Light-induced changes within photosystem II protects Microcoleus sp. in biological desert sand crusts against excess light.
The filamentous cyanobacterium Microcoleus vaginatus, a major primary producer in desert biological sand crusts, is exposed to frequent hydration (by early morning dew) followed by desiccation during potentially damaging excess light conditions. Nevertheless, its photosynthetic machinery is hardly affected by high light, unlike "model" organisms whereby light-induced oxidative stress leads to photoinactivation of the oxygen-evolving photosystem II (PSII). Field experiments showed a dramatic decline in the fluorescence yield with rising light intensity in both drying and artificially maintained wet plots. Laboratory experiments showed that, contrary to "model" organisms, photosynthesis persists in Microcoleus sp. even at light intensities 2-3 times higher than required to saturate oxygen evolution. This is despite an extensive loss (85-90%) of variable fluorescence and thermoluminescence, representing radiative PSII charge recombination that promotes the generation of damaging singlet oxygen. Light induced loss of variable fluorescence is not inhibited by the electron transfer inhibitors 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), 2,5-dibromo-3-methyl-6-isopropylbenzoquinone (DBMIB), nor the uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), thus indicating that reduction of plastoquinone or O(2), or lumen acidification essential for non-photochemical quenching (NPQ) are not involved. The rate of Q(A) (-) re-oxidation in the presence of DCMU is enhanced with time and intensity of illumination. The difference in temperatures required for maximal thermoluminescence emissions from S(2)/Q(A) (-) (Q band, 22 degrees C) and S(2,3)/Q(B) (-) (B band, 25 degrees C) charge recombinations is considerably smaller in Microcoleus as compared to "model" photosynthetic organisms, thus indicating a significant alteration of the S(2)/Q(A) (-) redox potential. We propose that enhancement of non-radiative charge recombination with rising light intensity may reduce harmful radiative recombination events thereby lowering (1)O(2) generation and oxidative photodamage under excess illumination. This effective photo-protective mechanism was apparently lost during the evolution from the ancestor cyanobacteria to the higher plant chloroplast.


Clinical features of acute attacks, chronic symptoms, and long-term complications among patients with acute hepatic porphyria in Japan: a real-world claims database study.
Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase-deficient porphyria. The objective of this retrospective cohort study was to provide information on the clinical features of AHP in Japan-including acute attacks, chronic symptoms, and long-term complications. Patients with AHP between April 2008 and June 2020 were selected from Japan's Medical Data Vision claims database. Patients with AHP were matched 1:10, by sex and age, to patients without AHP. The outcomes were evaluated overall, for patients age ≥ 55 years, and for the matched population. A total of 391 patients with AHP were included from the Japanese Medical Data Vision database. During the observation period (April 2008-June 2020), 18.2% (71/391) of patients experienced 1 acute attack and 10.5% (41/391) experienced ≥ 2 attacks. Chronic symptoms with rates ~ 10% or higher in the AHP population compared with the matched population included neurotic, stress-related, and somatoform disorders (21.7% vs. 6.7% [15.0% difference]); sleep disorders (23.0% vs. 9.9% [13.1% difference]); other and unspecified abdominal pain (13.6% vs. 3.7% [9.9% difference]); and nausea and vomiting, excluding chemotherapy-induced emesis (17.9% vs. 8.1% [9.8% difference]). Long-term complications with higher incidence rates in the AHP population compared with the matched population included fibrosis and cirrhosis of liver (15.9% vs. 3.0% [12.9% difference]), polyneuropathies and other disorders of the peripheral nervous system (20.5% vs. 7.9% [12.6% difference]), liver cancer (16.9% vs. 4.7% [12.2% difference]), renal failure (16.4% vs. 4.3% [12.1% difference]), and hypertension (26.1% vs. 18.8% [7.3% difference]). Among AHP patients age ≥ 55 years, the most common long-term complications were hypertension, kidney failure, and liver cancer. In Japan, patients with AHP experience a high clinical burden in terms of acute attacks, chronic symptoms, and long-term complications. The clinical burden related to chronic symptoms and long-term complications was substantially higher in Japanese patients with AHP compared with a matched population without AHP. Recognizing these signs and symptoms of AHP may aid physicians in making an earlier diagnosis, which may help patients avoid attack triggers, implement disease management, and reduce lifetime disease burden.


PTP4A3 (PRL-3) expression correlate with lymphatic metastases in gastric cancer.
Many studies have proved that protein tyrosine phosphatase type IVAmember 3 (PTP4A3, PRL-3) plays a major role in the metastasis of gastric cancer, especially to local lymph nodes. The objective of the current study was to assess the expression of PTP4A3 in gastric cancer in correlation with chosen anatomoclinical parameters and patients' survival. Atotal of 71 patients with gastric carcinomas were divided according to Lauren's, Goseki's, Bormann's and Kubo's classifications. The level of PTP4A3 was determined immunohistochemically using a mouse monoclonal anti-PTP4A3 antibody (clone 3B6, anti-human PTP4A3, Attogen Biomedical Research, USA). A statistically significant correlation was observed between PTP4A3 and Kubo's classifications (p=0.0454) and on the verge of statistical significance with Lauren's classification (p=0.0503). The expression of the protein was associated more with the poorly-differentiated mucoid carcinoma and diffused-type carcinoma (58% of cases). We demonstrated a statistically significant correlation between local lymph node involvement and positive expression of PTP4A3 in the primary tumour (p=0.0000). The current study seems to prove that PTP4A3 may have a significant impact on the lymphatic spread of gastric carcinoma. The protein expression is also significantly associated with gastric carcinomas having a worse prognosis, although patients' survival rate showed lack of correlation with PTP4A3 expression.


Orientation of calvaria and periodontal ligament cells in vitro by pairs of demineralized dentine particles.
Rat calvaria cells (RC cells) and monkey periodontal ligament fibroblasts (MPL cells) were cultured for 4-6 days with demineralized dentine, acid-washed glass particles or untreated glass particles to determine whether the presence of these particles can affect the orientation of the cells. Encapsulation of dentine particles began as early as the first day in culture and occasional cells were attached to, and oriented between adjacent particles. Multilayers of cells formed along the periphery of the dentine particles and the more superficial of these cells projected outwards in a radial fashion. Oriented cell sheets were evident between dentine particles after 3 days in culture. Finally, the cell sheets tore away from the surface of the culture fish to give rise to thick multilayered cellular bridges between dentine particles. The nuclear orientation index (ratio of L/W) for each RC cell lying between 15 randomly selected pairs of each particle type in 4-day cultures was measured along 2 axes; the length represented by the shortest distance between the 2 particles and the width perpendicular to this axis. The nuclear orientation index was 1.52 for cells between dentine, 1.13 between acid-washed glass and 1.06 between untreated glass. Control measurements of cells associated with single particles were 1.06, 1.09 and 1.06 respectively. The frequency of cellular orientation occurring between dentine particles was significantly greater than that occurring between acid-washed glass particles (chi 2 > 0.001) which in turn was significantly greater than that for untreated glass particles (chi 2 > 0.001). The observations and results suggest that the development and maintenance of the observed cell orientation depends upon development and maintenance in the cell sheet of tensional forces oriented parallel to the axis between the dentine particles, and that this is related directly to the capacity of the cells to attach to the particles.


Anti-IL-6 Receptor Antibody Inhibits Spontaneous Pain at the Pre-onset of Experimental Autoimmune Encephalomyelitis in Mice.
Chronic pain is a significant symptom in patients with autoimmune encephalomyelitis, such as multiple sclerosis and neuromyelitis optica. The most commonly used animal model of these diseases is experimental autoimmune encephalomyelitis (EAE). We previously reported that evoked pain, such as mechanical allodynia, was improved by an anti-IL-6 receptor antibody in EAE mice. However, few reports have evaluated spontaneous pain in EAE mice. Here, we assessed spontaneous pain in EAE mice by utilizing the Mouse Grimace Scale (MGS, a standardized murine facial expression-based coding system) and evaluated the influence of an anti-IL-6 receptor antibody (MR16-1). EAE was induced in female C57BL/6J mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein 35-55 emulsified in adjuvant and administration of pertussis toxin. Mice were placed individually in cubicles and filmed for about 10 min. Ten clear head shots per mouse from the video recording were given a score of 0, 1, or 2 for each of three facial action units: orbital tightening, nose bulge, and ear position. Clinical symptoms of EAE were also scored. Measurement of 5-HT in the spinal cord and functional imaging of the periaqueductal gray (PAG) were also performed. Compared with control mice, MGS score was significantly higher in EAE mice. MR16-1 prevented this increase, especially in pre-onset EAE mice. Promotion of spinal 5-HT turnover and reduction of PAG activity were observed in pre-onset EAE mice. These results suggest that MR16-1 prevented spontaneous pain developed before EAE onset.


Altered empathic responding in major depressive disorder: relation to symptom severity, illness burden, and psychosocial outcome.
Individuals with major depressive disorder (MDD) demonstrate deficits in multiple social cognitive domains; however, systematic investigations of empathic responding have not been performed. Twenty patients with MDD completed two measures of empathy, the Interpersonal Reactivity Index (IRI: Davis, 1980, 1983) and the Toronto Empathy Questionnaire (TEQ: Spreng et al., 2009). Relative to matched controls, patients with MDD reported significantly reduced levels of empathy measured broadly on the TEQ and specifically in cognitive ('Perspective Taking') and affective ('Empathic Concern') domains captured by the IRI. A higher illness burden (i.e., greater number of past depressive episodes) was associated with greater reductions in perspective taking ability. This study provides early evidence of impaired empathic abilities in patients with MDD that may worsen with illness progression. Alternatively, reductions in perspective taking ability may contribute to a more severe course of illness in this population. Further longitudinal work is needed to characterize the relation between social cognitive performance and social functioning in this population.


Standardization of antimicrobial disc susceptibility test for anaerobic bacteria.
Both agar diluiton and agar diffusion tests with 8 clinically useful or potentially useful antimicrobial agents were performed with 74 strains of Bacteroides fragilis. Correlation of results obtained by the two methods and applicability of the single disc test to the measurement of antimicrobial susceptibility of anaerobes were analyzed. Prediction of susceptibility, intermediate susceptibility, and resistance of anaerobic bacteria to antimicrobial agents, based on the measurement of inhibition zone diameter, appeared to be satisfactory generally.


