Inhibition of SALL4 suppresses carcinogenesis of colorectal cancer via regulating Gli1 expression.
SALL4 is a novel oncogene mediating tumorigenesis in multiple carcinomas. However, its actual role and mechanisms participating in the development of colorectal cancer remains unclear. Immunohistochemical staining and Western blot were conducted to detect the expression of SALL4 and other molecules. siRNA of SALL4 was transfected to silence SALL4 expression in Caco-2 cell line. Flow cytometry was used for cell cycle and apoptosis analysis. Wound healing and transwell assay were used for invasion test. CCK-8 test was employed for cell proliferation and drug sensitivity assessment. By inhibition of SALL4 expression, the proliferation, invasiveness and drug resistance were dramatically reduced while apoptosis rate was up-regulated. Gli1 was found to decrease its expression in SALL4 silencing cells. Moreover, the inhibition on tumorigenesis of Caco-2 by SALL4 silencing was antagonized by Gli1 up-regulation, suggesting Gli1 as a downstream target of SALL4 in cancer development. SALL4 inhibition limited oncogenesis on colorectal cancer by reducing Gli1 expression.


Self cleavage of a precursor RNA from bacteriophage T4.
We found that a precursor of an RNA molecule from T4-infected Escherichia coli cells (p2Spl; precursor of species 1) has the capacity to cleave itself in a specific position. This cleavage is similar to a cleavage carried out by the aid of a protein, RNase F, that has been previously identified. This cleavage could lead to the maturation of an RNA (species 1) found in T4-infected E. coli cells. The reaction is time and temperature-dependent and is relatively slow as compared to the protein-dependent reaction. It requires at least a monovalent cation and is aided by non-ionic detergents. In the absence of detergent the cleavage can occur but at a reduced rate. The substrate does not contain hidden nicks and a variety of experiments suggest that it does not contain a protein. Moreover, we found no indication that the cleavage is due to contaminating nucleases in the substrate or in the reagents. The intact secondary and tertiary structures of the molecule are necessary for the cleavage to occur. The finding of a self cleaving RNA molecule has interesting evolutionary implications.


Emerging Treatment Modalities for Neovascular Age-Related Macular Degeneration: A Systematic Overview.
Neovascular age-related macular degeneration (nAMD) represents a leading cause of irreversible visual loss affecting the quality of life of millions of elderly patients worldwide. Although the introduction of intravitreal injections with anti-vascular endothelial growth factors (anti-VEGF) agents has revolutionized the management of nAMD, their effectiveness and ultimate success are limited by several therapeutic challenges. Consequently, real-world efficacy appears significantly inferior to that reported by randomized controlled trials. Therefore, further innovative, long-term treatment options are essential to improve the prognosis and outcome of nAMD therapy. Emerging pharmacological therapies for nAMD and those currently in clinical trials are reviewed and their mechanism of action, safety, and efficacy are discussed. The evidence presented herein has been collected from online databases PubMed, Cochrane library, and the ClinicalTrials.gov site. A number of promising technologies and novel anti-VEGF therapies are currently being tested and some have already reached phase III trials. Anti-VEGF agents with enhanced durability and possibly efficacy, gene therapy, angiogenic targets, alternative drug delivery routes such as sustained delivery implants, drug carriers, and encapsulated cell technology are currently being explored. We briefly discuss the potential value of these options. Several options may optimize future nAMD management. On the basis of current, albeit limited evidence, the most promising technology to reach clinical practice soon appears to be the sustained drug delivery options, which may improve visual outcome and reduce the socioeconomic burden of nAMD.


Sclerostin is a promising therapeutic target for oral inflammation and regenerative dentistry.
Sclerostin is the protein product of the SOST gene and is known for its inhibitory effects on bone formation. The monoclonal antibody against sclerostin has been approved as a novel treatment method for osteoporosis. Oral health is one of the essential aspects of general human health. Hereditary bone dysplasia syndrome caused by sclerostin deficiency is often accompanied by some dental malformations, inspiring the therapeutic exploration of sclerostin in the oral and dental fields. Recent studies have found that sclerostin is expressed in several functional cell types in oral tissues, and the expression level of sclerostin is altered in pathological conditions. Sclerostin not only exerts similar negative outcomes on the formation of alveolar bone and bone-like tissues, including dentin and cementum, but also participates in the development of oral inflammatory diseases such as periodontitis, pulpitis, and peri-implantitis. This review aims to highlight related research progress of sclerostin in oral cavity, propose necessary further research in this field, and discuss its potential as a therapeutic target for dental indications and regenerative dentistry.


Ammonia-sensitive cellulose acetate-based films incorporated with Co-BIT microcrystals for smart packaging application.
Nowadays, there is an increasing demand for smart packaging materials capable of effectively monitoring the food freshness. In this study, new Co-based MOF (Co-BIT) microcrystals with ammonia-sensitivity and antibacterial function were constructed and then loaded within cellulose acetate (CA) matrix to create smart active packaging materials. The influences of Co-BIT loading upon structure, physical, and functional properties of the CA films were then thoroughly explored. It was observed that microcrystalline Co-BIT was uniformly integrated inside CA matrix, which caused significant promotions in mechanical strength (from 24.12 to 39.76 MPa), water barrier (from 9.32 × 10-6 to 2.73 × 10-6 g/m·h·Pa) and ultraviolet light protection performances of CA film. Additionally, the created CA/Co-BIT films displayed striking antibacterial efficacy (>95.0 % for both Escherichia coli and Staphylococcus aureus), favorable ammonia-sensitivity function as well as color stability. Finally, the CA/Co-BIT films were successfully applied for indicating the spoilage of shrimp through discernible color changes. These findings suggest that Co-BIT loaded CA composite films have great potential for use as smart active packaging.


Dental tissue remineralization by bioactive calcium phosphate nanoparticles formulations.
Recent health care products are based on formulations claimed to provide enamel remineralization and dentinal tubules occlusion through calcium-phosphate bioactive nanocompounds (ion-doped hydroxyapatite and precursor, amorphous calcium phosphate nanoparticles). This study aimed to characterize, test, and compare for the first time the structure and performance of a representative, market-available sample of remineralizing toothpastes and topical mousses. Formulations were characterized to determine their composition and investigate the presence of bioactive compounds and doping elements. A conventional fluoride-containing toothpaste was used as reference. The enamel remineralization and efficacy of dentinal tubules occlusion by tested formulations were investigated ex vivo on human hard tissues. All formulations containing Ca-P bioactive nanocompounds showed remineralizing ability by epitaxial growth of a layer showing the morphology and composition of human hydroxyapatite. Such layers also embedded nanosilica clusters. The presence of doping elements or casein phosphopeptide seemed essential to allow such performances, especially when hydroxyapatite and amorphous calcium phosphate compounds were doped with small amounts of CO32-, F-, Mg2+, and Sr2+. Topical mousse formulations showed a higher tubules occlusion capability than toothpastes, independently from their composition. Therefore, all tested formulations could be useful in restoring tooth structures in a biomimetic way, contrasting dental demineralization processes leading to caries.


Questions regarding the sequential neural generator theory of the somatosensory evoked potential raised by digital filtering.
Digital bandpass filtering (300-2500 Hz) designed for zero phase shift was applied to somato-sensory evoked potentials recorded with cephalic bipolar montages. Four consistent negative and corresponding positive peaks with latencies of about 16, 18, 19, and 20 msec were elicited with median nerve stimulation. Peroneal nerve stimulation also elicited 4 reproducible negative-positive peaks having latencies of about 24, 26, 28, and 30 msec. Interpeak latencies measured 1.3 +/- 0.2 msec and 1.8 +/- 0.25 msec for median and peroneal elicited SEPs respectively. Because cephalic bipolar recordings cancel most far-field potentials, multiple generators cannot account for all the additional components seen. It is hypothesized that some of the high frequency components recorded are due to activity in recurrent intrathalamic neuronal networks.


Metastatic germ cell tumor of the lung masquerading as primary rhabdomyosarcoma.
Two years after testicular resection was carried out in a 40-year-old man that revealed mixed germ cell tumor of more than one histological type (seminoma, embryonal cell carcinoma, and yolk sac tumor), he presented with an asymptomatic pulmonary nodule in his left lower lobe. Video-assisted thoracoscopic partial resection of the tumor revealed a 24 x 20 mm teratoma with somatic-type malignancy in which pleomorphic rhabdomyosarcoma was a major element. One year later, asymptomatic tumor recurrence occurred at both edges of the stapler line as 22 x 20 mm and 10 x 5 mm nodules composed only of pleomorphic rhabdomyosarcoma. Throughout the course there was no abdominal lymph node swelling detected by computed tomography (CT) and tumor markers were normal. Adjuvant chemotherapy was started after the tumor recurrence. Currently, the patient is still undergoing chemotherapy 5 months after the tumor recurrence. In conclusion, despite the fact that primary pulmonary rhabdromyosarcoma is a rare neoplasm, metastatic pulmonary germ cell tumor with somatic-type malignancy showing predominantly rhabdomyosarcomatous differentiation should be considered in the differential diagnosis of such lesions of the lung.


Antileishmanial activity of MDL 28170, a potent calpain inhibitor.
Several calpain inhibitors are under development and some are useful agents against important human pathogens. We therefore investigated the effect of MDL 28170, a potent calpain inhibitor, on the growth of Leishmania amazonensis. After 48 h of treatment, the inhibitor exhibited a dose-dependent antileishmanial activity, with a 50% lethal dose (LD(50)) of 23.3 microM. The inhibitor promoted cellular alterations, such as the parasites becoming short and round. A calpain-like protein migrating at 80 kDa was identified by Western blotting. In addition, the calpain-like molecules were identified on the cell surface of the flagellate. These results add new in vitro insights into the exploitation of calpain inhibitors in treating parasitic infections and add this family of peptidases to the list of potential targets for development of more potent and specific inhibitors against trypanosomatids.


Education as the key to rehabilitation.
Rehabilitation education is the key for successful transference to the home setting for the client and family. Can you picture a family at the rehabilitation facility on the day of discharge taking home a 19-year-old son with a severe head injury or a high spinal cord injury without this preparation? The client and family must be evaluated by the rehabilitation team to plan the individualized educational program. Education must start at admission and involve every member of the rehabilitation team in order to offer a complete educational program. The criteria for discharge of the client are based on an educational program successfully addressing self-care, self-direction, and self-responsibility.


