovary cells.
We analyzed the behavior of interstitial telomeric sequences (ITSs) in the progeny of Chinese Hamster Ovary (CHO) cells exposed to the radiomimetic compound bleomycin (BLM) in order to determine if ITSs play some role in the long-term clastogenic effect of this antibiotic. To this end, CHO cells were treated with a single concentration of BLM (2.5μg/ml), and the frequency of unstable chromosomal aberrations was determined at several times after treatment (18h, and 6, 15 and 34/36 days) by using PNA-FISH with a pan-telomeric probe [(TTAGGG)n repeats]. Cytogenetic analysis revealed a higher frequency of aberrations at 18h and 6 days after treatment in BLM-exposed cultures vs. untreated cultures, although the yield of BLM-induced aberrations decreased on average five times 6 days after treatment compared with the one induced 18h after treatment. Moreover, no significant differences in the frequency of aberrations were observed between untreated and BLM-exposed cells at 15 or 34/36 days after treatment. These data indicate that, in terms of unstable aberrations, the in vitro clastogenic effect of BLM on CHO cells persists for at least 6 days but less than 15 days after exposure. In addition, we found that BLM induces ITSs instability, cytogenetically detectable as acentric fragments (18h after treatment) or additional (new) FISH signals (6 days after treatment). We propose that the delayed effect of BLM on ITSs mainly results from breakage of heterochromatic ITSs blocks and further insertion of these sequences at the sites of monochromatid breaks occurring at G2 phase of the cell cycle, since most of the additional FISH signals were present as single dots and located at interstitial sites of the involved chromosomes.


Reversible inhibition by pyridoxal 5'-phosphate and irreversible inactivation by urea and guanidine hydrochloride of thymidylate synthase from Lactobacillus leichmannii.
Pyridoxal 5'-phosphate reversibly inhibited thymidylate synthase from Lactobacillus leichmannii. The inhibition was competitive with dUMP (Ki = 1 microM) and non-competitive with 5,10-CH2-THF (Ki = 0.08 microM). Treatment of native or pCMB-treated enzyme with urea (5 M) or guanidine hydrochloride (4 M) resulted in inactivation and dissociation of the homodimer (74 kDa) into monomer (37 kDa).


Lymphocyte accumulation in the spleen of retinoic acid receptor-related orphan receptor gamma-deficient mice.
The hormone nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORgamma) plays important roles in thymocyte development and lymphoid organogenesis. RORgamma and its thymus-specific isoform RORgammat are expressed in the thymus, but not in the spleen and bone marrow (BM). However, RORgamma(-/-) mice have 2- to 3-fold more splenocytes than wild-type controls due to an accumulation of conventional resting B lymphocytes. The increase in B lymphocytes in RORgamma(-/-) mice is caused neither by abnormal B cell development in the BM nor by an obvious defect in the peripheral T cell compartment. Furthermore, analyses of BM chimeras using either RORgamma(-/-) or recombinase-activating gene-2(-/-) mice as recipients and wild-type or RORgamma(-/-) mice as donors, respectively, demonstrate that the splenic microenvironment of RORgamma(-/-) mice is defective, since wild-type T and B lymphocytes accumulated in these chimeric mice. In addition, T lymphocyte homeostasis was altered due to a lowered thymic output in RORgamma(-/-) mice. Collectively, these results suggest that RORgamma regulates lymphocyte homeostasis at multiple levels.


Insights into open/closed conformations of the catalytically active human guanylate kinase as investigated by small-angle X-ray scattering.
Bio-catalysis is the outcome of a subtle interplay between internal motions in enzymes and chemical kinetics. Small-angle X-ray scattering (SAXS) investigation of an enzyme's internal motions during catalysis offers an integral view of the protein's structural plasticity, dynamics, and function, which is useful for understanding allosteric effects and developing novel medicines. Guanylate kinase (GMPK) is an essential enzyme involved in the guanine nucleotide metabolism of unicellular and multicellular organisms. It is also required for the intracellular activation of numerous antiviral and anticancer purine nucleoside analog prodrugs. Catalytically active recombinant human GMPK (hGMPK) was purified for the first time and changes in the size and shape of open/closed hGMPK were tracked by SAXS. The binding of substrates (GMP + AMPPNP or Ap5G or GMP + ADP) resulted in the compaction of size and shape of hGMPK. The structural changes between open and completely closed hGMPK conformation were confirmed by observing differences in the hGMPK secondary structures with circular dichroism spectroscopy.


Further characterization of estrogen receptors in the human oviduct.
Estrogen binding in human oviducts was studied in vitro by the dextran-coated charcoal assay and sucrose density ultracentrifugation. Estrogen binds with high affinity and limited capacity to cytosol of the human oviduct. The concentration of competitive inhibitors to produce 50% reduction in estrogen binding was 8 x 10(-8) M for the antiestrogen CI-628, 8 x 10(-7) M for the progestogen norethynodrel, and 3 x 10(-6) M for the testosterone derivative danazol at the ligand concentration of 1 nM estradiol. Nuclear estrogen binding was not inhibited by a 100-fold excess of progesterone or by a 10-fold excess of norethynodrel. Estrogen-binding protein with a sedimentation coefficient of 4S was seen in oviductal cytosol of all three anatomic segments. The nuclear 4S peak of estrogen binding was demonstrated in the ampullary tubal segment.


Psychotropic drug practice in nursing homes.
This study examined the administration of psychotropic medication to Medicaid recipients who resided continuously in an Illinois nursing home during 1984. Of these residents, 20,037 (60%) received at least one such medication during the year, with administration most likely for those from the ages of 45 to 74 years. Haloperidol, thioridazine, and flurazepam were the most frequently prescribed drugs of those examined. The study also investigated the relationship of demographic and institutional variables to the probability of drug administration and the amount administered. These variables were most strongly related to the probability of antipsychotic, antiparkinson, and antimanic (lithium) administration. The association of these variables with the amount of drug administered was strongest for antimanic and antipsychotic medications, particularly the latter. In all analyses, the addition of institutional variables increased goodness of fit minimally over that produced by demographic variables alone. This finding supports the conclusion that the prescription of psychotropic medication is more influenced by individual patient characteristics than by the nature of the institutional setting in which the patient resides.