Coping behaviors in relation to frequency and intensity of anxiety-provoking situations.
The relationships between coping strategies (constructive, passive, and escape), on the one hand, and anxiety reactions and individuals' frequency of experiences of anxiety, and situations' rate of recurrence, and general anxiety-inducing effect on the other, were explored. The investigated factors and their associations were studied both as individual characteristics and situational properties. Data for boys and girls were treated separately. The results for individuals showed that both trait-anxiety and frequency of stressful experience were related positively to escape strategies and negatively to constructive solutions. For situations, general situational effect correlated positively with escape solutions and negatively with constructivity. Rate of recurrence was correlated positively with constructive strategies and negatively with escape solutions. No significant sex differences were found.


Deep sequencing analysis of the developing mouse brain reveals a novel microRNA.
MicroRNAs (miRNAs) are small non-coding RNAs that can exert multilevel inhibition/repression at a post-transcriptional or protein synthesis level during disease or development. Characterisation of miRNAs in adult mammalian brains by deep sequencing has been reported previously. However, to date, no small RNA profiling of the developing brain has been undertaken using this method. We have performed deep sequencing and small RNA analysis of a developing (E15.5) mouse brain. We identified the expression of 294 known miRNAs in the E15.5 developing mouse brain, which were mostly represented by let-7 family and other brain-specific miRNAs such as miR-9 and miR-124. We also discovered 4 putative 22-23 nt miRNAs: mm_br_e15_1181, mm_br_e15_279920, mm_br_e15_96719 and mm_br_e15_294354 each with a 70-76 nt predicted pre-miRNA. We validated the 4 putative miRNAs and further characterised one of them, mm_br_e15_1181, throughout embryogenesis. Mm_br_e15_1181 biogenesis was Dicer1-dependent and was expressed in E3.5 blastocysts and E7 whole embryos. Embryo-wide expression patterns were observed at E9.5 and E11.5 followed by a near complete loss of expression by E13.5, with expression restricted to a specialised layer of cells within the developing and early postnatal brain. Mm_br_e15_1181 was upregulated during neurodifferentiation of P19 teratocarcinoma cells. This novel miRNA has been identified as miR-3099. We have generated and analysed the first deep sequencing dataset of small RNA sequences of the developing mouse brain. The analysis revealed a novel miRNA, miR-3099, with potential regulatory effects on early embryogenesis, and involvement in neuronal cell differentiation/function in the brain during late embryonic and early neonatal development.


Contrast-induced acute kidney injury and mortality in ST elevation myocardial infarction treated with primary percutaneous coronary intervention.
Contrast-induced acute kidney injury (CI-AKI) is a common and potentially severe complication in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). There is no consensus on the best definition of CI-AKI to identify patients at risk of haemodialysis or death. The objective of this study was to assess the association of CI-AKI, using four definitions, on inhospital mortality, mortality or haemodialysis requirement over 1-year follow-up, in patients with STEMI treated with pPCI. In this prospective, observational study, all patients with STEMI referred for pPCI were included. We identified independent variables associated with CI-AKI and mortality. We included 1114 consecutive patients with STEMI treated by pPCI. CI-AKI occurred in 18.3%, 12.2%, 15.6% and 10.5% of patients according to the CIN, Acute Kidney Injury Network (AKIN), Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) Modification of Diet in Renal Disease (MDRD) and RIFLE Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) definitions, respectively. The RIFLE (CKD-EPI) definition was the most discriminant definition to identify patients at higher risk of inhospital mortality (27.1% vs 4.0%; adjusted OR 2.7 (95% CI 1.4 to 5.1), p=0.003), 1-year mortality (27.4% vs 6.6%; adjusted OR 2.8 (95% CI 1.5 to 5.3), p=0.002) and haemodialysis requirement at 1-year follow-up (15.6% vs 2.7%; adjusted OR 6.7 (95% CI 3.3 to 13.6), p=0.001). Haemodynamic instability, cardiac arrest, preexisting renal failure, elderly age and a high contrast media volume were independently associated with 1-year mortality. Of interest, contrast-media volume was not correlated to increase of creatininaemia (r=0.06) or decrease in estimated glomerular filtration rate (r=0.05) after percutaneous coronary intervention in our population. CI-AKI is a frequent and serious complication of STEMI treated by pPCI. The RIFLE definition is the most accurate definition to identify patients with CI-AKI at high risk of mortality or haemodialysis.


Analysis of Small Critical Regions of Swi1 Conferring Prion Formation, Maintenance, and Transmission.
Saccharomyces cerevisiae contains several prion elements, which are epigenetically transmitted as self-perpetuating protein conformations. One such prion is [SWI+ ], whose protein determinant is Swi1, a subunit of the SWI/SNF chromatin-remodeling complex. We previously reported that [SWI+ ] formation results in a partial loss-of-function phenotype of poor growth in nonglucose medium and abolishment of multicellular features. We also showed that the first 38 amino acids of Swi1 propagated [SWI+]. We show here that a region as small as the first 32 amino acids of Swi1 (Swi11-32) can decorate [SWI+] aggregation and stably maintain and transmit [SWI+] independently of full-length Swi1. Regions smaller than Swi11-32 are either incapable of aggregation or unstably propagate [SWI+]. When fused to Sup35MC, the [PSI+ ] determinant lacking its PrD, Swi11-31 and Swi11-32 can act as transferable prion domains (PrDs). The resulting fusions give rise to a novel chimeric prion, [SPS+], exhibiting [PSI+]-like nonsense suppression. Thus, an NH2-terminal region of ∼30 amino acids of Swi1 contains all the necessary information for in vivo prion formation, maintenance, and transmission. This PrD is unique in size and composition: glutamine free, asparagine rich, and the smallest defined to date. Our findings broaden our understanding of what features allow a protein region to serve as a PrD.


Rhodothermus bifroesti sp. nov., a thermophilic bacterium isolated from the basaltic subsurface of the volcanic island Surtsey.
Novel thermophilic heterotrophic bacteria were isolated from the subsurface of the volcanic island Surtsey off the south coast of Iceland. The strains were isolated from tephra core and borehole fluid samples collected below 70 m depth. The Gram-negative bacteria were rod-shaped (0.3-0.4 µm wide, 1.5-7 µm long), aerobic, non-sporulating and non-motile. Optimal growth was observed at 70 °C, at pH 7-7.5 and with 1% NaCl. Phylogenetic analysis identified the strains as members of the genus Rhodothermus. The type strain, ISCAR-7401T, was genetically distinct from its closest relatives Rhodothermus marinus DSM 4252T and Rhodothermus profundi PRI 2902T based on 16S rRNA gene sequence similarity (95.81 and 96.01%, respectively), genomic average nucleotide identity (73.73 and 72.61%, respectively) and digital DNA-DNA hybridization (17.6 and 16.9%, respectively). The major fatty acids of ISCAR-7401T were iso-C17:0, anteiso-C15:0, anteiso-C17:0 and iso-C15:0 (>10 %). The major isoprenoid quinone was MK-7 while phosphatidylethanolamine, diphosphatidylglycerol, an unidentified aminophospholipid and a phospholipid were the predominant polar lipid components. Based on comparative chemotaxonomic, genomic and phylogenetic analyses, we propose that the isolated strain represents a novel species of the genus Rhodothermus with the name Rhodothermus bifroesti sp. nov. The type strain is ISCAR-7401T (=DSM 112103T=CIP 111906T).


Orthostatic Hypotension: Mechanisms, Causes, Management.
Orthostatic hypotension (OH) occurs when mechanisms for the regulation of orthostatic BP control fails. Such regulation depends on the baroreflexes, normal blood volume, and defenses against excessive venous pooling. OH is common in the elderly and is associated with an increase in mortality rate. There are many causes of OH. Aging coupled with diseases such as diabetes and Parkinson's disease results in a prevalence of 10-30% in the elderly. These conditions cause baroreflex failure with resulting combination of OH, supine hypertension, and loss of diurnal variation of BP. The treatment of OH is imperfect since it is impossible to normalize standing BP without generating excessive supine hypertension. The practical goal is to improve standing BP so as to minimize symptoms and to improve standing time in order to be able to undertake orthostatic activities of daily living, without excessive supine hypertension. It is possible to achieve these goals with a combination of fludrocortisone, a pressor agent (midodrine or droxidopa), supplemented with procedures to improve orthostatic defenses during periods of increased orthostatic stress. Such procedures include water bolus treatment and physical countermaneuvers. We provide a pragmatic guide on patient education and the patient-orientated approach to the moment to moment management of OH.


CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions.
Several acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine-glycosaminoglycan (GAG) interactions are important for chemokine activity in vivo. Therefore, the GAG-chemokine interaction has been explored as target for inhibition of chemokine activity. It was demonstrated that CXCL9(74-103) binds with high affinity to GAGs, competed with active chemokines for GAG binding and thereby inhibited CXCL8- and monosodium urate (MSU) crystal-induced neutrophil migration to joints. To evaluate the affinity and specificity of the COOH-terminal part of CXCL9 toward different GAGs in detail, we chemically synthesized several COOH-terminal CXCL9 peptides including the shorter CXCL9(74-93). Compared to CXCL9(74-103), CXCL9(74-93) showed equally high affinity for heparin and heparan sulfate (HS), but lower affinity for binding to chondroitin sulfate (CS) and cellular GAGs. Correspondingly, both peptides competed with equal efficiency for CXCL8 binding to heparin and HS but not to cellular GAGs. In addition, differences in anti-inflammatory activity between both peptides were detected in vivo. CXCL8-induced neutrophil migration to the peritoneal cavity and to the knee joint were inhibited with similar potency by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not by CXCL9(86-103). In contrast, neutrophil extravasation in the MSU crystal-induced gout model, in which multiple chemoattractants are induced, was not affected by CXCL9(74-93). This could be explained by (1) the lower affinity of CXCL9(74-93) for CS, the most abundant GAG in joints, and (2) by reduced competition with GAG binding of CXCL1, the most abundant ELR+ CXC chemokine in this gout model. Mechanistically we showed by intravital microscopy that fluorescent CXCL9(74-103) coats the vessel wall in vivo and that CXCL9(74-103) inhibits CXCL8-induced adhesion of neutrophils to the vessel wall in the murine cremaster muscle model. Thus, both affinity and specificity of chemokines and the peptides for different GAGs and the presence of specific GAGs in different tissues will determine whether competition can occur. In summary, both CXCL9 peptides inhibited neutrophil migration in vivo through interference with GAG interactions in several animal models. Shortening CXCL9(74-103) from the COOH-terminus limited its GAG-binding spectrum.