[Anterior wall infarct in an angiographically demonstrated muscle bridge of the ramus interventricularis anterior].
Coronary angiography in a 58-year-old man who had sustained an anterior-wall myocardial infarction demonstrated a myocardial bridge over the anterior interventricular branch as the only abnormal finding which, in the absence of any arteriosclerotic changes proximal or at the level of the bridge, suggests a causal relationship.


The effects of chromium and copper supplementation on mitogen-stimulated T cell proliferation in hypercholesterolaemic postmenopausal women.
The purpose of this study was to analyse effects of chromium and/or copper supplementation on immune function in hypercholesterolaemic postmenopausal women. A 2 x 2 factorial research design was used and 40 subjects were supplemented with 0.394 g lactose, 200 microg Cr, 3.0 mg Cu, or 200 microg Cr and 3.0 mg Cu/d for 12 weeks. A significant interactive effect of Cr and Cu supplementation on lymphocyte proliferation was observed with ConA 50 microg/ml stimulation. After 12 weeks of supplementation, ConA-stimulated (50 microg/ml) lymphocyte proliferation was significantly lower when Cu was added to the Cr supplementation group. Moreover, ConA-stimulated (100 microg/ml) lymphocyte proliferation was significantly lower in the Cu supplementation group compared to the Cr supplementation group after 12 weeks of supplementation. These results suggest that Cu blocks enhancement of lymphocyte proliferation by Cr supplementation and that Cu supplementation has potential suppressive effects on the immune function in these subjects.


Sixteen years' experience with the Heitz Boyer-Hovelacque procedure for exstrophy of the bladder.
The various methods of managing bladder exstrophy are described. Bladder reconstruction and ureterosigmoidostomy are discussed and evaluated. The satisfactory results obtained with 21 patients treated by the Heitz Boyer-Hovelacque operation are reported and it is concluded that this is the procedure of choice when urinary diversion is needed for the exstrophic bladder.


Cyclic GMP and cyclic AMP changes in response to folic acid pulses during cell development of Dictyostelium discoideum.
Folic acid pulses induced developmental processes in agip 71, a morphogenetic mutant of Dictyostelium discoideum, strain Ax-2. Cells that had received folic acid pulses were able to form EDTA-stable cell aggregates and to complete full differentiation to fruiting bodies. In these cells no autonomous periodic activities were observed by light scattering. Folic acid pulses elicited increases in the concentrations of cyclic GMP and cyclic AMP. In undifferentiated cells, folic acid caused a rapid increase in the level of cyclic GMP without a significant change in the level of cyclic AMP. In an advanced developmental state folic acid caused an increase in cyclic AMP in addition to two successsive peaks of cyclic GMP. Experiments performed with the parent strain, Ax-2, also showed that during the development towards aggregation competence, cells acquired the ability to produce a cyclic AMP peak in response to folic acid.


What's new in pediatric dermatology.
This report discusses some of the newly described diseases in pediatric dermatology and recent developments in other diseases that are pertinent to this field.


[Effect of semi-synthetic penicillins and cephaloridine on indices of immunologic reactivity and protein metabolism during treatment of puerperal infection].
The effect of semisynthetic penicillins, such as methicillin and oxacillin and cephalosporins, such as cephaloridin of immunity and protein metabolism was studied on 63 patients with postnatal mastitis and endomyometritis. It was shown that the above antibiotics had no significant effect on the immunological reactivity and protein metabolism. However, lower titers of alpha-antitoxin, lysine levels and C-reactive protein content were registered in the mastitis patients treated with cephaloridin. Therefore, while recomending antibacterial drugs their effect on the immunity and protein metabolism should be taken into account and from this point of view semisynthetic penicillins are preferable in treatment of mastitis patients and semisynthetic penicillins and cephaloridin are preferable in treatment of endomyometritis patients.


Methylmercury upregulates RE-1 silencing transcription factor (REST) in SH-SY5Y cells and mouse cerebellum.
Methylmercury (MeHg) is a highly neurotoxic compound that, in adequate doses, can cause damage to the brain, including developmental defects and in severe cases cell death. The RE-1-silencing transcription factor (REST) has been found to be involved in the neurotoxic effects of environmental pollutants such as polychlorinated biphenyls (PCBs). In this study, we investigated the effects of MeHg treatment on REST expression and its role in MeHg-induced neurotoxicity in neuroblastoma SH-SY5Y cells. We found that MeHg exposure caused a dose- and time- dependent apoptotic cell death, as evidenced by the appearance of apoptotic hallmarks including caspase-3 processing and annexin V uptake. Moreover, MeHg increased REST gene and gene product expression. MeHg-induced apoptotic cell death was completely abolished by REST knockdown. Interestingly, MeHg (1μM/24h) increased the expression of REST Corepressor (Co-REST) and its binding with REST whereas the other REST cofactor mammalian SIN3 homolog A transcription regulator (mSin3A) was not modified. In addition, we demonstrated that the acetylation of histone protein H4 was reduced after MeHg treatment and was critical for MeHg-induced apoptosis. Accordingly, the pan-histone deacetylase inhibitor trichostatin-A (TSA) prevented MeHg-induced histone protein H4 deacetylation, thereby reverting MeHg-induced neurotoxic effect. Male mice subcutaneously injected with 10mg/kg of MeHg for 10 days showed an increase in REST expression in the granule cell layer of the cerebellum together with a decrease in histone H4 acetylation. Collectively, we demonstrated that methylmercury exposure can cause neurotoxicity by activating REST gene expression and H4 deacetylation.


3H-dopamine accumulation by rat brain synaptic vesicles in a membrane-impermeable medium.
3H-Dopamine (DA) accumulation by storage vesicles from whole rat brain was significantly stablized in a buffer system based upon the membrane-impermeant D-potassium tartrate. 3H-DA uptake saturated by twenty minutes (Km 2.1 X 10(-5)M) and remained stable for periods of 40-60 minutes. Accumulated DA was rapidly exchangeable with exogenous DA. Total levels of accumulation (pmol/mg protein) were 41.7 +/- 2.9 (37 degrees), 11.9 +/- 2.5 (4 degrees), 31.3 +/- 1.8 (absence of ATP), 26.3 +/- 2.7 (reserpine, 10(-6)M), 26.1 +/- 0.67 (no ATP + reserpine 10(-6), and 14.6 +/- 2.4 (carbonylcyanide-p-triflouromethoxyphenylhydrazone, FCCP, 10(-6)M). Depletion of endogenous DA levels by pretreatment of the animals with alpha-methyl-p-tyrosine greatly diminished the reserpine-insensitive DA accumulation. After depletion of endogenous DA, ATP-independent uptake was significantly retarded, but eventually reached near-control levels. This uptake was abolished in the presence of FCCP (10(-6)M). The results suggest that endogenous levels of DA and ATP contribute to the reserpine- and ATP-insensitive DA accumulation observed in vesicles from untreated animals. HPLC analysis demonstrated no conversion of DA to norepinephrine (NE) in the course of the experiments.


Nonpharmacological interventions for treating fatigue in adolescents: A systematic review and narrative synthesis of randomised controlled trials.
Fatigue is common in adolescence and can be highly disabling if experienced persistently, with adverse psychosocial outcomes. There is a need to better understand what nonpharmacological treatments are available for adolescents suffering with persistent fatigue. The current review systematically identified, synthesised, and evaluated the evidence regarding nonpharmacological interventions for fatigue in adolescents, focusing on evaluating effectiveness, describing intervention components, and mapping interventions onto the behaviour change technique taxonomy (BCTT). CENTRAL, EMBASE, PsycINFO, PubMed, and Web of Science were systematically searched for articles including (1) adolescents aged 10-19 years old, (2) fatigue as a primary or secondary outcome, (3) nonpharmacological interventions, and (4) randomised controlled trials. Study screening, data extraction, quality assessment, and BCTT mapping were performed independently by two reviewers. Findings were presented as a narrative synthesis, with interventions ranked by promise. 5626 papers were identified and double-screened, resulting in the inclusion of 21 articles reporting 16 trials. Five interventions were classified as likely promising. Interventions often involved psychoeducation, cognitive behavioural therapy, and/or physical activity, incorporating various BCTT domains, most commonly shaping knowledge, repetition and substitution, and goals and planning. However, there did not seem to be any observable differences between fatigue-targeted and non-fatigue-targeted interventions. Overall study quality was mixed, particularly in relation to power and outcome measures. There are several promising nonpharmacological interventions for adolescent fatigue, although further work is needed to determine effectiveness. Future trials need to ensure design rigour, focusing on adequate powering, validated outcome measures, and adhering to best practice reporting guidelines.


Changes in photoinduced cutaneous erythema with topical application of a combination of vitamins C and E before and after UV exposure.
Ultraviolet radiation is harmful for human skin, and photodamaging pathologies such as actinic erythema, are formerly described as a consequence of UV direct effect on DNA and indirectly by local immune reactions. However, the degree of participation of oxidative stress in actinic erythema and the role of antioxidants in photoprotection are still not fully understood. To evaluate the possible palliative role of a combination of the antioxidants vitamins C and E in human cutaneous erythema when applied topically before and after UV exposure. The study included 20 volunteers of phototypes II, II-III and III with no solar exposure for two months prior to the study. The volunteers were submitted to a phototest consisting on the analysis of the minimal erythemal dose (MED) under different treatments: 1. Untreated irradiated skin; 2. Irradiated skin previously treated with vehicle; 3. Irradiated skin previously treated with a combination of vitamins (2.5% vit E-5% vit C); and 4. Skin treated with the antioxidant combination after irradiation. Cutaneous erythema was evaluated 24h after exposure and the MED was calculated for each treatment. The application of vehicle did not significantly affect the MED compared to untreated irradiated skin. Application of the antioxidant combination, prior to irradiation, increased the MED in all phototypes compared with untreated irradiated skin with an average increase of 36.9%. Antioxidants applied after exposure promoted an average increase of the MED by 19.8%. Combination of topical antioxidants (vitamins C and E) shows photoprotection activity against erythema, mainly owing to their high absorption properties. Moreover, their antioxidant activity could be considered as additive, and independent of their optical properties.