The development of a CDK2-docking site peptide that inhibits p53 and sensitizes cells to death.
Cyclin-dependent protein kinases play important roles in cell cycle progression and are attractive targets for the design of anti-proliferative drugs. Two distinct synthetic CDK1/2 inhibitors, Roscovitine and NU2058, are pharmacologically distinct in their ability to modify p53-dependent transcription and perturb cell cycle progression. Although such active-site CDK1/2 inhibitors comprise the most standard type of enzyme inhibitor, many protein kinases are proving to harbour high affinity docking sites that may provide a potentially novel interface for the design of kinase-inhibitors. We examined whether CDK2 has a docking site for its oligomeric substrate p53, whether small-peptide leads can be developed that inhibit CDK2 function, and whether such peptide-inhibitors are pharmacologically distinct from Roscovitine or NU2058. A docking site for CDK2 was identified in the tetramerization domain of p53 at a site that is distinct from the phospho-acceptor site. Peptides derived from the tetramerization domain of p53 block CDK2 phosphorylation and identification of critical CDK2 contacts in the tetramerization domain of p53 suggest that kinase docking does not require tetramerization of the substrate. Transient transfection assays were developed to show that the GFP-CDK2 docking site fusion protein (GFP-CIP) attenuates p53 activity in vivo and suppresses p21WAF1 induction which is similar to NU2058 but distinct from Roscovitine. A stable cell line with an inducible GFP-CIP gene attenuates p53 activity and induces significant cell death in a drug-resistant melanoma cell line, sensitizes cells to death induced by Doxorubicin, and suppresses cell growth in a colony formation assay. These data indicate that CDK2, in addition to cyclin A, can have a high affinity docking site for a substrate and highlights the possibility that CDK2 docking sites may represent effective targets for inhibitor design.


Status of cardiovascular health in US children up to 11 years of age: the National Health and Nutrition Examination Surveys 2003-2010.
The American Heart Association recently defined cardiovascular health (CVH) to monitor it over time for all Americans. Nationally representative prevalence estimates for children under 12 years according to sex and race/ethnicity have not been reported. The study sample comprised 8961 children aged 2 to 11 years from 2003 to 2010 National Health and Nutrition Examination Surveys. National prevalence of ideal, intermediate, and poor CVH as defined by American Heart Association was estimated for each of 4 available metrics (body mass index [BMI], healthy diet score, total cholesterol, and blood pressure). No children had ideal levels for either zero or all 4 metrics. Ideal healthy diet score was least prevalent, ranging from 0 to 0.1%, whereas ideal blood pressure was most prevalent ranging from 88% to 93% across sex, race/ethnicity groups. Ideal BMI was less frequent at ages 6 to 11 years than at ages 2 to 5 years (67% versus 77%). Approximately 40% of children had intermediate or poor total cholesterol levels. The dietary intake of diet score components was associated with BMI, which was associated with blood pressure and total cholesterol. Ideal CVH status for BMI, total cholesterol, and blood pressure was prevalent in young children, whereas ideal diet was rare. Diet and BMI were important components to achieve ideal CVH metrics in children. Limited availability of data for all CVH metrics is a major obstacle for CVH assessment in the youngest age groups and represents an important missed opportunity for surveillance and secular trends analyses with aging.


Infrared-emitting colloidal nanocrystals: synthesis, assembly, spectroscopy, and applications.
Semiconductor nanocrystals produced by means of colloidal chemistry in a solvent medium are an attractive class of nanometer-sized building blocks from which to create complex materials with unique properties for a variety of applications. Their optical and electronic properties can be tailored easily, both by their chemical composition and particle size. While colloidal nanocrystals emitting in the infrared region have seen a burst of attention during the last decade there is clearly a paucity of review articles covering their synthesis, assembly, spectroscopic characterization, and applications. This Review comprehensively addresses these topics for II-VI, III-V, and IV-VI nanocrystals, examples being HgTe and Cd(x)Hg(1-) (x)Te, InP and InAs, and PbS, PbSe, and PbTe, respectively. Among the applications discussed here are optical amplifier media for telecommunications systems, electroluminescence devices, and noninvasive optical imaging in biology.


Inhibitory effects of dioscorea polysaccharide on TNF-α-induced insulin resistance in mouse FL83B cells.
Dioscorea is a traditional medicinal food in Asia. This study investigated the anti-insulin resistance of dioscorea polysaccharide (DPS) in inflammatory factor (tumor necrosis factor-α; TNF-α) induced mouse normal liver FL83B cells. Insulin resistance was induced by treating cells with TNF-α (20 ng/mL) for 5 h; subsequently, the medium was replaced with insulin and DPS for 60 min of incubation (model 1; alleviating group). In addition, cells were cotreated with TNF-α and DPS for 5 h in model 2 (preventing group). DPS effectively increased glucose uptake and glucose transporter 2 (GLUT2) expression of insulin-resistant cells. Furthermore, DPS stimulated insulin receptor substrate (IRS) tyrosyl phosphorylation and increased p-Akt level to alleviate insulin resistance in models 1 and 2. Finally, the possible mechanism of DPS promoting insulin sensitivity in TNF-α-induced FL83B cells was investigated in this study. DPS may attenuate c-Jun N-terminal kinases (JNK) and insulin resistance caused by TNF-α induction; therefore, DPS also elevated the levels of p-IRS(Tyr) and p-Akt(Ser) to improve insulin sensitivity in the TNF-α-induced FL83B cells.


A genetic locus closely linked to a protease inhibitor gene complex controls the level of multiple RNA transcripts.
The two major protease inhibitors in mouse plasma are alpha 1-protease inhibitor (alpha 1-PI), putative inhibitor of neutrophil elastase, and contrapsin, an inhibitor in vitro of trypsinlike proteases. We have shown by nucleotide sequence analysis that these two inhibitors are related (R. E. Hill, P. H. Shaw, P. A. Boyd, H. Baumann, and N. D. Hastie, Nature (London) 311:175-177, 1984). Here, we show that the contrapsin and alpha 1-PI genes are members of two different multigene families, each containing at least three genes in mice and rats. We established the chromosomal locations of these genes by analyzing the segregation of restriction fragment length polymorphisms in recombinant inbred mouse strains. These experiments show that the multiple genes in each family are clustered and that the two gene families are closely linked on chromosome 12. Thus the genes for contrapsin and alpha 1-PI are likely to have evolved by duplication of a common ancestral gene. The contrapsin multigene family codes for multiple mRNA transcripts in the liver. There is a genetic difference among inbred mouse strains in the regulation of two of these transcripts. In some inbred strains the transcripts are synthesized constitutively; in others they are induced by inflammation. We mapped in recombinant inbred strains the regulatory locus responsible for this genetic variation and found it is linked to the contrapsin multigene family, which suggests a cis-acting regulatory element. We also found that the contrapsin and the alpha 1-PI multigene families have acquired very different regulatory responses since the time of the gene duplication event.


Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate.
Etomidate is no longer administered as a continuous infusion for anesthetic maintenance or sedation, because it results in profound and persistent suppression of adrenocortical steroid synthesis with potentially lethal consequences in critically ill patients. We hypothesized that rapidly metabolized soft analogues of etomidate could be developed that do not produce persistent adrenocortical dysfunction even after prolonged continuous infusion. We hope that such agents might also provide more rapid and predictable anesthetic emergence. We have developed the soft etomidate analogue cyclopropyl-methoxycarbonyl etomidate (CPMM). Upon termination of 120-minute continuous infusions, hypnotic and encephalographic recoveries occur in four minutes. The aims of this study were to assess adrenocortical function during and following 120-minute continuous infusion of CPMM and to compare the results with those obtained using etomidate. Dexamethasone-suppressed rats were randomized into an etomidate group, CPMM group, or control group. Rats in the etomidate and CPMM groups received 120-minute continuous infusions of etomidate and CPMM, respectively. Rats in the control group received neither hypnotic. In the first study, adrenocortical function during hypnotic infusion was assessed by administering adrenocorticotropic hormone (ACTH) 90 minutes after the start of the hypnotic infusion and measuring plasma corticosterone concentrations at the end of the infusion 30 minutes later. In the second study, adrenocortical recovery following hypnotic infusion was assessed by administering ACTH every 30 minutes after infusion termination and measuring plasma corticosterone concentrations 30 minutes after each ACTH dose. During hypnotic infusion, ACTH-stimulated serum corticosterone concentrations were significantly lower in the CPMM and etomidate groups than in the control group (100 ± 64 ng/ml and 33 ± 32 ng/ml versus 615 ± 265 ng/ml, respectively). After hypnotic infusion, ACTH-stimulated serum corticosterone concentrations recovered to control values within 30 minutes in the CPMM group but remained suppressed relative to those in the control group for more than 3 hours in the etomidate group. Both CPMM and etomidate suppress adrenocortical function during continuous infusion. However, recovery occurs significantly more rapidly following infusion of CPMM.


Emergency Department Use and Inpatient Admissions and Costs Among Adolescents With Deliberate Self-Harm: A Five-Year Follow-Up Study.
Self-harm rates among U.S. adolescents have risen substantially. Health and social outcomes among contemporary self-harming youths are infrequently tracked and poorly understood. This study investigated long-term health service utilization (emergency department [ED] visits and inpatient admissions) and inpatient costs among a recent cohort of adolescents with deliberate self-harm. This retrospective cohort study used statewide, all-payer, longitudinally linked discharge data from California. All residents ages 10-19 presenting to EDs in 2010 with deliberate self-harm (N=5,396) were compared with two control groups: a random sample of adolescent ED patients with other complaints, matched on sex, age, residential zip code, and month of index visit (general control patients, N=14,921), and matched ED patients with psychiatric complaints but no self-harm (psychiatric control patients, N=15,835). Outcomes included 5-year rates of ED visits, inpatient admissions, and inpatient costs, overall and for psychiatric and nonpsychiatric complaints separately. Self-harm patients' ED use, inpatient admissions, and inpatient costs were significantly higher than those of general control patients (by 39%, 81%, and 21%, respectively), when the analysis controlled for confounding demographic and utilization characteristics. Associations mostly persisted, although smaller in magnitude, in comparisons between self-harm and psychiatric control patients. Psychiatric and nonpsychiatric complaints contributed to self-harming adolescents' excess health service utilization and costs. Deliberate self-harm among adolescents was found to be associated with long-lasting and costly patterns of health service utilization, often but not exclusively for psychiatric complaints. Future research should investigate the pathways underlying these associations and incorporate service utilization as a key patient outcome.


Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior.
To compare the clinical behavior and outcome of uterine carcinosarcomas and grade 3 endometrioid carcinomas. Data on patients with grade 3 endometrioid adenocarcinomas and uterine carcinosarcomas, from 1988 to 2004, was obtained from the Surveillance, Epidemiology, and End Results database. Mortality was analyzed using Cox proportional hazards models. Survival analysis was performed with the Kaplan-Meier method and log rank test. The cohort included 8,986 women with 5,024 (56%) grade 3 endometrioid carcinomas and 3,962 (44%) uterine carcinosarcomas. Women with uterine carcinosarcomas were older (aged 70 years compared with 66 years; P<.001) and more often nonwhite (23% compared with 15%; P<.001). These women presented with more advanced disease (stage III/IV 41% compared with 31%; P<.001). Multivariable analysis demonstrated that uterine carcinosarcoma histology, advanced age, nonwhite race, and advanced stage were independent predictors of poor survival. Cancer-specific mortality was 45% lower in women with grade 3 endometrioid carcinomas (hazard ratio 0.55; 95% confidence interval [CI] 0.5-0.6). The 5-year cancer-specific survival was lower for women with uterine carcinosarcoma for each disease stage. Survival for stage IC was 38% (95% CI 33-45%) for uterine carcinosarcoma compared with 68% (95% CI 63-73%) for grade 3 endometrioid carcinoma. For stage III, survival was 22% (95% CI 19-26%) for uterine carcinosarcoma compared with 45% (95% CI 41-49%) for grade 3 endometrioid carcinoma. Carcinosarcomas present at more advanced stage and have worse survival than grade 3 endometrioid carcinomas. Carcinosarcomas may represent a distinct biologic entity. II.


Effect of mechanical damage and wound healing on the viscoelastic properties of stems of flax cultivars (Linum usitatissimum L. cv. Eden and cv. Drakkar).
As plant fibres are increasingly used in technical textiles and their composites, underlying principles of wound healing in living plant fibres are relevant to product quality, and provide inspiration for biomimetic healing in synthetic materials. In this work, two Linum usitatissimum cultivars differing in their stem mechanical properties, cv. Eden (stems resistant to lodging) and cv. Drakkar (with more flexible stems), were grown without wound or with stems previously wounded with a cut parallel or transversal to the stem. To investigate wound healing efficiency, growth traits, stem biomechanics with Dynamic Mechanical Analysis and anatomy were analysed after 25-day recovery. Longitudinal incisions formed open wounds while transversal incisions generated stem growth restoring the whole cross-section but not the original stem organisation. In the case of transversal wound healing, all the bast fibre bundles in the perturbed area became lignified and pulled apart by parenchyma cells growth. Both Linum cultivars showed a healing efficiency from 79% to 95% with higher scores for transversal healing. Morphological and anatomical modifications of Linum were related to mechanical properties and healing ability. Alongside with an increased understanding of wound healing in plants, our results highlight their possible impact on textile quality and fibre yield.


A generative adversarial neural network with multi-attention feature extraction for fundus lesion segmentation.
Fundus lesion segmentation determines the location and size of diabetes retinopathy in fundus image, which assists doctors in developing the best eye treatment plan. However, owing to the scattered distribution and the similarity of lesions, it is extremely difficult to extract representative lesions feature and accurately segment lesions area. To solve the thorny problem, a generative adversarial network with multi-attention feature extraction is developed to segment diabetic retinopathy region. The main contributions are as follows: (1) An improved residual U-Net network combining with self-attention mechanism is designed as generative network to fully extract local and global feature of lesions while reducing the loss of key feature information. Considering the correlation between the same lesions feature of different samples, external attention mechanism is introduced in the residual U-Net network to focus on the relevant features of the same lesions in different samples throughout the entire dataset. (2) A discriminative network based on the PatchGAN structure is designed to further enhance the segmentation ability of generation network by discriminating between true and false samples. The proposed network is evaluated on the public dataset IDRiD, which achieved the Dice correlation coefficients of 75.7%, 76.53%, 50.06%, and 45.89% for EX, SE, MA, and HE, respectively. The experimental results show the generative adversarial neural network qualified for accurate segmentation of diabetic retinopathy from fundus image well.


Estimating the bioavailability factors needed for setting dietary reference values.
Estimated average requirements for micronutrients are central to deriving Dietary Reference Values. These are used for nutrition policies and programs, and also for regulatory and labeling purposes, and are traditionally devised to cover the needs of virtually all individuals in any population group. In order to estimate the average requirement, an appropriate endpoint (biomarker) is selected which describes the relationship between dietary intake and health. However, for some micronutrients, such as zinc, there are no good biomarkers, and for others, such as iron, the intake-status relationship is confounded by variations in absorption. Average requirements for these nutrients are derived using a factorial approach in which physiological needs for tissue growth and maintenance and endogenous losses are estimated, and the total converted to a dietary requirement by taking into account the overall absorption from the diet; i. e. multiplying the requirement by a bioavailability factor. The latter can be determined using algorithms, or estimates from absorption studies, some of which are described in this short review paper.


[Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective].
Most patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are dissatisfied with medical care. They complain about e. g. the lack of medical recognition of ME/CFS as a neuroimmunological disease and the medical perception of those affected as "difficult patients". As part of an exploratory qualitative survey, 544 medically diagnosed ME/CFS patients (> 20 years; 455 ♀, 89 ♂) were asked about their subjective experiences with regard to the doctor-patient relationships (DP relationship) to their treating physicians. The questionnaire was structured analogously to a focused, standardized guideline interview. The written answers were evaluated using a qualitative content analysis according to Mayring. The participants reported a significant deterioration in their health situation and their quality of life as a result of misdiagnoses and incorrect treatments, the strained DP relationship and the lack of support from the physicians. All of this leads to fear of visiting the doctor, a general loss of trust in physicians, a feeling of helplessness up to bitterness and resignation - with suicide as the last mental option for some patients to escape from this precarious situation. During medical consultations, other participants only addressed health problems that were not related to ME/CFS, or only went to the doctor in an emergency, or refrained from contacting doctors entirely. The DP relationship described by the participants as problematic in their opinion has significant negative health consequences for them. It is therefore of great urgency to develop a patient-centred treatment concept that focuses on ME/CFS patients as experts on their own illness.


Dyslipidemia in Dialysis Patients.
Dyslipidemia is a well-established traditional risk factor for cardiovascular events in the general population, particularly those with preexisting cardiovascular disease (CVD). In this population, reductions in total and low density lipoprotein cholesterol (LDL-C) levels are effective in reducing coronary artery events and mortality. Dyslipidemia is more common in patients with chronic kidney disease (CKD) and is believed to contribute to the high prevalence of CVD in these patients. To date, the treatment of dyslipidemia in patients with CKD followed the guidelines recommended by the US National Cholesterol Education Program Adult Treatment Panel III (ATP III) for the treatment of lipid abnormalities. These guidelines recommend that initiation of lipid-lowering therapy be based on LDL-C level and the projected 10-year risk for coronary artery disease (CAD). However, we now recognize that the relationship between serum cholesterol and CVD is more complex in patients with CKD, particularly those receiving maintenance hemodialysis. This has been demonstrated by the failure of three large randomized clinical trials to show a beneficial effect of lipid-lowering therapy in reducing mortality in dialysis patients despite significant reduction in LDL-C levels. These results have caused uncertainty among nephrologists about how best to manage dyslipidemia in their patients. In this review, the role of dyslipidemia as a risk factor for atherosclerosis in ESRD patients and the results of the 3 clinical trials and other studies, including their limitations will be discussed, and a schema for treating dyslipidemia in dialysis patients will be proposed.


Oscillating tolerance in synchronized cultures of Staphylococcus aureus.
Cells of synchronized cultures of Staphylococcus aureus showed an oscillating MBC/MIC ratio when tested with penicillin G. Although the MICs did not differ significantly throughout the cell cycle, the MBC was at its maximum when actively dividing cells were inoculated.


Using Chained or Tandem Schedules With Functional Communication Training: A Systematic Review.
Chained and tandem schedules are a common method for thinning schedules of reinforcement following functional communication training (FCT) in the treatment of problem behavior. We conducted a systematic literature review and meta-analysis of chained and tandem schedules following FCT to describe treatment characteristics and evaluate effects. We identified 38 articles and found reductions in problem behavior across four measures. Results of a random-effects multilevel meta-analysis of rigorous evaluations showed a significant effect of chained or tandem schedules + FCT on problem behavior relative to baseline. We observed resurgence in 77% of cases and 31% of schedule-thinning transitions. Results showed chained schedules resulted in greater reductions in problem behavior relative to tandem schedules. Exploratory moderator analyses suggested extinction, combined reinforcement, and delay and denial tolerance training procedures were associated with greater reductions in problem behavior relative to other treatment characteristics. Implications for practice and future research are discussed.