Physical recovery after laparoscopic vs. open liver resection - A prospective cohort study.
While the number of laparoscopic liver resections (LLRs) is increasing worldwide, its impact on physical recovery remains unclear. We hypothesized that LLR is associated with better physical recovery than open liver resection (OLR). To address this question, we investigated the impact of laparoscopic liver resection compared to open liver resection on physical recovery in a prospective trial. Twenty-one patients who underwent LR were included in this study (11 OLR (52.4%) and 10 LLR (47.6%), respectively). Physical recovery was measured by bicycle stress testing at months 1 and 6 after surgery and compared to preoperative stress testing. Standardized performance for bicycle stress testing was calculated based on age, sex, height and weight. Physical recovery was compared between groups as change of performance (%). Median age was 58 years (Inter Quartile Range (IQR): 44-68), and the main indications for LR were colorectal liver metastases (n = 10; 45%) and hepatocellular carcinoma (n = 6; 27%). The one-month change of performance level was -8% (IQR: -12-1) compared to the preoperative level with no significant difference between open and laparoscopic LR (LLR: -8% (-11 - 1); OLR: -6% (-12 - 4), p = 0.833). Furthermore, 6 months postoperatively, patients in both groups had not reached back their preoperative performance level (LLR: -5.7% (-8.4 - 18.6); OLR -4. 8% (-12.6 - 1.9), p = 0.833). In this study, we report an impaired physical recovery after LR that was not fully restored 6 months after surgery. There was no significant difference between open and laparoscopic LR in terms of bicycle stress testing. Limitations of the study include the limited sample size and differences, albeit non-statistically significant, in the baseline characteristics of the two groups. To rule out a possible role of age or underlying indication for liver resection on physical recovery, future randomized controlled trials need to be performed.


Multiplexed Protease Specificity Profiling Using Isobaric Labeling.
The determination of a protease's cleavage site specificity is one of the major goals in degradomics. In the last years, the use of proteome-derived peptide libraries and liquid chromatography-mass spectrometry (LC-MS) in a proteomic identification of protease cleavage sites (PICS) experiment became popular for that purpose.In this chapter, we offer a step-by-step protocol for the execution of a quantitative proteomic identification of protease cleavage sites (Q-PICS) experiment, which enables the relative quantification of proteolytic events by isobaric labeling, e.g., with tandem mass tags (TMT). In this way, the cleavage site specificity and activity of a protease can be compared under different reaction conditions (e.g., buffer, pH, temperature, inhibitor). Multiplexing can further be used to analyze replicate experiments in parallel, decreasing instrument times and work effort significantly, or to perform internal controls.


Impact of high strain rate deformation on the mechanical behavior, fracture mechanisms and anisotropic response of 2060 Al-Cu-Li alloy.
Since AA2060-T8 was introduced in the past few years, investigating the mechanical response, fracture mechanisms, and anisotropic behaviour of AA2060-T8 sheets under high strain rate deformation has been crucial. Thus, uniaxial tensile tests were performed under quasi-static, intermediate, and high strain rate conditions using universal testing machines as well as split Hopkinson tensile bars. The experimental results showed that the ductility of AA2060-T8 sheets was improved during high strain rate deformation because of the adiabatic softening and the inertia effect which contribute to slow down the necking development, and these results were verified by the fracture morphologies of high strain rate tensile samples. Furthermore, the strain rate hardening influence of AA2060-T8 was significant. Therefore, the Johnson-Cook constitutive model was modified to consider the effects of both strain and strain rates on the strain hardening coefficient. The results obtained from the improved Johnson-Cook constitutive model are in remarkable accordance with those obtained from experimental work. Thus, the improved Johnson-Cook model can predict the flow behavior of AA2060-T8 sheets at room temperature over a wide range of strain rates. The results of the present study can efficiently be used to develop a new manufacturing route based on impact hydroforming technology (IHF) to manufacture sound thin-walled-complex shape components from AA2060-T8 sheets at room temperature.


Altered hACE2 binding affinity and S1/S2 cleavage efficiency of SARS-CoV-2 spike protein mutants affect viral cell entry.
SARS-CoV-2 variants are constantly emerging, hampering public health measures in controlling the number of infections. While it is well established that mutations in spike proteins observed for the different variants directly affect virus entry into host cells, there remains a need for further expansion of systematic and multifaceted comparisons. Here, we comprehensively studied the effect of spike protein mutations on spike expression and proteolytic activation, binding affinity, viral entry efficiency and host cell tropism of eight variants of concern (VOC) and variants of interest (VOI). We found that both the full-length spike and its receptor-binding domain (RBD) of Omicron bind to hACE2 with an affinity similar to that of the wild-type. In addition, Alpha, Beta, Delta and Lambda pseudoviruses gained significantly enhanced cell entry ability compared to the wild-type, while the Omicron pseudoviruses showed a slightly increased cell entry, suggesting the vastly increased rate of transmission observed for Omicron variant is not associated with its affinity to hACE2. We also found that the spikes of Omicron and Mu showed lower S1/S2 cleavage efficiency and inefficiently utilized TMPRSS2 to enter host cells than others, suggesting that they prefer the endocytosis pathway to enter host cells. Furthermore, all variants' pseudoviruses we tested gained the ability to enter the animal ACE2-expressing cells. Especially the infection potential of rats and mice showed significantly increased, strongly suggesting that rodents possibly become a reservoir for viral evolution. The insights gained from this study provide valuable guidance for a targeted approach to epidemic control, and contribute to a better understanding of SARS-CoV-2 evolution.


Differential alterations in branched-chain amino acid decarboxylation in liver of hypophysectomized rats.
Valine decarboxylation was significantly increased and leucine decarboxylation was significantly decreased in rat liver slices following hypophysectomy. In both normal and hypophysectomized rats decarboxylation of leucine exceeded that of valine in slices whereas the reverse was observed with the respective keto acids and mitochondria.


[Students' views on current training].
Nursing training is governed by the 2009 reference framework. But is it still appropriate? If not, what do students need to learn their future profession in three years? These are the questions that the National Federation of Nursing Students wanted to answer by launching, in April 2022, its "Grandes consultations". Traveling to the thirteen regions of France, its representatives met with teaching teams, local stakeholders and, above all, students, who were thus able to make their voices heard.


Connectivity maps for biosimilar drug discovery in venoms: the case of Gila monster venom and the anti-diabetes drug Byetta®.
Like most natural product libraries animal venoms have long been recognized as potentially rich source of biologically active molecules with the potential to be mined for the discovery of drugs, drug leads and/or biosimilars. In this work we demonstrate as a proof of concept a novel approach to explore venoms for potential biosimilarity to other drugs based on their ability to alter the transcriptomes of test cell lines followed by informatic searches and Connectivity Mapping to match the action of the venom on the cell gene expression to that of other drugs in the Connectivity Map (C-Map) database. As our test animal venom we chose Heloderma suspectum venom (Gila monster) since exendin-4, a glucagon-like peptide 1 receptor agonist, isolated from the venom is currently on the market to treat type 2 diabetes. The action of Byetta(®) (exentide, synthetic exendin-4), was also used in transcriptome studies. Analysis of transcriptomes from cells treated with the venom or the drug showed similarities as well as differences. The former case was primarily attributed to the fact that Gila monster venom likely contains a variety of biologically active molecules that could alter the MCF7 cell transcriptome compared to that of the single perturbant Byetta(®). Using Ingenuity Pathway Analysis software, insulin-like growth factor 1 signaling was identified in the category of "Top Canonical Pathways" for both the venom and Byetta(®). In the category of "Top Molecules" up-regulated, both venom and Byetta(®) shared IL-8, cyclic AMP-dependent transcription factor 3 (ATF-3), neuron-derived orphan receptor 1 (NR4A3), dexamethasone-induced Ras-related protein 1 (RASD1) and early growth response protein 1, (EGR-1) all with potential relevance in diabetes. Using Connectivity Mapping, Gila monster venom showed positive correlation with 1732 instances and negative correlation with 793 instances in the Connectivity database whereas Byetta(®) showed positive correlation with 1692 instances and negative correlation with 868 instances. Interestingly, the Gila monster venom and Byetta(®) both showed positive correlation with the anti-diabetic drugs troglitazone, of the thiazolidinedione class, and metformin, of the biguanide class, although Byetta(®) as a glucagon-like peptide-1 (GLP-1) agonist functions in a different manner than either of these two classes of anti-diabetic drugs. In summary, despite the fact that Gila monster venom contains a mixture of biologically active molecules, similarities in terms of perturbation of gene expression profiles on MCF7 cells were observed between the venom and the drug Byetta(®). Furthermore, using Connectivity Mapping the Gila monster venom was demonstrated to have nodes of positive correlation to several anti-diabetic drugs two of which were the same as observed with Byetta(®). Therefore, this study suggests that by using this approach novel drug activities heretofore unconsidered may be discovered in venoms using informatic tools and Connectivity Mapping.


Ocean currents show global intensification of weak tropical cyclones.
Theory1 and numerical modelling2 suggest that tropical cyclones (TCs) will strengthen with rising ocean temperatures. Even though models have reached broad agreement on projected TC intensification3-5, observed trends in TC intensity remain inconclusive and under active debate6-10 in all ocean basins except the North Atlantic, where aircraft reconnaissance data greatly reduce uncertainties11. The conventional satellite-based estimates are not accurate enough to ascertain the trend in TC intensity6,11, suffering from contamination by heavy rain, clouds, breaking waves and spray12. Here we show that weak TCs (that is, tropical storms to category-1 TCs based on the Saffir-Simpson scale) have intensified in all ocean basins during the period 1991-2020, based on huge amounts of highly accurate ocean current data derived from surface drifters. These drifters have submerged 'holy sock' drogues at 15 m depth to reduce biases induced by processes at the air-sea interface and thereby accurately measure near-surface currents, even under the most destructive TCs. The ocean current speeds show a robust upward trend of ~4.0 cm s-1 per decade globally, corresponding to a positive trend of 1.8 m s-1 per decade in the TC intensity. Our analysis further indicates that globally TCs have strengthened across the entirety of the intensity distribution. These results serve as a historical baseline that is crucial for assessing model physics, simulations and projections given the failure of state-of-the-art climate models in fully replicating these trends13.


Integration of Oral Health Screening, Intervention, and Referral Into the Pediatric Well-Child Visit.
Parents of children usually understand the importance of getting primary care pediatric well-child checkups during certain stages of childhood, yet few know the importance of early routine dental visits to proactively incorporate good oral hygiene and relate the connection of oral care to overall systemic physical health. The purpose was to determine the impact of integrating oral health screening, intervention, and referral into the pediatric well-child visit. Children (aged 0-18 years) received oral health screening, oral photographs, fluoride varnish, oral health education, and referral during well-child visits. Forty-two percent of our population had never had a dental examination. Fifty-eight percent had no established dental home, and 73% drank sugar-sweetened beverages weekly. The overall impact of this model was providing comprehensive oral health care to children who have never been to the dentist and providing a smooth transition between medical and dental, increasing access to care.