A calpain inhibitor enhances the survival of Schwann cells in vitro and after transplantation into the injured spinal cord.
Despite the diversity of cells available for transplantation into sites of spinal cord injury (SCI), and the known ability of transplanted cells to integrate into host tissue, functional improvement associated with cellular transplantation has been limited. One factor potentially limiting the efficacy of transplanted cells is poor cell survival. Recently we demonstrated rapid and early death of Schwann cells (SCs) within the first 24 h after transplantation, by both necrosis and apoptosis, which results in fewer than 20% of the cells surviving beyond 1 week. To enhance SC transplant survival, in vitro and in vivo models to rapidly screen compounds for their ability to promote SC survival are needed. The current study utilized in vitro models of apoptosis and necrosis, and based on withdrawal of serum and mitogens and the application of hydrogen peroxide, we screened several inhibitors of apoptosis and necrosis. Of the compounds tested, the calpain inhibitor MDL28170 enhanced SC survival both in vitro in response to oxidative stress induced by application of H2O2, and in vivo following delayed transplantation into the moderately contused spinal cord. The results support the use of calpain inhibitors as a promising new treatment for promoting the survival of transplanted cells. They also suggest that in vitro assays for cell survival may be useful for establishing new compounds that can then be tested in vivo for their ability to promote transplanted SC survival.


Team-Triggered Practical Fixed-Time Consensus of Double-Integrator Agents With Uncertain Disturbance.
This article addresses the team-triggered fixed-time consensus problems for a class of double-integrator agents subject to uncertain disturbance. Compared with the finite-time results, the convergence time of the fixed-time results is independent of the initial conditions. Furthermore, a novel team-triggered control (TTC) strategy is presented. This control strategy incorporates the event-triggered control (ETC) and self-triggered control (STC). The ETC and STC are proposed to achieve the fixed-time consensus of second-order multiagent systems (MASs), and no Zeno behavior occurs. The TTC scheme, derived by combining the ETC scheme and the STC scheme, is able to relax the requirement of continuous communication and thus lowering the energy consumption of communication while ensuring the performance of the system. The effectiveness of the proposed algorithms is validated by numerical simulations.


Quantitative Analysis and Discrimination of Partially Fermented Teas from Different Origins Using Visible/Near-Infrared Spectroscopy Coupled with Chemometrics.
Partially fermented tea such as oolong tea is a popular drink worldwide. Preventing fraud in partially fermented tea has become imperative to protect producers and consumers from possible economic losses. Visible/near-infrared (VIS/NIR) spectroscopy integrated with stepwise multiple linear regression (SMLR) and support vector machine (SVM) methods were used for origin discrimination of partially fermented tea from Vietnam, China, and different production areas in Taiwan using the full visible NIR wavelength range (400-2498 nm). The SMLR and SVM models achieved satisfactory results. Models using data from chemical constituents' specific wavelength ranges exhibited a high correlation with the spectra of teas, and the SMLR analyses improved discrimination of the types and origins when performing SVM analyses. The SVM models' identification accuracies regarding different production areas in Taiwan were effectively enhanced using a combination of the data within specific wavelength ranges of several constituents. The accuracy rates were 100% for the discrimination of types, origins, and production areas of tea in the calibration and prediction sets using the optimal SVM models integrated with the specific wavelength ranges of the constituents in tea. NIR could be an effective tool for rapid, nondestructive, and accurate inspection of types, origins, and production areas of teas.


Dismissal of RNA Polymerase II Underlies a Large Ligand-Induced Enhancer Decommissioning Program.
Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E2-induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements. Surprisingly, these basally active estrogen-repressed (BAER) enhancers are decommissioned by ERα-dependent recruitment of the histone demethylase KDM2A, functioning independently of its demethylase activity. Rather, KDM2A tethers the E3 ubiquitin-protein ligase NEDD4 to ubiquitylate/dismiss Pol II to abrogate eRNA transcription, with consequent target gene downregulation. Thus, our data reveal that Pol II ubiquitylation/dismissal may serve as a potentially broad strategy utilized by indirectly bound nuclear receptors to abrogate large programs of pioneer factor-mediated, eRNA-producing enhancers.


[Development of vaccines for HIV-1. Relevance of subtype-specific cellular immunity].
It has been almost 30 years since the detection of the first HIV-1 cases and yet an effective and safe vaccine has not been developed. Although, advances in antiretroviral therapy (HAART) have produced a major impact on the pandemic, and even though HIV/aids remains a major concern for developing countries, where access to therapy is limited. The last report from UNAIDS notified 33 million people living with HIV/aids, worldwide, while in Argentina it is estimated that 120,000 persons have been infected. One of the challenges to address and ultimately overcome when developing a vaccine is the high variability of HIV-1. The M group, responsible for the pandemic, is divided into 10 subtypes and several sub-subtypes, in addition to the 48 circulating recombinant forms (CRF) and over one hundred unique recombinant forms (URF). The HIV epidemic in Argentina is as complex as in the rest of the world, characterized by the high prevalence of infections caused by subtype B and BF variants. Despite the wide range of publications focused on the immune response against HIV as well as to vaccine development, how to overcome variability on vaccine antigen selection is still unclear. Studies performed in our laboratory showed the impact of the immunogenicity of BF recombinant variants, both in humans and in animal models. These results are of great concern in vaccine development for our region.


Adaptive evolution of SCML1 in primates, a gene involved in male reproduction.
Genes involved in male reproduction are often the targets of natural and/or sexual selection. SCML1 is a recently identified X-linked gene with preferential expression in testis. To test whether SCML1 is the target of selection in primates, we sequenced and compared the coding region of SCML1 in major primate lineages, and we observed the signature of positive selection in primates. We analyzed the molecular evolutionary pattern of SCML1 in diverse primate species, and we observed a strong signature of adaptive evolution which is caused by Darwinian positive selection. When compared with the paralogous genes (SCML2 and SCMH1) of the same family, SCML1 evolved rapidly in primates, which is consistent with the proposed adaptive evolution, suggesting functional modification after gene duplication. Gene expression analysis in rhesus macaques shows that during male sexual maturation, there is a significant expression change in testis, implying that SCML1 likely plays a role in testis development and spermatogenesis. The immunohistochemical data indicates that SCML1 is preferentially expressed in germ stem cells of testis, therefore likely involved in spermatogenesis. The adaptive evolution of SCML1 in primates provides a new case in understanding the evolutionary process of genes involved in primate male reproduction.


Urokinase-targeted fusion by oncolytic Sendai virus eradicates orthotopic glioblastomas by pronounced synergy with interferon-β gene.
Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity [rSeV/dMFct14 (uPA2), named "BioKnife"] for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-β (IFN-β) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-β (BioKnife-IFNβ), cell-cell fusion of 9L-L/R strongly facilitated the expression of IFN-β, and in turn, IFN-β significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNβ may have significant potential to improve the survival of GM patients in a clinical setting.


Structural and kinetic studies on uranyl(V) carbonate complex using 13C NMR spectroscopy.
We have measured 13C NMR spectra of uranyl(V) carbonate complex in D2O solution containing 1.003 M Na2(13)CO3 at various temperatures. Two singlet signals corresponding to free and coordinated CO3(2-) were observed at 169.13 and 106.70 ppm, respectively. From the peak area ratio, the structure of the uranyl(V) carbonate complex was determined as [U(V)O2(CO3)3]5-. Furthermore, kinetic analyses of the exchange reaction of free and coordinated CO3(2-) in [U(V)O2(CO3)3]5- were carried out using 13C NMR line-broadening. As a result, the first-order rate constant at 298 K and the activation parameters for CO3(2-) exchange reaction in [U(V)O2(CO3)3]5- were evaluated as 1.13 x 10(3) s(-1) and deltaH(double dagger) = 62.0 +/- 0.7 kJ x mol(-1), deltaS(double dagger) = 22 +/- 3 J x mol(-1) x K(-1), respectively. We suggest that the exchange follows a dissociative mechanism as in the corresponding [U(VI)O2(CO3)3]4- complex.


Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung.
47 tumor samples, 45 of which were obtained at thoracotomy for non-small cell lung cancer were examined for mutational activation of the oncogenes H-ras, K-ras, and N-ras. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. ras gene mutations were present in nine of 35 adenocarcinomas of the lung (all K-ras), in two of two lung metastases of colorectal adenocarcinomas (1 x K-ras, 1 x N-ras) and in one adenocarcinoma sample obtained at autopsy (H-ras). All K-ras and H-ras mutations were in either position 1 or 2 of codon 12, while the N-ras mutation was in position 2 of codon 61. The potential clinical significance of K-ras activation was analyzed using the combined results of this and of our earlier study (S. Rodenhuis et al., New Engl. J. Med., 317: 929-935, 1987). Lung adenocarcinomas with K-ras mutations tended to be smaller and were less likely to have spread to regional lymph nodes at presentation. With a median follow up of 10 months, survival data are still immature. None of six adenocarcinomas of nonsmokers had a K-ras mutation and only one of four who had stopped smoking more than 5 years before. We conclude that mutational K-ras activation is present in about a third of adenocarcinomas of the lung and that the mutational event may be a direct result of one or more carcinogenic ingredients of tobacco smoke. Studies involving larger numbers of patients are required to confirm the association of K-ras activation with smoking and the inverse relation with tumor progression.


Attitudes mediate the intergenerational transmission of corporal punishment in China.
This research aimed to examine the intergenerational transmission of corporal punishment and the role of parents' attitudes toward corporal punishment in the transmission processes in Chinese societies. Based on social-cognitive theory, it was hypothesized that parents' attitudes toward corporal punishment would mediate the transmission of corporal punishment. Seven hundred and eighty-five fathers and eight hundred and eleven mothers with elementary school-age children (data collected in winter 2009) were recruited through convenience sampling techniques. The Chinese version of Parent-Child Conflict Tactics Scale (CTSPC) and Attitude toward Physical Punishment Scale (ATPP) were used as the main assessment tools to measure parents' corporal punishment experiences in childhood, current use of corporal punishment and attitudes toward corporal punishment. Findings revealed that the strength of intergenerational transmission of corporal punishment was strong and parents' attitudes toward corporal punishment played a mediating role in the continuity of corporal punishment for both fathers and mothers in China. The findings highlighted the role of attitudes in the intergenerational transmission of corporal punishment within the Chinese cultural context and also suggested the need for intervention programs to focus on modification of maladaptive attitudes toward what is appropriate and effective discipline.


Cross-sectional assessment of determinants of STIs among men who have sex with men and transgender women in Kigali, Rwanda.
STIs among men who have sex with men (MSM) and transgender women (TGW) continue to increase. In Rwanda, STI management relies on syndromic management with limited empirical data characterising the burden of specific STIs among MSM/TGW. This study evaluated the prevalence of syphilis, Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) and associated factors among MSM/TGW in Kigali. From March to August 2018, 737 MSM/TGW >18 years were enrolled using respondent-driven sampling (RDS). Structured interviews and HIV/STI screening were conducted. Syphilis was screened with rapid plasma reagin confirmed by Treponema pallidum hemagglutination assay. CT/NG were tested by Cepheid GeneXpert. RDS-adjusted multivariable Poisson regression models with robust variance estimation were used to evaluate factors associated with any STI, and determinants of urethral and rectal STIs separately. Prevalence of any STI was 20% (RDS adjusted: 16.7% (95% CI: 13.2% to 20.2%)). Syphilis was 5.7% (RDS adjusted: 6.8% (95% CI: 4.3% to 9.4%)). CT was 9.1% (RDS adjusted: 6.1% (95% CI: 3.9% to 8.4%)) and NG was 8.8% (RDS adjusted: 7.1% (95% CI: 4.9% to 9.2%)). STIs were more common among older MSM and those with HIV (p<0.05). Of CT infections, 67% were urethral, 27% rectal and 6% were dual site. For NG infections, 52% were rectal, 29% urethral and 19% were dual site. Overall, 25.8% (23 of 89) of those with confirmed STI and returned for their results were symptomatic at time of testing.STI symptoms in the previous year (adjusted prevalence ratio (aPR): 1.94 (95% CI: 1.26 to 2.98)) were positively associated with any STI. Being circumcised was negatively associated with any STI (aPR: 0.47 (95% CI: 0.31 to 0.73)). HIV was positively associated with rectal STIs (aPR: 3.50 (95% CI: 1.09 to 11.21)) but negatively associated with urethral STIs. MSM/TGW, especially those living with HIV, are at high risk of STIs in Rwanda with the vast majority being asymptomatic. These data suggest the potential utility of active STI surveillance strategies using highly sensitive laboratory methods among those at high risk given the anatomical distribution and limited symptomatology of STIs observed among Rwandan MSM/TGW.


Noise facilitation in associative memories of exponential capacity.
Recent advances in associative memory design through structured pattern sets and graph-based inference algorithms have allowed reliable learning and recall of an exponential number of patterns that satisfy certain subspace constraints. Although these designs correct external errors in recall, they assume neurons that compute noiselessly, in contrast to the highly variable neurons in brain regions thought to operate associatively, such as hippocampus and olfactory cortex. Here we consider associative memories with boundedly noisy internal computations and analytically characterize performance. As long as the internal noise level is below a specified threshold, the error probability in the recall phase can be made exceedingly small. More surprising, we show that internal noise improves the performance of the recall phase while the pattern retrieval capacity remains intact: the number of stored patterns does not reduce with noise (up to a threshold). Computational experiments lend additional support to our theoretical analysis. This work suggests a functional benefit to noisy neurons in biological neuronal networks.


HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy.
Receptor-mediated mitophagy is a crucial process involved in mitochondria quality control. AMBRA1 is a mitophagy receptor for the selective removal of damaged mitochondria in mammalian cells. A critical unresolved issue is how AMBRA1-mediated mitophagy is controlled in response to cellular stress. Here, we investigated the role of BCL2-family proteins on AMBRA1-dependent mitophagy and showed that MCL1 delays AMBRA1-dependent mitophagy. Indeed, MCL1 overexpression is sufficient to inhibit recruitment to mitochondria of the E3 Ubiquitin ligase HUWE1, a crucial dynamic partner of AMBRA1, upon AMBRA1-mediated mitophagy induction. In addition, we found that during mitophagy induced by AMBRA1, MCL1 levels decreased but were sustained by inhibition of the GSK-3β kinase, which delayed AMBRA1-mediated mitophagy. Also, we showed that MCL1 was phosphorylated by GSK-3β at a conserved GSK-3 phosphorylation site (S159) during AMBRA1-mediated mitophagy and that this event was accompanied by HUWE1-dependent MCL1 degradation. Altogether, our results demonstrate that MCL1 stability is regulated by the kinase GSK-3β and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy. Our work thus defines MCL1 as an upstream stress-sensitive protein, functional in AMBRA1-mediated mitophagy.


A particular expression pattern of CD13 epitope 7H5 in chronic lymphocytic leukaemia--a possible new therapeutic target.
A total of 50 patients with chronic lymphocytic leukaemia (CLL), as well as the B-cell leukaemia cell lines MEC-1, JVM-3, and BV-173 were studied in order to assess the incidence of CD13/aminopeptidase N (APN) immunolabelling with a monoclonal antibody 7H5 compared to LeuM7 and to CD13 mRNA levels, and to correlate these data with the cytotoxic and apoptosis-induction activity of the natural phenolic APN inhibitor curcumin. CD13/APN was detected in a significant proportion of B-CLL patients (42/50, 84%), immunolabelled by 7H5 (42/50) ± LeuM7 (10/50). Molecular analysis for CD13 transcripts confirmed these data, resulting in a specific RT-PCR product in CD13 positive cases. Curcumin showed concentration-dependent cytoreductive efficacy and apoptosis-induction activity in all tested cell lines and primary cultures from CLL mononuclear cells. There was a clear tendency for a better response in CD13 positive cases. The incidence of CD13/APN in CLL suggests that the inhibition of APN/CD13 by curcumin may be an effective new molecular target for a more efficient therapy for these patients and warrants further investigations.


Rocking media over ex vivo corneas improves this model and allows the study of the effect of proinflammatory cytokines on wound healing.
The aim of this work was to develop an in vitro cornea model to study the effect of proinflammatory cytokines on wound healing. Initial studies investigated how to maintain the ex vivo models for up to 4 weeks without loss of epithelium. To study the effect of cytokines, corneas were cultured with the interleukins IL-17A, IL-22, or a combination of IL-17A and IL-22, or lipopolysaccharide (LPS). The effect of IL-17A on wound healing was then examined. With static culture conditions, organ cultures deteriorated within 2 weeks. With gentle rocking of media over the corneas and carbon dioxide perfusion, the ex vivo models survived for up to 4 weeks without loss of epithelium. The cytokine that caused the most damage to the cornea was IL-17A. Under static conditions, wound healing of the central corneal epithelium occurred within 9 days, but only a single-layered epithelium formed whether the cornea was exposed to IL-17A or not. With rocking of media gently over the corneas, a multilayered epithelium was achieved 9 days after wounding. In the presence of IL-17A, however, there was no wound healing evident. Characterization of the cells showed that wherever epithelium was present, both differentiated cells and highly proliferative cells were present. We propose that introducing rocking to extend the effective working life of this model and the introduction of IL-17A to this model to induce aspects of inflammation extend its usefulness to study the effects of agents that influence corneal regeneration under normal and inflamed conditions.


GNG11 (G-protein subunit γ 11) suppresses cell growth with induction of reactive oxygen species and abnormal nuclear morphology in human SUSM-1 cells.
Enforced expression of GNG11, G-protein subunit γ 11, induces cellular senescence in normal human diploid fibroblasts. We here examined the effect of the expression of GNG11 on the growth of immortalized human cell lines, and found that it suppressed the growth of SUSM-1 cells, but not of HeLa cells. We then compared these two cell lines to understand the molecular basis for the action of GNG11. We found that expression of GNG11 induced the generation of reactive oxygen species (ROS) and abnormal nuclear morphology in SUSM-1 cells but not in HeLa cells. Increased ROS generation by GNG11 would likely be caused by the down-regulation of the antioxidant enzymes in SUSM-1 cells. We also found that SUSM-1 cells, even under normal culture conditions, showed higher levels of ROS and higher incidence of abnormal nuclear morphology than HeLa cells, and that abnormal nuclear morphology was relevant to the increased ROS generation in SUSM-1 cells. Thus, SUSM-1 and HeLa cells showed differences in the regulation of ROS and nuclear morphology, which might account for their different responses to the expression of GNG11. Thus, SUSM-1 cells may provide a unique system to study the regulatory relationship between ROS generation, nuclear morphology, and G-protein signaling.


Reviewing the genetic alterations in high-risk cutaneous squamous cell carcinoma: A search for prognostic markers and therapeutic targets.
Cutaneous squamous cell carcinoma (SCC) is second only in incidence to basal cell carcinoma (BCC), effecting up to 500 000 people in the United States annually. Metastasis to regional lymph nodes occurs in approximately 5% of cases and imparts significant morbidity. Standard treatment in this group involves a combination of surgery and adjuvant radiation. Currently, there are no clinically useful biomarkers of metastatic potential in primary cutaneous SCC and histological predictors can be unreliable. The high level of mutational burden in normal UV-exposed skin has hampered the search for novel drivers of invasive disease, and indeed metastatic potential. This review outlines the clinical problems in high-risk and metastatic cutaneous SCCs, reviews the known genetic events and molecular mechanisms in high-risk primary cutaneous SCC and metastasis, and identifies avenues for further investigation and potential therapy.


Assessment of Oral Chemotherapy Nonadherence in Chronic Myeloid Leukemia Patients Using Brief Measures in Community Cancer Clinics: A Pilot Study.
The purpose of this pilot study was to assess Chronic Myeloid Leukemia (CML) patients' adherence to, beliefs about, and barriers to oral anticancer agents (OAC) using brief self-report measures in community-based cancer clinics. Patients completed a structured interview including a health literacy assessment, a Brief Medication Questionnaire, two single-item self-report adherence questions, and the Medications Adherence Reasons Scale. Of the 86 participants, 88.4% were white; 55.8% male; mean age, 58.7 years; and 22.1% had limited health literacy. Nonadherence (missing at least one dose in the last week) was reported by 18.6% of participants and associated (p < 0.003) with less-than-excellent perceived ability to take CML medications (16.3%). Black participants reported more difficulty taking CML medications than white participants (28.6% vs. 8.3%, p = 0.053). Among all participants, 43.0% reported their CML medicine was ineffective and 24.4% that taking CML pills was somewhat to very hard. The most common reasons for missing a dose were simply missed it (24.4%) and side effects (18.6%). Most patients perceived their ability to take CML medication was good to excellent, yet nearly one in five reported missing at least one dose in the last week. Brief, no-cost self-report assessments to screen CML patients' OAC adherence, barriers, and beliefs could facilitate counseling in busy community cancer clinics.