Hybrid structures of cobalt-molybdenum bimetallic oxide embedded in flower-like molybdenum disulfide for sensitive detection of the antibiotic drug nitrofurantoin.
Excessive residues of nitrofurantoin (NFT) can cause serious contamination of water bodies and food, and potential harm to ecosystems and food safety. Given that, rapid and efficient detection of NFT in real samples is of particular importance. MoS2 is a promising electrochemical material for this application. Here, MoS2 was modulated by Metal-organic framework through the interfacial microenvironment to enhance the catalytic activity and carbonized to form Co2Mo3O8 nanosheets with high electrical activity. The resulting Co2Mo3O8/MoS2 hybrid structure can be used to prepare highly sensitive NFT electrochemical sensor. The Co2Mo3O8/MoS2@CC electrochemical sensor exhibits strong electrochemical properties due to its fast electron transfer, excellent electrical conductivity, abundant defect sites, and high redox response. Based on this, this electrochemical sensor exhibited excellent electrocatalytic activity for NFT with a wide linear detection range, low detection limit, and high sensitivity. Moreover, the electrode was successfully applied to detect NFT in milk, honey, and tap water, strongly confirming its potential in real samples. This work could furnish the evidence for interfacial microenvironmental regulation of MoS2, and also offer a novel candidate material for NFT sensing.


Metabolism of propafenone and verapamil by cryopreserved human, rat, mouse and dog hepatocytes: comparison with metabolism in vivo.
In the present study we examined the metabolism of [(14)C]propafenone (P) and [(14)C]verapamil (V) using cryopreserved human, dog (Beagle), rat (Sprague-Dawley) and mouse (NMRI) hepatocytes. The percentage ratios of the metabolites were identified after extraction by HPLC with UV and radioactivity detection. Phase-II metabolites were cleaved using beta-glucuronidase. Metabolism of the drugs by cryopreserved hepatocytes was compared with that in the respective species in vivo. All phase-I and -II metabolites known from in vivo experiments: 5-hydroxy-P (5-OH-P); 4'-hydroxy-P (4'-OH-P); N-despropyl-P (NdesP) and the respective glucuronides, were identified after incubation with cryopreserved hepatocytes. Interspecies differences were observed concerning the preferential position of propafenone hydroxylation: 5-OH-P made up 91, 51, 16 and 3% of the total metabolites after incubation with cryopreserved human ( n=4), dog ( n=3), rat ( n=3) and mouse ( n=4) hepatocytes respectively. These results are consistent with interspecies differences known from in vivo experiments. The metabolism of V is more complex than that of P. Nevertheless, all phase-I metabolites known from in vivo experiments and the expected glucuronides were identified after incubation with cryopreserved hepatocytes from all four species. As expected from the results of in vivo experiments, there were no major interspecies differences with respect to phase-I metabolites although the conjugation of verapamil phase-I metabolites by cryopreserved canine hepatocytes was much weaker than for the other species. In conclusion, phase-I and phase-II metabolism of P and V was evaluated using hepatocytes in vitro. All of the relevant interspecies differences known from in vivo experiments were identified after short-term incubation with cryopreserved hepatocytes in suspension.


Development and validation of an electronic frailty index using routine primary care electronic health record data.
frailty is an especially problematic expression of population ageing. International guidelines recommend routine identification of frailty to provide evidence-based treatment, but currently available tools require additional resource. to develop and validate an electronic frailty index (eFI) using routinely available primary care electronic health record data. retrospective cohort study. Development and internal validation cohorts were established using a randomly split sample of the ResearchOne primary care database. External validation cohort established using THIN database. patients aged 65-95, registered with a ResearchOne or THIN practice on 14 October 2008. we constructed the eFI using the cumulative deficit frailty model as our theoretical framework. The eFI score is calculated by the presence or absence of individual deficits as a proportion of the total possible. Categories of fit, mild, moderate and severe frailty were defined using population quartiles. outcomes were 1-, 3- and 5-year mortality, hospitalisation and nursing home admission. hazard ratios (HRs) were estimated using bivariate and multivariate Cox regression analyses. Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was assessed using pseudo-R(2) estimates. we include data from a total of 931,541 patients. The eFI incorporates 36 deficits constructed using 2,171 CTV3 codes. One-year adjusted HR for mortality was 1.92 (95% CI 1.81-2.04) for mild frailty, 3.10 (95% CI 2.91-3.31) for moderate frailty and 4.52 (95% CI 4.16-4.91) for severe frailty. Corresponding estimates for hospitalisation were 1.93 (95% CI 1.86-2.01), 3.04 (95% CI 2.90-3.19) and 4.73 (95% CI 4.43-5.06) and for nursing home admission were 1.89 (95% CI 1.63-2.15), 3.19 (95% CI 2.73-3.73) and 4.76 (95% CI 3.92-5.77), with good to moderate discrimination but low calibration estimates. the eFI uses routine data to identify older people with mild, moderate and severe frailty, with robust predictive validity for outcomes of mortality, hospitalisation and nursing home admission. Routine implementation of the eFI could enable delivery of evidence-based interventions to improve outcomes for this vulnerable group.


Quantification of [(123)I]PE2I binding to dopamine transporters with SPET.
The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with single-photon emission tomography (SPET). The aim of the present study was to describe a method for accurate quantification of binding data following a bolus injection of [(123)I]PE2I. Six healthy subjects (age 51+/-24 years) underwent xenon-133 SPET for quantification of regional CBF and [(123)I]PE2I SPET for quantification of DAT binding. rCBFs were within normal limits in all subjects. Fitting data to a two-tissue compartment model resulted in striatal K(1) values of 0.39+/-0.08 ml ml(-1) min(-1), equal to a first-pass extraction fraction of 0.72+/-0.13. Distribution volumes (DVs) were calculated using compartment analysis, area under the curve analysis and Logan analysis. Logan analysis is preferred since stable DV values were already obtained 120 min after [(123)I]PE2I injection. Mean striatal DV was 37.9+/-9.6 ml ml(-1) and mean occipital cortex DV was 5.5+/-0.7 ml ml(-1). In the absence of local pathology in a reference tissue, Logan analysis without blood sampling is an attractive method for accurate quantification of striatal [(123)I]PE2I binding. The distribution volume ratio (DVR) (6.6+/-1.4) was in good agreement with the DVR calculated with blood (6.7+/-1.4).


Obstructive sleep apnea in non-dialyzed chronic kidney disease patients: Association with body adiposity and sarcopenia.
Obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease (CVD), the main cause of mortality in chronic kidney disease (CKD). Although the prevalence of OSA in patients with CKD has not been established, a few studies suggest that it is higher than in the general population, potentially increasing the risk for CVD. Obesity increases the risk, whereas sarcopenia has been suggested as a consequence of OSA in the general population. To our knowledge, these associations have not been adequately evaluated in patients with CKD. The aim of this study was to evaluate OSA frequency and its association with total and upper body adiposity and sarcopenia in non-dialyzed CKD patients. This cross-sectional study included 73 patients with stages 3b-4 CKD (42 men, 62.9 ± 1.1 y of age). Glomerular filtration rate was estimated by the CKD-Epidemiology Collaboration equation. Patients were assessed for OSA by Watch-PAT200 (apnea-hypopnea index ≥5 events hourly; Itamar Medical), total body adiposity by dual-energy x-ray absorptiometry (DXA) and body mass index (BMI), upper body adiposity by anthropometric parameters and by trunk and visceral fat by DXA, and sarcopenia. OSA frequency was 67% (N = 49). Both total and upper body adiposity were associated with the presence and severity of OSA. In non-obese patients (BMI <30 kg/m2), upper body obesity increased significantly the frequency of OSA. OSA association with sarcopenia was blunted when BMI was included in regression model. Results from the present study suggest that in non-dialyzed CKD patients OSA is very common and associated with total and upper body obesity, but not with sarcopenia.


Tafel-analysis of the AP-CITROX decontamination technology of Inconel alloy 690.
Safe, effective, cost-effective, easy feasible and low-waste decontamination technologies are fundamental importance from environmental and radiation protection aspects. In this study the effectiveness of AP-CITROX decontamination technology of Inconel alloy 690 was investigated. Non-radioactive representative metal samples were formed to test of decontamination technology and the clear-, the corroded-, the decontaminated layer were analysed electrochemically. The results indicate that the passivation step of the technology was not completed.


Assessment of patent ductus arteriosus shunting using diastolic pressure analysis.
Ductal shunting significantly affected the time necessary for aortic diastolic pressure to fall to one-half an initially selected value (t1/2). Fourteen premature infants with clinical evidence of left-to-right ductal shunting had a mean t1/2 of 277 msec (range 133 to 383 msec) compared with a mean t1/2 of 455 msec (range 332 to 567 msec) in 14 neonates with no clinical evidence of ductal shunting (P less than 0.01). Seven older infants with ductal shunting confirmed at cardiac catheterization had a mean t1/2 of 360 msec (range 240 to 392 msec). Infant catheterization data and animal studies are suggestive of an inverse relationship between the magnitude of shunt and the t1/2. The t1/2 determined by diastolic pressure analysis is a useful method for serial evaluation of ductus arteriosus shunting.


Mesenchymal Stromal Cells: Heterogeneity and Therapeutical Applications.
Mesenchymal stromal cells nowadays emerge as a major player in the field of regenerative medicine and translational research. They constitute, with their derived products, the most frequently used cell type in different therapies. However, their heterogeneity, including different subpopulations, the anatomic source of isolation, and high donor-to-donor variability, constitutes a major controversial issue that affects their use in clinical applications. Furthermore, the intrinsic and extrinsic molecular mechanisms underlying their self-renewal and fate specification are still not completely elucidated. This review dissects the different heterogeneity aspects of the tissue source associated with a distinct developmental origin that need to be considered when generating homogenous products before their usage for clinical applications.


Expression of obesity-related genes in human spermatozoa affects the outcomes of reproductive treatments.
To study the abundance of obesity-related gene (ORG) mRNA in human spermatozoa and its association with sperm quality parameters, embryonic development, and pregnancy rates after assisted reproduction treatment (ART). Cross-sectional study of spermatozoa ORG mRNA expression, and sperm and embryonic development parameters of infertile couples attending a single ART center. University, in collaboration with a medically assisted reproduction center. One hundred six couples seeking fertility treatment and receiving ART. Expression of spermatozoa ORG mRNA was assessed by quantitative reverse transcription-polymerase chain reaction. Sperm and embryonic development parameters were measured by board-certified embryologists. Serum β-human chorionic gonadotropin levels and fetal heartbeat detection on ultrasound were used to document biochemical and clinical pregnancy, respectively. Correlations between the abundance of ORG transcripts in spermatozoa and sperm quality, embryonic development, and achievement of pregnancy. The abundance of spermatozoa FTO mRNA was positively correlated with total sperm count (r = 0.5030), fertilization rate (r = 0.4854), embryo cleavage rate (r = 0.5705), and high-quality embryo rate (r = 0.6982). The abundance of spermatozoa MC4R transcript was negatively correlated with sperm viability (r = -0.3111) and positively correlated with biochemical pregnancy (r = 0.4420). The abundance of MC4R and GNPDA2 transcripts was higher in spermatozoa of men with asthenozoospermia and teratozoospermia than in those with normozoospermia. To our knowledge, this is the first report showing that the abundance of MC4R and FTO transcripts in spermatozoa is associated with sperm and embryo quality parameters, as well as pregnancy rates. Overall, these results further support the view that male factors beyond classic sperm quality parameters, namely the abundance of ORG transcripts, also affect the outcome of ART.


Expression change of TNF-α in myocardium and hepatic tissue of rats with compound stress of hyperthermia and lipopolysaccharide.
To investigate the expression characteristics of TNF-α in myocardium and hepatic tissue of rats with compound stress of hyperthermia and lipopolysaccharide (LPS). Male SPF Wistar rats were randomly divided into room temperature+physiological saline group (Group C), hyperthermia+physiological saline group (Group H), room temperature+LPS group (Group L) and hyperthermia+LPS group (Group HL). The rats were put in simulated climate cabin. Group HL and Group H were exposed in the environment at a dry bulb temperature (TDB) of (35.0±0.5) °C, while Group L and Group C were exposed in the environment at a TDB of (26.0±0.5) °C. The rats in Group HL and Group L were given tail intravenous injection of LPS 10 mg/kg, while the rats in Group H and Group C were given tail intravenous injection of 9 g/L NaCl 10 mL/kg. After the stress, immunohistochemical SABC staining method was used to detect the expression characteristics of TNF-α in myocardium and hepatic tissue of rats, and those rats were given routine pathological examinations. The expression of TNF-α in myocardium and hepatic tissue in Group HL was enhanced remarkably, and the tissue damages of Group HL were severest. The cardiotoxicity and hepatotoxicity caused by compound stress of hyperthermia and LPS is closely related to the expression of TNF-α.


Central wave reflection is associated with peripheral arterial resistance in addition to arterial stiffness in subjects without antihypertensive medication.
Augmentation index, a marker of central wave reflection, is influenced by age, sex, height, blood pressure, heart rate, and arterial stiffness. However, the detailed haemodynamic determinants of augmentation index, and their relations, remain uncertain. We examined the association of augmentation index with vascular resistance and other haemodynamic and non-haemodynamic factors. Background information, laboratory values, and haemodynamics of 488 subjects (239 men, 249 women) without antihypertensive medication were obtained. Indices of central wave reflection, systemic vascular resistance, cardiac function, and pulse wave velocity were measured using continuous radial pulse wave analysis and whole-body impedance cardiography. In a regression model including only haemodynamic variables, augmentation index in males and female subjects, respectively, was associated with systemic vascular resistance (β = 0.425, β = 0.336), pulse wave velocity (β = 0.409, β = 0.400) (P < 0.001 for all), stroke volume (β = 0.256, β = 0.278) (P = 0.001 for both) and heart rate (β = -0.150, β = -0.156) (P = 0.049 and P = 0.036). When age, height, weight, smoking habits, and laboratory values were included in the regression model, the most significant explanatory variables for augmentation index in males and females, respectively, were age (β = 0.577, β = 0.557) and systemic vascular resistance (β = 0.437, β = 0.295) (P < 0.001 for all). In the final regression model, pulse wave velocity was not a significant explanatory variable for augmentation index, probably due to the high correlation of this variable with age (Spearman's correlation ≥0.617). Augmentation index is strongly associated with systemic vascular resistance in addition to arterial stiffness. ClinicalTrials.gov, NCT01742702 .


Prognostic value of heart rate turbulence for risk assessment in patients with unstable angina and non-ST elevation myocardial infarction.
We sought to examine the prognostic value of heart rate turbulence derived from electrocardiographic recordings initiated in the emergency department for patients with non-ST elevation myocardial infarction (NSTEMI) or unstable angina. Twenty-four-hour Holter recordings were started in patients with cardiac symptoms approximately 45 minutes after arrival in the emergency department. Patients subsequently diagnosed with NSTEMI or unstable angina who had recordings with ≥18 hours of sinus rhythm and sufficient data to compute Thrombolysis In Myocardial Infarction (TIMI) risk scores were chosen for analysis (n = 166). Endpoints were emergent re-entry to the cardiac emergency department and/or death at 30 days and one year. In Cox regression models, heart rate turbulence and TIMI risk scores together were significant predictors of 30-day (model chi square 13.200, P = 0.001, C-statistic 0.725) and one-year (model chi square 31.160, P < 0.001, C-statistic 0.695) endpoints, outperforming either measure alone. Measurement of heart rate turbulence, initiated upon arrival at the emergency department, may provide additional incremental value in the risk assessment for patients with NSTEMI or unstable angina.


Reversible bilateral phrenic nerve paralysis.
Bilateral phrenic nerve paralysis is a rare potentially life-threatening condition which is usually due to trauma (including surgery) or neurologic disease. We present a patient with apparent rapid onset bilateral phrenic nerve paralysis whose primary symptom was severe positional (supine) dyspnea with profound supine oxygen desaturation. Nerve conduction study abnormalities of the phrenic nerves and some left brachial plexus nerves suggested a diagnosis of ALS. He was treated with supportive night time ventilatory assistance (BiPAP) and over 4 years his condition recovered essentially completely. In retrospect the most likely diagnosis was a rare brachial plexopathy referred to as neuralgic amyotrophy.


The outcome of endodontic treatment: a retrospective study of 2000 cases performed by a specialist.
The purpose of this study was to evaluate the treatment outcome of initial endodontic treatment and nonsurgical retreatment performed by an endodontic specialist in his private office. A total of 2,000 teeth were examined clinically and radiographically and the results were analyzed statistically by Pearson or Fisher's Exact test and multivariate logistic regression. The multivariate analysis evaluated joint associations among various factors, using logistic regression models. The dependent variable for this analysis was the dichotomous outcome: healed versus disease. The overall endodontic success rate was 91.45%, and the healed rate was significantly higher for initial endodontic treatments than for nonsurgical retreatments; teeth without lesion than for those with lesions; teeth treated without complications than for those with complications; recall period of 18-24 months than for other periods, and teeth with final coronal restoration than for those without. Of the 1376 teeth treated in the initial endodontic treatment sample, the success rate was 94.0%. Multivariate analysis identified the presence of procedural complications (file breakage, perforation and flare-up), as well as the absence of the restorations at follow-ups as the significant predictors of outcome, showing lower rates of success. Of the 624 teeth in the nonsurgical retreatment sample, 85.9% were successful. Stepwise logistic regression analysis revealed that preoperative radiolucency was a strong statistically significant factor to determine lower rates of success than in its absence. Two additional variables (age and tooth type) were found to have a significant influence on the outcome of the retreatment sample. A higher healed rate was observed for the 50-59 years age groups than others, while multirooted (molars) teeth revealed a significantly lower percentage of success than pre-molars and anterior teeth.


Asthma and rhinitis: comorbidities.
The connection between asthma and rhinitis is not a new discovery. Significant progress has been made in understanding the relationship of these two conditions, however, and the implications of the asthma-rhinitis link make it increasingly important. Patients who have asthma and rhinitis tend to have more severe disease with higher treatment costs. Treatment of rhinitis may improve asthma control, and early treatment of allergies may prevent the development of asthma. This article more fully explores the epidemiologic, pathophysiologic, and clinical relationships between asthma and rhinitis.


M-CSF in a new biomarker panel with HE4 and CA 125 in the diagnostics of epithelial ovarian cancer patients.
We investigated plasma levels of M-CSF and conventional tumor markers (HE4 and CA 125) in epithelial ovarian cancer patients as compared to control groups: benign ovarian tumor patients (cysts) and healthy subjects. M-CSF levels were determined by ELISA, HE4 and CA 125 levels - by CMIA method. Our results have demonstrated significant differences in the concentration levels of M-CSF, CA 125 and HE4 between the groups of ovarian cancer patients, cysts patients and the healthy controls. In the groups tested M-CSF demonstrated equal to or higher values than both CA 125 and HE4 in diagnostic sensitivity (SE), positive and negative predictive values (PPV, NPV), and in the area under the ROC curve (AUC), particularly in the group with the serous epithelial sub-type of OC. Moreover, CA 125 showed better results of the aforementioned diagnostic criteria than HE4. The combined use of the parameters studied resulted in a further, significant increase in the value of the diagnostic indicators and in the value of the diagnostic power (AUC), especially in the early stages of ovarian cancer. These findings suggest a high usefulness of M-CSF in diagnosing the serous sub-type of epithelial ovarian cancer and in discriminating between cancer and non-carcinoma lesions, particularly in new diagnostic panels in combination with CA 125 and HE4 for the detection of EOC in the early stages.


Assessment of the impact of adherence and other predictors during HAART on various CD4 cell responses in resource-limited settings.
The aim of this study was to quantify, by modeling, the impact of significant predictors on CD4 cell response during antiretroviral therapy in a resource-limited setting. Modeling was used to determine which antiretroviral therapy response predictors (baseline CD4 cell count, clinical state, age, and adherence) significantly influence immunological response in terms of CD4 cell gain compared to a reference value at different periods of monitoring. At 6 months, CD4 cell response was significantly influenced by baseline CD4 count alone. The probability of no increase in CD4 cells was 2.6 higher in patients with a baseline CD4 cell count of ≥200/mm(3). At 12 months, CD4 cell response was significantly influenced by both baseline CD4 cell count and adherence. The probability of no increase in CD4 cells was three times higher in patients with a baseline CD4 cell count of ≥200/mm(3) and 0.15 times lower with adherent patients. At 18 months, CD4 cell response was also significantly influenced by both baseline CD4 cell count and adherence. The probability of no increase in CD4 cells was 5.1 times higher in patients with a baseline CD4 cell count of ≥200/mm(3) and 0.28 times lower with adherent patients. At 24 months, optimal CD4 cell response was significantly influenced by adherence alone. Adherence increased the probability (by 5.8) of an optimal increase in CD4 cells. Age and baseline clinical state had no significant influence on immunological response. The relationship between adherence and CD4 cell response was the most significant compared to that of baseline CD4 cell count. Counseling before initiation of treatment and educational therapy during follow-up must always help to strengthen adherence and optimize the efficiency of antiretroviral therapy in a resource-limited setting.