Intravitreal bevacizumab versus triamcinolone acetonide for macular edema due to branch retinal vein occlusion: a matched study.
Branch retinal vein occlusion (BRVO) is a common retinal vascular disorder of the elderly and both intravitreal triamcinolone acetonide (TA) and intravitreal bevacizumab were reported to be effective. The purpose of this study was to compare intravitreal bevacizumab with intravitreal TA for the treatment of macular edema resulting from BRVO. The retrospectively comparative interventional study included a bevacizumab group of 34 BRVO patients (1.25 mg bevacizumab) and a TA group of 34 BRVO patients (4.0 mg TA), and the two groups were matched by baseline best corrected visual acuity (BCVA). Examinations were designed to be carried out at 1 day, 3 days, 1 month, 2 months, 3 months, 6 months and 1 year after each injection. The mean follow-up was (148.43 +/- 130.56) days. Main outcome parameters were BCVA and morphometric measurements of the macula obtained by optical coherence tomography. In all follow-ups, the mean changes of BCVA (LogMAR) between two groups were not significantly different (P > 0.10). Similarly, the rates of patients who got BCVA improvement > or = 2 lines or lost BCVA > or = 2 lines were not significantly different, either (P > 0.10). In both groups, compared with baseline, the mean central macular thickness (CMT) got reduction from 4 weeks to 1 year after initial injection, however, which lost statistical significance at 6-month follow-up in TA group (P = 0.25) and lost significance at 3-month and 6-month follow-up in bevacizumab group (P = 0.07, 0.21). The mean CMT between two groups differed at 3-month follow-up (P < 0.01), while almost kept parallel in other follow-ups (all P > 0.40). In TA group, retinal pigment epithelium tear occurred in 1 eye at 8 weeks after initial injection and 12 eyes (35.3%) got intraocular pressure > 21 mmHg. In bevacizumab group, no severe complications were observed. For BRVO, intravitreal bevacizumab versus intravitreal TA causes a similar increase in visual acuity and reduction of macular edema (except 3-month follow-up) with minor complications during 1 year.


Stemless reverse humeral component neck-shaft angle has an influence on initial fixation.
Stemless anatomic humeral components are commonly used and are an accepted alternative to traditional stemmed implants in patients with good bone quality. Presently, little literature exists on the design and implantation parameters that influence primary time-zero fixation of stemless reverse humeral implants. Accordingly, this finite element analysis study assessed the surgical implantation variable of neck-shaft angle, and its effect on the primary time-zero fixation of reversed stemless humeral implants. Eight computed tomography-derived humeral finite element models were used to examine a generic stemless humeral implant at varying neck-shaft angles of 130°, 135°, 140°, 145°, and 150°. Four loading scenarios (30° shoulder abduction with neutral forearm rotation, 30° shoulder abduction with forearm supination, a head-height lifting motion, and a single-handed steering motion) were employed. Implantation inclinations were compared based on the maximum bone-implant interface distraction detected after loading. The implant-bone distraction was greatest in the 130° neck-shaft angle implantation cases. All implant loading scenarios elicited significantly lower micromotion magnitudes when neck-shaft angle was increased (P = .0001). With every 5° increase in neck-shaft angle, there was an average 17% reduction in bone-implant distraction. The neck-shaft angle of implantation for a stemless reverse humeral component is a modifiable parameter that appears to influence time-zero implant stability. Lower, more varus, neck-shaft angles increase bone-implant distractions with simulated activities of daily living. It is therefore suggested that humeral head osteotomies at a higher neck-shaft angle may be beneficial to maximize stemless humeral component stability.


Blastic Plasmacytoid Dendritic Cell Neoplasm: State of the Art and Prospects.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare tumour, which usually affects elderly males and presents in the skin with frequent involvement of the bone-marrow, peripheral blood and lymph nodes. It has a dismal prognosis, with most patients dying within one year when treated by conventional chemotherapies. The diagnosis is challenging, since neoplastic cells can resemble lymphoblasts or small immunoblasts, and require the use of a large panel of antibodies, including those against CD4, CD56, CD123, CD303, TCL1, and TCF4. The morphologic and in part phenotypic ambiguity explains the uncertainties as to the histogenesis of the neoplasm that led to the use of various denominations. Recently, a series of molecular studies based on karyotyping, gene expression profiling, and next generation sequencing, have largely unveiled the pathobiology of the tumour and proposed the potentially beneficial use of new drugs. The latter include SL-401, anti-CD123 immunotherapies, venetoclax, BET-inhibitors, and demethylating agents. The epidemiologic, clinical, diagnostic, molecular, and therapeutic features of BPDCN are thoroughly revised in order to contribute to an up-to-date approach to this tumour that has remained an orphan disease for too long.


The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance.
Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.


Autophagy impairment by African swine fever virus.
African swine fever is a devastating disease of domestic swine and wild boar caused by a large double-stranded DNA virus that encodes for more than 150 open reading frames. There is no licensed vaccine for the disease and the most promising current candidates are modified live viruses that have been attenuated by deletion of virulence factors. Like many viruses African swine fever virus significantly alters the host cell machinery to benefit its replication and viral genes that modify host pathways represent promising targets for development of gene deleted vaccines. Autophagy is an important cellular pathway that is involved in cellular homeostasis, innate and adaptive immunity and therefore is manipulated by a number of different viruses. Autophagy is regulated by a complex protein cascade and here we show that African swine fever virus can block formation of autophagosomes, a critical functional step of the autophagy pathway through at least two different mechanisms. Interestingly this does not require the A179L gene that has been shown to interact with Beclin-1, an important autophagy regulator.


Partial characterization of the embryo-derived platelet-activating factor in mice.
The platelet-activating factor (PAF) produced by mouse embryos showed similar kinetics of action and dose-response curve, in a bioassay, as did 1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphocholine (PAF-acether). The activity of the embryo-derived PAF was not affected by inhibitors of the ADP (pyruvate kinase with phosphoenol pyruvate) or cyclo-oxygenase (indomethacin) pathways of platelet activation. Chlorpromazine, an inhibitor of the PAF-acether pathway of platelet activation, caused a significant inhibition of the effects of embryo-derived PAF. Phospholipases A2, C and D significantly inhibited the activity while lipase had no effect, suggesting a phospholipid structure. All the embryo-derived PAF was found in the chloroform fraction after chloroform:methanol (2:1 v/v) extraction, as was PAF-acether. Both factors migrated at a similar rate (Rf 0.10-0.12) on silica thin-layer chromatography (chloroform:methanol:water; 65:35:4 by vol.). The embryo-derived PAF therefore displays chemical, biochemical and physiological properties similar to those of PAF-acether.


Comparison of the role of esterases in the differential age-related sensitivity to chlorpyrifos and methamidophos.
More than 30 years ago, scientists recognized that, at a given dosage, the young rat was more sensitive than the adult to the toxicity of many organophosphorus, anticholinesterase pesticides. This observation went basically unexamined until recently. Renewed interest has emerged in scrutinizing this age-related sensitivity to pesticides, especially in light of the many new pesticides which are currently marketed. Our laboratory has been involved in comparing the age-related sensitivity of young and adult rats to chlorpyrifos [Dursban, Lorsban; O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate] and methamidophos (Monitor; O,S-dimethyl phosphoamidothioate). Using chlorpyrifos, there is marked age-related sensitivity: direct oral dosing of the preweanling rat (postnatal day 17; PND17) with chlorpyrifos causes a toxic response (defined either behaviorally or biochemically) at a approximately 5-fold lower dosage than in adults (oral, maximum tolerated dose for the PND17 is 20 mg/kg versus 100 mg/kg for the adult). Other studies have indicated that the rat detoxifies chlorpyrifos and its oxon by binding to carboxylesterases and hydrolysis by A-esterases. The young rat is deficient in both these detoxification enzymes, which may explain the increased sensitivity of the young to chlorpyrifos toxicity. The age-related pattern for methamidophos is distinctly different: the oral, maximum tolerated dose is the same (8 mg/kg) whether the animal is 17 days old or an adult. We present data which indicate that methamidophos is not detoxified appreciably either in vivo or in vitro by A-esterases or carboxylesterases. Therefore, we submit the following hypothesis: organophosphorus pesticides, like chlorpyrifos, which are detoxified via A-esterases or carboxylesterases are more likely to exhibit age-related differences in sensitivity than pesticides which are not detoxified via these routes.


Isolation and characterization of microvessels from normal brain and brain tumors.
We describe a new technique for isolating microvessels from both brain and brain tumors. This method is relatively quick and provides a microvessel preparation free of contamination by other brain tissue. Using this method, structurally intact microvessels from normal rat brain and from a malignant rat astrocytoma were isolated and characterized with light microscopy, scanning electron microscopy and transmission electron microscopy. In contrast to microvessels derived from normal rat brain, rat astrocytoma microvessels had endothelial cells with multilayered basement membranes, extensive microvilli on the cell surfaces, and a significant increase in the number of pinocytes in the cytoplasm. Furthermore, astrocytoma microvessel endothelial cells had pleomorphic electron dense nuclei with pale perichromatin, whereas the nuclei of endothelial cells of microvessels derived from normal brain tissue were finely granular and homogeneous with characteristically electron dense perichromatin. The morphologic characteristics of the astrocytoma microvessels are similar to the histologic changes seen in astrocytoma tissue in situ, and correlate well with the known altered functions of brain tumor neovasculature.