Identification of unique VLA-4 antagonists from a combinatorial library.
A combinatorial library of 28 pools of 180 compounds (345 diastereomers) was designed and prepared in support of the delineation of the SAR of two prototypical VLA-4 antagonists. Deconvolution of the active pools led to the identification of three novel series of VLA-4 antagonists with low nanomolar potencies.


The Griess test: an inexpensive screening test for asymptomatic bacteriuria in pregnancy.
This study was designed to compare urine microscopy and the Griess test as screening tests for asymptomatic bacteriuria (AB) in pregnancy, using urine culture as a gold standard. Urine microscopy, Griess test and urine culture were carried out on urine samples from 483 antenatal women. AB was detected by urine culture in 30 (6.8%) of the patients. The Griess test and urine microscopy were found to have a sensitivity of 63.3% and 60%, specificity of 99.5% and 83.6%; and positive predictive value of 90.5% and 21.1% respectively. Most of the infections missed by the Griess test were either <100,000 colony count on culture or caused by gram positive cocci. The cost of the Griess test was only one tenth of that of urine microscopy. The Griess test is a simple and inexpensive test that when compared to urine microscopy has equal sensitivity, and better specificity and positive predictive value for the detection of AB in pregnancy than urine microscopy.


Granulomatous liver disease.
Hepatic granulomata are not infrequently encountered in liver biopsy and often are associated with systemic disease. The clinical presentation varies with the particular systemic process. From a biochemical standpoint, the most common abnormalities are elevated serum alkaline phosphatase and γ-glutamyltransferase. The observation of granulomata in a liver biopsy specimen warrants workup to identify a possible cause. Clues may be obtained in the medical history, on physical examination, or with specialized blood testing or radiologic studies. Treatment involves therapy of the underlying cause of the disease associated with the development of the granulomatous hepatitis.


Effects of bevacizumab on neuronal viability of retinal ganglion cells in rats.
The aim of this study was to investigate the effects of single and repeated intravitreal injections of bevacizumab on various retinal layers focusing more on retinal ganglion cells (RGCs) in healthy rats. Male Wistar rats were treated with intravitreal injection of bevacizimab (4 μL) within right eye. Left eyes were injected with the same volume of balanced salt solution (BSS) and used as control. Ten rats received a single intravitreal injection and ten rats had three injections, with seven days time interval. Histological and immunohistochemical evaluations and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay were performed in order to find out if some degree of apoptosis could occur on RGCs. Histological and immunohistochemical analyses showed that bevacizumab induces neuronal loss compared to control eyes, after multiple injections. RGCs apoptosis after multiple treatments was demonstrated to occur by TUNEL, Annexin V and Bax assays. The loss of ganglion cells following repeated injections was confirmed and quantified by the decrease in RGC specific protein Brn3a measured by western blotting in ten additional rats. The present results need to be considered when multiple intravitreal injection of bevacizumab are performed to treat retinal diseases.


Facile synthesis of graphene oxide-silver nanocomposite and its modified electrode for enhanced electrochemical detection of nitrite ions.
In this report, silver nanoparticles (Ag NPs) were successfully deposited on graphene oxide (GO) sheets to form GO-Ag nanocomposite using garlic extract and sunlight and the nanocomposite modified glassy carbon (GC) electrode was applied as an electrochemical sensor for the detection of nitrite ions. The formation of GO-Ag nanocomposite was confirmed by using UV-visible absorption spectroscopy, TEM, XRD and FTIR spectroscopy analyses. Further, TEM pictures showed a uniform distribution Ag on GO sheets with an average size of 19 nm. The nanocomposite modified electrode produced synergistic catalytic current in nitrite oxidation with a negative shift in overpotential. The limit of detection (LOD) values were found as 2.1 µM and 37 nM, respectively using linear sweep voltammetry (LSV) and amperometric i-t curve techniques. The proposed sensor was stable, reproducible, sensitive and selective toward the detection nitrite and could be applied for the detection of nitrite in real water sample.


Genomic potential for exopolysaccharide production and differential polysaccharide degradation in closely related Alteromonas sp. PRIM-21 and Alteromonas fortis 1T.
Members of the genus Alteromonas are widely distributed in diverse marine environments and are often associated with marine organisms. Their ability to produce exopolysaccharides (EPS) and depolymerize sulfated algal polysaccharides has provided industrial importance to some species. Here, we describe the draft genome of an algae-associated strain namely, Alteromonas sp. PRIM-21 isolated from the southwest coast of India to understand the EPS biosynthetic pathways as well as polysaccharide depolymerization system in comparison to the closely related strain Alteromonas fortis 1T that shares 99.8% 16S rRNA gene sequence similarity. Whole-genome shotgun sequencing of Alteromonas sp. PRIM-21 yielded 50 contigs with a total length of 4,638,422 bp having 43.86% GC content. The resultant genome shared 95.9% OrthoANI value with A. fortis 1 T, and contained 4125 predicted protein-coding genes, 71 tRNA and 10 rRNA genes. Genes involved in Wzx/Wzy-, ABC transporter- and synthase-dependent pathways for EPS production and secretion were common in both Alteromonas sp. PRIM-21 and A. fortis 1T. However, the distribution of carbohydrate-active enzymes (CAZymes) was heterogeneous. The strain PRIM-21 harbored polysaccharide lyases for the degradation of alginate, ulvan, arabinogalactan and chondroitin. This was further validated from the culture-based assays using seven different polysaccharides. The depolymerizing ability of the bacteria may be useful in deriving nutrients from the biopolymers produced in the algal host while the EPS biosynthesis may provide additional advantages for life in the stressful marine environment. The results also highlight the genetic heterogeneity in terms of polysaccharide utilization among the closely related Alteromonas strains.


Necrotizing sarcoid granulomatosis.
We report a patient with necrotizing sarcoid granulomatosis (NSG) and point out that while the latter may have certain histological and radiological features distinct from sarcoidosis, sophisticated immunological tests show that the two disorders have essentially similar underlying immune mechanisms. We also stress that although the clinical course of NSG has been repeatedly described as benign and responsive to steroid therapy, the young patient may initially be critically ill with symptoms suggestive of an infective process rather than a granulomatous cause.


Opposite effects of high- and low-frequency transcranial random noise stimulation probed with visual motion adaptation.
Transcranial random noise stimulation (tRNS) is a recent neuro-modulation technique whose effects at both behavioural and neural level are still debated. Here we employed the well-known phenomenon of motion after-effect (MAE) in order to investigate the effects of high- vs. low-frequency tRNS on motion adaptation and recovery. Participants were asked to estimate the MAE duration following prolonged adaptation (20 s) to a complex moving pattern, while being stimulated with either sham or tRNS across different blocks. Different groups were administered with either high- or low-frequency tRNS. Stimulation sites were either bilateral human MT complex (hMT+) or frontal areas. The results showed that, whereas no effects on MAE duration were induced by stimulating frontal areas, when applied to the bilateral hMT+, high-frequency tRNS caused a significant decrease in MAE duration whereas low-frequency tRNS caused a significant corresponding increase in MAE duration. These findings indicate that high- and low-frequency tRNS have opposed effects on the adaptation-dependent unbalance between neurons tuned to opposite motion directions, and thus on neuronal excitability.


The lessons from in vitro lithotripsy for the clinical treatment of gallstones.
Fifty-eight gallbladder stones were treated in vitro, using a Wolf Piezolith 2300 lithotripter, to discover whether complete fragmentation (i.e., no particles greater than 2 mm diameter) could be achieved by lithotripsy alone. In 16 stones this was accomplished with up to 6000 shocks being administered. The degree of fragmentation was judged first by eye during the experiment and then by both microscopy and sieving of the debris. Eye judgement proved to be an unreliable indicator with 23 of the 42 stones in the failed lithotripsy group receiving 6000 shocks or less. Cholesterol analysis and high resolution radiography revealed no significant differences between the successfully and unsuccessfully fragmented stones, but X-ray diffractometry did show a higher incidence of inorganic calcium salts in the latter group. This study shows that lithotripsy can successfully fragment gallbladder stones, but that a minimum of 6000 shocks, using the Piezolith 2300, should be given to ensure adequate treatment. Additionally, the presence of radiopaque stones does not necessarily preclude successful treatment by this method.


Screening of suitable cationic dopants for solar absorber material CZTS/Se: A first principles study.
The earth abundant and non-toxic solar absorber material kesterite Cu2ZnSn(S/Se)4 has been studied to achieve high power conversion efficiency beyond various limitations, such as secondary phases, antisite defects, band gap adjustment and microstructure. To alleviate these hurdles, we employed screening based approach to find suitable cationic dopant that can promote the current density and the theoretical maximum upper limit of the energy conversion efficiency (P(%)) of CZTS/Se solar devices. For this task, the hybrid functional (Heyd, Scuseria and Ernzerhof, HSE06) were used to study the electronic and optical properties of cation (Al, Sb, Ga, Ba) doped CZTS/Se. Our in-depth investigation reveals that the Sb atom is suitable dopant of CZTS/CZTSe and also it has comparable bulk modulus as of pure material. The optical absorption coefficient of Sb doped CZTS/Se is considerably larger than the pure materials because of easy formation of visible range exciton due to the presence of defect state below the Fermi level, which leads to an increase in the current density and P(%). Our results demonstrate that the lower formation energy, preferable energy gap and excellent optical absorption of the Sb doped CZTS/Se make it potential component for relatively high efficient solar cells.


Stem cell therapy for neurological disorders: A focus on aging.
Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.


Vulval squamous cell carcinoma arising in localized Darier's disease.
Darier's disease (keratosis follicularis) is a rare vulval lesion and it has been associated with squamous and non-squamous tumors from different origin. A vulval squamous cell carcinoma (SCC) arising in a localized Darier's disease is presented. To our knowledge, this is the first case to report the association of a vulval SCC and a localized Darier's disease. The possibility of delaying or overlooking the diagnosis of a vulval carcinoma is also illustrated. It is suggested to resect the whole lesion of Darier's disease localized to the vulva or take multiple biopsies.


Multiple sclerosis and mortality statistics.
We have previously found a 3-fold increase in prevalence and a corresponding increase in incidence of multiple sclerosis (MS) from 1963 to 1983 in the county of Hordaland, Norway. When studying the official mortality statistics and the deceased patients in our clinical MS-material, no increase in death rate could be observed in the same period. We also found that official mortality statistics include both over- and underestimates of MS-patients. Of definite MS-patients in the clinical material, 91.7% were registered with MS on the death certificates, either as underlying or contributory cause of death. When studying only underlying cause of death, we found that 59.5% of deceased definite MS patients were registered as MS on the death certificates. This study shows that official mortality statistics reflect a change in incidence of MS both incompletely and with a delay of several decades.


Safety of Antithrombotic Agents in Elderly Patients with Acute Coronary Syndromes.
There are unique challenges in the treatment and prevention of acute coronary syndromes (ACS) with antithrombotics in elderly patients: elderly patients usually require multiple drugs due to comorbidities, are highly susceptible to adverse drug reactions and drug-drug interactions, may have cognitive problems affecting compliance and complications, are especially exposed to the risk of falls and, most importantly, ageing is an independent risk factor for bleeding. Antithrombotic drugs, alone or in association, further and variously amplify age-related bleeding risk. Moreover, age-related changes in primary haemostasis may potentially affect the pharmacodynamics of some antiplatelet drugs. Thus, elderly subjects might be more or less sensitive to standard antiplatelet regimens depending on individual characteristics affecting antiplatelet drug response. Importantly, elderly patients are a rapidly growing population worldwide, have the highest incidence of ACS, but are poorly represented in clinical trials. As a consequence, evidence on antithrombotic drug benefits and risks is limited. Thus, in the real-world setting, older people are often denied antithrombotic drugs because of unjustified concerns, or might be over-treated and exposed to excessive bleeding risk. Personalized antithrombotic therapy in elderly patients is particularly critical, to minimize risks without affecting efficacy.


Aryl hydrocarbon receptor and Krüppel like factor 10 mediate a transcriptional axis modulating immune homeostasis in mosquitoes.
Immune responses require delicate controls to maintain homeostasis while executing effective defense. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. The Krüppel-like factor 10 (KLF10) is a C2H2 zinc-finger containing transcription factor. The functions of mosquito AhR and KLF10 have not been characterized. Here we show that AhR and KLF10 constitute a transcriptional axis to modulate immune responses in mosquito Anopheles gambiae. The manipulation of AhR activities via agonists or antagonists repressed or enhanced the mosquito antibacterial immunity, respectively. KLF10 was recognized as one of the AhR target genes in the context. Phenotypically, silencing KLF10 reversed the immune suppression caused by the AhR agonist. The transcriptome comparison revealed that silencing AhR and KLF10 plus challenge altered the expression of 2245 genes in the same way. The results suggest that KLF10 is downstream of AhR in a transcriptional network responsible for immunomodulation. This AhR-KLF10 axis regulates a set of genes involved in metabolism and circadian rhythms in the context. The axis was required to suppress the adverse effect caused by the overactivation of the immune pathway IMD via the inhibitor gene Caspar silencing without a bacterial challenge. These results demonstrate that the AhR-KLF10 axis mediates an immunoregulatory transcriptional network as a negative loop to maintain immune homeostasis.


Effect of Cu on the fluorescence of the Cu-hyperaccumulator lichen Stereocaulon sorediiferum.
Stereocaulon sorediiferum is expected to be a Cu-hyperaccumulator lichen and has fluorescent substances. To clarify the relationship between the fluorescence (FL) of the lichen and its Cu concentration, we collected S. sorediiferum samples at Cu-contaminated and uncontaminated sites in Japan, determined the concentration of Cu, K, Mg, Al, Ca, Mn, Fe, Zn, chlorophyll a,b, and total carotenoids in them, analyzed lichen secondary metabolites and fluorescent substances extracted from them, and measured the FL of them and their extracts. We found that the FL intensity of S. sorediiferum samples is significantly negatively correlated with their Cu concentration. The application of its FL for Cu monitoring may allow a new nondestructive quantitative method for assessing Cu contamination. The spectroscopic and chromatographic analysis shows that the fluorescent substances negatively correlated with Cu concentration are not major lichen secondary metabolites (lobaric acid and atranorin) and remain after immersion in acetone. The correlation analysis and the comparison with the causal relationship between Cu concentration and the chlorophyll a/b ratio suggest that the reason for the decrease in FL intensity with increasing Cu concentration is a structural change of the fluorescent substances by accumulated Cu. These findings lead to a better understanding of the relationship between the FL of S. sorediiferum and its Cu concentration and provide new insights into fluorescent lichen substances.


Neprilysin Inhibition as a PARADIGM Shift in Heart Failure Therapy.
Heart failure is a growing global public health problem. With the aging population, increased risk factors for heart failure development, and better survival after myocardial infarction, the prevalence is only expected to increase in the coming years. Although existing therapies have improved the clinical course of heart failure patients, new approaches are urgently needed to enhance quality of life and reduce morbidity and mortality. However, there has been little progress in the treatment of chronic heart failure in the past decade with only two new drugs approved by the US FDA over this time. Better understanding of the neurohormonal axis of heart failure has lead to the development of LCZ696, a first-in-class novel agent that acts as an angiotensin receptor blocker and neprilysin inhibitor. In the PARADIGM-HF study, LCZ696 was superior to an angiotensin-converting enzyme inhibitor in reducing mortality and HF hospitalizations and improving quality of life across a broad spectrum of symptomatic patients with heart failure with reduced ejection fraction. While evaluation of long-term effects is still needed, the completed trials on LCZ696 demonstrate that the drug is generally well-tolerated with a safe side effect profile. LCZ696 should be strongly considered as a favorable alternative to angiotensin converting enzyme inhibitors and angiotensin receptor blockers in appropriate heart failure patients.


Suppression of obsessive-compulsive symptoms after epilepsy surgery.
We report two male patients with medically intractable epilepsy and obsessive-compulsive disorder (OCD) symptoms. Both patients experienced remission of obsessive-compulsive symptoms after surgical treatment of epilepsy. Although the surgeries targeted different brain regions, the two patients had in common unilateral anterior cingulate cortex ablation. On the basis of these observations, we discuss the pathophysiology of OCD symptoms, emphasizing the role of corticosubcortical pathways in their genesis. Our data suggest that surgeries that affect neural loops associated with obsessive-compulsive symptoms can lead to an improvement of OCD; however, the structures responsible for this effect cannot be conclusively determined.


Relationship between video head impulse test (vHIT) and caloric test in patients with vestibular neuritis.
The caloric test is the gold standard for the loss of vestibular function diagnosis. The Video Head Impulse Test (vHIT) assesses the same reflex by using a video- assisted examination of the impulsive maneuver. We intend to compare the variation of results of the vHIT and the caloric test in patients with vestibular neuritis with respect to their initial condition at two different moments of their evolution and to check the level of correlation between them and with that of the DHI test We explored 20 patients with neuritis by using both vHIT and the caloric test on the same day. We assessed the correlation between these two tests and with the DHI test for each patient at two different moments of their evolution. We calculated gain asymmetry and compared it with the canal paresis, but we found neither a linear correlation between them, nor a correlation between the DHI test or improvement of these two other tests. We conclude that the covert saccades maintain a similar speed whilst present in the VHIT, but the overts diminish their speed over time. The VHIT and the caloric test show different responses of the vestibulo-ocular reflex, because they stimulate different frequencies of this reflex. No correlation was found between the VHIT, the caloric test and the DHI test. The tests appear to complement one another.


Reverse Trigger Phenotypes in Acute Respiratory Distress Syndrome.
Rationale: Reverse triggering is an underexplored form of dyssynchrony with important clinical implications in patients with acute respiratory distress syndrome.Objectives: This retrospective study identified reverse trigger phenotypes and characterized their impacts on Vt and transpulmonary pressure.Methods: Fifty-five patients with acute respiratory distress syndrome on pressure-regulated ventilator modes were included. Four phenotypes of reverse triggering with and without breath stacking and their impact on lung inflation and deflation were investigated.Measurements and Main Results: Inflation volumes, respiratory muscle pressure generation, and transpulmonary pressures were determined and phenotypes differentiated using Campbell diagrams of respiratory activity. Reverse triggering was detected in 25 patients, 15 with associated breath stacking, and 13 with stable reverse triggering consistent with respiratory entrainment. Phenotypes were associated with variable levels of inspiratory effort (mean 4-10 cm H2O per phenotype). Early reverse triggering with early expiratory relaxation increased Vts (88 [64-113] ml) and inspiratory transpulmonary pressures (3 [2-3] cm H2O) compared with passive breaths. Early reverse triggering with delayed expiratory relaxation increased Vts (128 [86-170] ml) and increased inspiratory and mean-expiratory transpulmonary pressure (7 [5-9] cm H2O and 5 [4-6] cm H2O). Mid-cycle reverse triggering (initiation during inflation and maximal effort during deflation) increased Vt (51 [38-64] ml), increased inspiratory and mean-expiratory transpulmonary pressure (3 [2-4] cm H2O and 3 [2-3] cm H2O), and caused incomplete exhalation. Late reverse triggering (occurring exclusively during exhalation) increased mean expiratory transpulmonary pressure (2 [1-2] cm H2O) and caused incomplete exhalation. Breath stacking resulted in large delivered volumes (176 [155-197] ml).Conclusions: Reverse triggering causes variable physiological effects, depending on the phenotype. Differentiation of phenotype effects may be important to understand the clinical impacts of these events.


Variant proteins of the Plasmodium falciparum RIFIN family show distinct subcellular localization and developmental expression patterns.
In order to avoid immune recognition in favor of a chronic infection, the malaria parasite Plasmodium falciparum has developed means to express clonally variant antigens at the surface of the infected erythrocyte (IE). Proteins of the var and rif multicopy gene families, encoding PfEMP1 and RIFINs, respectively, have been implicated in these processes. Here, we studied members of the latter family and present data revealing different subcellular localization patterns for RIFIN variants belonging to two distinct subgroups, which have been designated A- and B-type RIFINs. While A-type RIFINs were found to be associated with the parasite and transported to the surface of infected erythrocytes via Maurer's clefts, B-type RIFINs appeared to be mostly retained inside the parasite. However, expression of both subtypes does not seem to be mutually exclusive. Moreover, both A- and B-type variants were also expressed in the merozoite, present either in the apical region (A-type) or in the cytosol (B-type). The presence of RIFINs in merozoites suggests that antigenic variation in P. falciparum is not only restricted to parasite-derived proteins at the IE surface, but the phenomenon also prevails in other life cycle stages. Interestingly, some RIFIN variants were detected only in intracellular stages and not in merozoites, pointing to differential developmental expression patterns for distinct members of this large protein family.