Allosteric control of ACE2 peptidase domain dynamics.
The Angiotensin Converting Enzyme 2 (ACE2) assists the regulation of blood pressure and is the main target of the coronaviruses responsible for SARS and COVID19. The catalytic function of ACE2 relies on the opening and closing motion of its peptidase domain (PD). In this study, we investigated the possibility of allosterically controlling the ACE2 PD functional dynamics. After confirming that ACE2 PD binding site opening-closing motion is dominant in characterizing its conformational landscape, we observed that few mutations in the viral receptor binding domain fragments were able to impart different effects on the binding site opening of ACE2 PD. This showed that binding to the solvent exposed area of ACE2 PD can effectively alter the conformational profile of the protein, and thus likely its catalytic function. Using a targeted machine learning model and relative entropy-based statistical analysis, we proposed the mechanism for the allosteric perturbation that regulates the ACE2 PD binding site dynamics at atomistic level. The key residues and the source of the allosteric regulation of ACE PD dynamics are also presented.


Comparison of resident and intern salaries with the current living wage as a quantitative estimate of financial strain among postgraduate veterinary trainees.
To compare resident and intern salaries with current regional living wages as a quantitative estimate of financial strain. 152 residency programs and 141 internship programs listed with the Veterinary Internship and Residency Matching Program for the 2021-2022 training year. Data were collected for program annual salary and location. Regional living wage for each location was determined with the Massachusetts Institute of Technology Living Wage Calculator, and annual salary was compared with living wage to estimate income surplus before and after taxes. Results for programs in academia and private practice were compared. Spearman correlation was used to determine whether program annual salary was significantly associated with regional living wage. Mean ± SD income surplus before taxes was $7,786 ± 9,426 for clinical residency programs, $16,672 ± 5,105 for laboratory animal programs, and $5,829 ± 8,119 for internships. Academic residencies and internships offered salaries significantly lower than those offered in private practice, and income surpluses before and after taxes were significantly lower for academic programs than for private practice programs. There were weak and moderate, respectively, correlations between program annual salary and regional living wage for residency (r = 0.369) and internship (r = 0.570) programs. Postgraduate training prolongs financial instability, and annual salaries generally do not meet the minimum income standard of a living wage. Financial stress has implications for mental health and diversity, and these findings invite deeper consideration of current remuneration practices for veterinary residents and interns.


Influence of feed restriction and sex on growth performance and carcass and meat quality of Iberian pigs reared indoors.
Iberian x Duroc pigs (n = 168), with an average age of 152 d and 42 +/- 2 kg, were used to investigate the effect of feeding regimen [ad libitum access to feed (AL) vs. 82% of AL from 152 to 201 d of age and 72% from 202 to 263 d of age (FR)] and sex (intact females, castrated females, and castrated males) on growth performance and carcass and meat quality. For the last 54 d before slaughter at 317 d of age, all pigs had AL access to feed. Between 152 and 263 d of age, pigs consuming AL had greater (P < 0.001) ADFI and ADG than FR pigs; however, when all pigs received AL access to feed (264 to 317 d of age), ADFI (P < 0.05), ADG (P < 0.001), and G:F (P < 0.01) increased in FR pigs compared with AL pigs. During the entire feeding period (152 to 317 d of age), ADG in FR pigs was less (P < 0.01) than in AL pigs. Feed-restricted pigs tended to have greater (P < 0.10) yields of trimmed hams and shoulders and less carcass fat than AL pigs, but feeding regimens did not affect chemical composition and color of meat. Intact females tended (P < 0.10) to have greater G:F and produced carcasses with less (P < 0.05) fat, greater (P < 0.01) proportions of primal cuts, and greater (P < 0.05) CP in the LM than castrated females and castrated males. It was concluded from this experiment that feed restriction applied from 152 to 263 d of age improved primal cut yields without affecting G:F, pork quality, and cured ham production traits. Moreover, intact females were superior to their castrated counterparts (particularly castrated females) in growth performance and primal cut yields. Therefore, feed restriction in intact females can be recommended as an acceptable practice for the production of Iberian pigs under intensive conditions.


Ethical Challenges of Personal Disclosure in Gaining Entry with Religious Congregations.
This is a story about learning how to navigate my social identities as a non-religious gay man attempting to conduct data-based consultation with a religious congregation. Beyond my own growth in knowing myself better, this story speaks to the larger ethical challenge of how we build trust in community relationships, and in particular how much of our personal selves we need to disclose in the process of an individual or group deciding to work with us. Individuals and groups make decisions to work with us based on who they perceive us to be; thus, what is our ethical obligation to disclose aspects of who we are to promote full informed consent? To illustrate this ethical challenge of personal disclosure, I tell the story of discussions I had with three different religious leaders and a congregational committee about potentially working together. Throughout these stories, I reflect on my own messy process of growth as a window into the more general question of how we navigate our identities and values as community psychologists in the work we do with communities.


Implementation of an enhanced recovery after surgery (ERAS) protocol for total abdominal hysterectomies in the division of gynecologic oncology: a network-wide quality improvement initiative.
Enhanced Recovery After Surgery (ERAS) protocols have been shown to decrease length of stay and postoperative opioid usage in colorectal and bariatric surgeries performed at large academic centers. Hysterectomies are the second most common surgical procedure among women in the United States. Hysterectomies performed in an open fashion, or total abdominal hysterectomies (TAHs), account for a large portion of procedures performed by gynecologic oncologists secondary to current oncology guidelines and surgical complexity. Implementation of an ERAS protocol for gynecologic oncology TAHs is one way in which patient outcomes may be improved. An ERAS protocol for gynecologic oncology surgeries performed in a community hospital was instituted with the goal to optimize patient outcomes preoperatively. The primary outcome of interest was to reduce patient opioid usage. Secondary outcomes included compliance with the ERAS protocol, length of stay, and cost. Thirdly, this study aimed to demonstrate the unique challenges of implementing a large-scale protocol across a community network. An ERAS protocol was implemented in 2018, with multidisciplinary input from the Departments of Gynecologic Oncology, Anesthesia, Pharmacy, Nursing, Information Technology, and Quality Improvement to develop a comprehensive ERAS order set. This was implemented across a 12-site hospital system network that consisted of both urban and rural hospital settings. A retrospective review of patient charts was performed to assess measured outcomes. Parametric and nonparametric tests were utilized for statistical analysis with p<0.05 denoting statistical significance. If the p value was >0.05 and <0.09, this was considered a trend toward significant. A total of 124 patients underwent a TAH utilizing the ERAS protocol during 2018 and 2019. The control arm consisted of 59 patients who underwent a TAH prior to the ERAS protocol intervention, which was the standard of care in 2017. After 2 years of implementation of the ERAS protocol intervention, we found that 48 % of the ERAS patients had minimal opioid requirements after surgery (oral morphine equivalent [OME] range 0-40) with decreased postoperative opioid requirements in the ERAS group (p=0.03). Although not statistically significant, utilization of the ERAS protocol for gynecologic oncology TAHs trended toward shorter hospital length of stay from 5.18 to 4.17 days (p=0.07). The median total hospital costs per patient also showed a nonsignificant decrease in cost from $13,342.00 in the non-ERAS cohort and $13,703.00 in the ERAS cohort (p=0.8). A large-scale quality improvement (QI) initiative is feasible utilizing a multidisciplinary team to implement an ERAS protocol for TAHs in the division of Gynecologic Oncology with promising results. This large-scale QI result was comparable to studies that conducted quality-improvement ERAS initiatives at single academic institutions and should be considered within community networks.


Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients.
The prototypic long pentraxin PTX3, a soluble pattern recognition receptor, plays an important role in innate defense against selected pathogens by favoring their elimination and the initiation of protective responses. PTX3 has notably beneficial effects in mice infected with Aspergillus fumigatus and Pseudomonas aeruginosa. Cystic fibrosis (CF), a severe inherited autosomal recessive disease, is characterized by recurrent lung infections, especially by these two pathogens. We thus hypothesized that the status of PTX3 may be altered in CF patients. Level and integrity of PTX3 were analyzed in the sputum samples from 51 CF patients and 7 patients with chronic obstructive pulmonary disease (COPD). The levels of PTX3 were increased in serums from CF patients, but low in their respiratory secretions. PTX3 concentrations in sputum samples were dramatically lower in CF patients than in COPD patients. The low concentration of PTX3 resulted from a proteolysis cleavage by elastase and A. fumigatus proteases. Interestingly, the N-ter domain of PTX3, involved in protection against A. fumigatus, is preferentially degraded by these proteases. These results indicate that the selective proteolysis of PTX3 in the CF lung may explain, in part, the recurrent lung infections by PTX3-sensitive pathogens in CF patients.


Orbital Schwannoma: Radiographic and Histopathologic Correlation in 15 Cases.
To evaluate the relationship between radiographic and histopathologic features of orbital schwannoma. Retrospective review of 15 patients with orbital schwannoma managed at an ocular oncology service. The mean patient age at the time of presentation was 42 years old (median 40, range 15-64 years). The orbital schwannoma was found incidentally (n = 2) or with symptoms of proptosis (n = 2), blurred vision (n = 3), pain (n = 3), eyelid swelling (n = 2), diplopia (n = 2), or headache (n = 1). The mean duration of symptoms was 15 months (median, 9; range 1-60 months). The tumor occupied the superior (n = 11) or inferior (n = 4) orbit. Antero-posterior tumor location involved the anterior (n = 2), middle (n = 3), posterior (n = 4), or entire (n = 6) orbit. MRI was performed in 12 patients (80%) and CT was the only form of imaging in 3 patients (20%). The T1-weighted MRI (n = 11) showed the mass as isointense (n = 10) or hyperintense (n = 1) to the extraocular muscles). On T2-weighted MRI (n = 10), the mass demonstrated hyperintensity (n = 9) or hypointensity (n = 1). Histopathologic assessment demonstrated Antoni A (n = 12) and Antoni B (n = 12) patterns. Antoni A pattern correlated with hyperintensity on T1-weighted MRI and hypointensity on T2-weighted MRI. Antoni B pattern correlated with hypointensity on T1-weighted MRI and hyperintensity on T2-weighted MRI. As Antoni B approached >50% of the solid mass (n = 8), both T1- and T2-weighted MRI images were more likely to be heterogeneous (n = 7, 88% and n = 6, 75%, respectively). Orbital schwannomas are nearly always benign, well-encapsulated slowly progressive tumors. Due to the biphasic distribution of Antoni A and Antoni B pattern, the appearance on MRI has a variable degree of heterogeneity. Antoni A pattern correlated with hyperintensity and Antoni B pattern correlated with hypointensity on T1-weighted MRI.