Regulation of proton-to-electron stoichiometry in photosynthetic electron transport: physiological function in photoprotection.
The primary stable products of photosynthetic electron flow are NADPH and ATP. Stoichiometry of their production depends on the ratio of protons pumped across the thylakoid membrane to electrons passed through the electron transport pathway (H(+)/e(-) ratio). Flexible requirements of the ATP/NADPH ratio by various assimilatory reactions in chloroplasts must be fulfilled by the H(+)/e(-) ratio during the electron flow. In addition to the well-known role of Delta pH during ATP synthesis, Delta pH also functions as a trigger of the down-regulation of photosystem II (PSII) photochemistry. Excessive light energy is safely dissipated as heat by this regulatory process to suppress the generation of toxic reactive oxygen species. Thus, regulation of the H(+)/e(-) ratio may function in the photoprotection, as well as in the regulation of the ATP/NADPH production ratio. It has long been the consensus that the H(+)/e(-) ratio can be controlled by regulating the proton-transporting Q-cycle in the cytochrome b(6)f complex and by the cyclic electron flow around photosystem I (PSI). Despite the possible physiological importance and the long history of interest, the molecular identity of Q-cycle regulation and the cyclic electron flow around PSI have been remained unclear. The recent improvements in research tools, including the genetic approach using chlorophyll fluorescence imaging and establishment of the chloroplast transformation technique, are providing new insights into classical topics. In this review, we focus on regulation of the H(+)/e(-) ratio especially from the view of photosynthetic regulation.


Continuous Energy Harvesting from Ubiquitous Humidity Gradients using Liquid-Infused Nanofluidics.
Humidity-based power generation that converts internal energy of water molecules into electricity is an emerging approach for harvesting clean energy from nature. Here it is proposed that intrinsic gradient within a humidity field near sweating surfaces, such as rivers, soil, or animal skin, is a promising power resource when integrated with liquid-infused nanofluidics. Specifically, capillary-stabilized ionic liquid (IL, Omim+ Cl- ) film is exposed to the above humidity field to create a sustained transmembrane water-content difference, which enables asymmetric ion-diffusion across the nanoconfined fluidics, facilitating long-term electricity generation with the power density of ≈12.11 µW cm-2 . This high record is attributed to the nanoconfined IL that integrates van der Waals and electrostatic interactions to block movement of Omim+ clusters while allowing for directional diffusion of moisture-liberated Cl+ . This humidity gradient triggers large ion-diffusion flux for power generation indicates great potential of sweating surfaces considering that most of the earth is covered by water or soil.


Agenesis of the vermiform appendix in a thalidomide child.
A case of congenital absence of the appendix occurring in a child with severe thalidomide deformities is described. The literature on agenesis of the appendix is reviewed. The frequency and significance of internal abnormalities in thalidomide children are discussed.


Baseline demographic, clinical and multimodal imaging features of young patients with type 2 macular telangiectasia.
Macular telangiectasia (MacTel) type 2 is observed in patients in their 5th-8th decades of life. The clinical and imaging findings in younger patients is unknown in larger cohorts. The study purpose is to report prevalence, baseline clinical and spectral domain optical coherence tomography (SDOCT) findings in young MacTel patients below 40 years. This hospital-based, multicentre, retrospective, cross-sectional study included patients between 2011 and 2023. Retinal photographs from multiple imaging techniques were evaluated to diagnose and stage type 2 MacTel and describe their SDOCT findings. Imaging characteristics were correlated with clinical stages and visual acuity. Among all MacTel patients seen in hospital, prevalence of young MacTel cases less than age 40 was 1.77% (32/1806; 62 eyes). Youngest participant was 34 years, while mean age was 38.44 ± 1.795 years. Sixteen patients (50%) were diabetics. Perifoveal greying (n = 56, 90%) and perifoveal hyperreflective middle retinal layers (n = 47, 76%) were the most prevalent clinical and SDOCT imaging finding respectively. Less than 10% (n = 6) eyes had proliferative disease. Presence of retinal pigment clumps (RPC) (7% vs. 67%; p = 0.002) coincided with proliferative MacTel. Poor vision was associated with presence of outer retinal layer SDOCT findings like outward bending of inner retinal layers (p = 0.047), RPC (p = 0.007), subfoveal neurosensory detachment (p = 0.048) and subretinal neovascular membrane (p = 0.001). Type 2 MacTel before age 40 is rare, common in women and diabetics, and affects vision in advanced stage. Disease symmetry, comparison with older cases, and longitudinal SDOCT changes in such patients require further study.


Synthesis of 6-oxy functionalized campest-4-en-3-ones: efficient hydroperoxidation at C-6 of campest-5-en-3-one with molecular oxygen and silica gel.
As a reference compound library for the investigation of biosynthesis of brassinosteroids, focused on a pathway from campesterol (1) to campestanol (2), 6-oxy functionalized campest-4-en-3-ones as well as campest-5-en-3-one (7) and campestane-3,6-dione were prepared from 1. Oxidation of 1 with pyridinium chlorochromate buffered by calcium carbonate gave 5-en-3-one (7) in 76% yield. Treatment of 7 with silica gel under an oxygen atmosphere in ethyl ether at room temperature produced efficient hydroperoxidation at the C-6 position to give 6alpha-hydroperoxycampest-4-en-3-one and 6beta-hydroperoxycampest-4-en-3-one in 34% and 49% yields, respectively. These compounds were converted to 6alpha-hydroxycampest-4-en-3-one and 6beta-hydroxycampest-4-en-3-one by reduction with triethyl phosphite. This provided the first example of the practical use of hydroperoxidation at C-6 of a Delta(5(6))-unsaturated 3-oxo-steroid with molecular oxygen and silica gel. On the other hand, oxidation of 1 with pyridinium chlorochromate in the absence of calcium carbonate gave campest-4-ene-3,6-dione in 64% yield. This compound was then converted in a highly stereoselective manner to campestane-3,6-dione with A/B trans ring junction by reduction with titanium (III) chloride in 85% yield.


[Cytotoxic T cell].
Cytotoxic T cell (CTL) covers several subtypes, which are CD8+, CD4 and CD4-CD8-. CTL derives from T cell repertoire in lymphoid hematopoietic stem cells. It matures in thymus and is activated in peripheral lymphoid tissues. Effector CTL kills the target cells by 2 ways. One is apoptotic effect mediated by FasL-Fas pathway and the other one is cytolytic effect mediated by granzymes. CTL has aroused great attention due to its significance in anti-tumor and anti-virus.


Additive-lathe 3D bioprinting of bilayered nerve conduits incorporated with supportive cells.
Nerve conduits have been identified as one of the most promising treatments for peripheral nerve injuries, yet it remains unsolved how to develop ideal nerve conduits with both appropriate biological and mechanical properties. Existing nerve conduits must make trade-offs between mechanical strength and biocompatibility. Here, we propose a multi-nozzle additive-lathe 3D bioprinting technology to fabricate a bilayered nerve conduit. The materials for printing consisted of gelatin methacrylate (GelMA)-based inner layer, which was cellularized with bone marrow mesenchymal stem cells (BMSCs) and GelMA/poly(ethylene glycol) diacrylate (PEGDA)-based outer layer. The high viability and extensive morphological spreading of BMSCs encapsulated in the inner layer was achieved by adjusting the degree of methacryloyl substitution and the concentration of GelMA. Strong mechanical performance of the outer layer was obtained by the addition of PEGDA. The performance of the bilayered nerve conduits was assessed using in vitro culture of PC12 cells. The cell density of PC12 cells attached to cellularized bilayered nerve conduits was more than 4 times of that on acellular bilayered nerve conduits. The proliferation rate of PC12 cells attached to cellularized bilayered nerve conduits was over 9 times higher than that on acellular bilayered nerve conduits. These results demonstrate the additive-lathe 3D bioprinting of BMSCs embedded bilayered nerve conduits holds great potential in facilitating peripheral nerve repair.


[Roentgenendovascular stenting (stent-graft) of the external iliac artery for elimination of post-traumatic arteriovenous anastomosis].
Presented herein is a case report concerning successful treatment of the post-traumatic pathological anastomosis between the left external iliac artery and iliac vein using the stent-graft Jostent-graft. The anastomosis emerged after gunshot injury to the abdominal cavity.


MRI Super-Resolution Through Generative Degradation Learning.
Spatial resolution plays a critically important role in MRI for the precise delineation of the imaged tissues. Unfortunately, acquisitions with high spatial resolution require increased imaging time, which increases the potential of subject motion, and suffers from reduced signal-to-noise ratio (SNR). Super-resolution reconstruction (SRR) has recently emerged as a technique that allows for a trade-off between high spatial resolution, high SNR, and short scan duration. Deconvolution-based SRR has recently received significant interest due to the convenience of using the image space. The most critical factor to succeed in deconvolution is the accuracy of the estimated blur kernels that characterize how the image was degraded in the acquisition process. Current methods use handcrafted filters, such as Gaussian filters, to approximate the blur kernels, and have achieved promising SRR results. As the image degradation is complex and varies with different sequences and scanners, handcrafted filters, unfortunately, do not necessarily ensure the success of the deconvolution. We sought to develop a technique that enables accurately estimating blur kernels from the image data itself. We designed a deep architecture that utilizes an adversarial scheme with a generative neural network against its degradation counterparts. This design allows for the SRR tailored to an individual subject, as the training requires the scan-specific data only, i.e., it does not require auxiliary datasets of high-quality images, which are practically challenging to obtain. With this technique, we achieved high-quality brain MRI at an isotropic resolution of 0.125 cubic mm with six minutes of imaging time. Extensive experiments on both simulated low-resolution data and clinical data acquired from ten pediatric patients demonstrated that our approach achieved superior SRR results as compared to state-of-the-art deconvolution-based methods, while in parallel, at substantially reduced imaging time in comparison to direct high-resolution acquisitions.