3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the First Dual BACE-1/GSK-3β Fragment Hits against Alzheimer's Disease.
One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3β dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation. Notably, compound 2, endowed with well-balanced potencies against the two isolated enzymes (IC50 of 16 and 7 μM against BACE-1 and GSK-3β, respectively), displayed effective neuroprotective and neurogenic activities and no neurotoxicity in cell-based assays. It also showed good brain permeability in a pharmacokinetic assessment in mice. Overall, triazinone derivatives, thanks to the simultaneous modulation of multiple points of the diseased network, might emerge as suitable candidates to be tested in in vivo Alzheimer's disease models.


Beauty Inside Out: Examining Beauty Product Use Among Diverse Women and Femme-Identifying Individuals in Northern Manhattan and South Bronx Through an Environmental Justice Framework.
The disproportionate use of chemical straighteners and skin lighteners by women of color is a growing public health concern given the link between product use and adverse health effects. Prior studies examined product use as an individual choice but neglected social-structural factors, which influence beauty perceptions and personal decisions around product use. We used a community-based participatory research approach to characterize product use by demographics and investigated how racialized beauty norms impact use among 297 women and femme-identifying individuals in Northern Manhattan and the South Bronx. Product use varied by race/ethnicity, nativity, and messaging from family and peers. Black respondents were more likely to ever use chemical straighteners than non-Black respondents (OR = 2.0; 95% CI = 1.2-3.2), as were respondents who heard that family members express a preference for straight hair compared with respondents whose family members expressed mixed preferences about hairstyles (OR = 2.0; 95% CI = 1.1-3.7). Compared with non-Asian respondents and respondents born in the United States, Asian respondents and respondents born in other countries, respectively, had threefold higher odds of ever using skin lighteners (Asian: OR = 3.2; 95% CI = 1.4-7.0; born in other countries: OR = 3.4; 95% CI = 1.9-6.1). Respondents' perceptions that others believe straight hair or lighter skin confer benefits such as beauty, professionalism, or youth were associated with greater use of chemical straighteners and skin lighteners. These findings highlight the pervasiveness of racialized beauty norms and point to the need to reduce the demand for and sale of these products through community education, market-based strategies, and public policy.


[Noise level evaluation in acute ear trauma].
Subjective noise in the ears can be defined as a pathological acoustic sensation arising in the ear in different pathology of the acoustic analyzer. To make the treatment of the injury more effective, topical diagnosis of the acoustic analyzer affection is desirable.


Microtubins: a novel class of small synthetic microtubule targeting drugs that inhibit cancer cell proliferation.
Microtubule targeting drugs like taxanes, vinca alkaloids, and epothilones are widely-used and effective chemotherapeutic agents that target the dynamic instability of microtubules and inhibit spindle functioning. However, these drugs have limitations associated with their production, solubility, efficacy and unwanted toxicities, thus driving the need to identify novel antimitotic drugs that can be used as anticancer agents. We have discovered and characterized the Microtubins (Microtubule inhibitors), a novel class of small synthetic compounds, which target tubulin to inhibit microtubule polymerization, arrest cancer cells predominantly in mitosis, activate the spindle assembly checkpoint and trigger an apoptotic cell death. Importantly, the Microtubins do not compete for the known vinca or colchicine binding sites. Additionally, through chemical synthesis and structure-activity relationship studies, we have determined that specific modifications to the Microtubin phenyl ring can activate or inhibit its bioactivity. Combined, these data define the Microtubins as a novel class of compounds that inhibit cancer cell proliferation by perturbing microtubule polymerization and they could be used to develop novel cancer therapeutics.


Interaction of concanavalin A with the cell wall of Bacillus subtilis.
Interactions between concanavalin A and cell wall digests of Bacillus subtilis 168 resulted in insoluble complexes as observed by double gel diffusion, turbidity, and analysis of the precipitate. The macromolecular constituent of the cell walls complexing with concanavalin A was the polyglucosylglycerol phosphate teichoic acid. The complex exhibited two pH optima: 3.1 and 7.4. The complex could be dissociated by saccharides which bind to concanavalin A. In contrast to concanavalin A-neutral polysaccharide complexes, formation of the concanavalin A-wall complex was inhibited by salts. It was subsequently shown that salts induce conformational changes in cell wall digests. The data suggested that for complex formation to occur a rigid rod conformation in the glucosylated teichoic acid is probably necessary. Concanavalin A can be used as a probe to study structural features of bacterial cell walls.


Associations among adolescent sleep problems, emotion regulation, and affective disorders: Findings from a nationally representative sample.
Sleep problems in youth reliably forecast the development of anxiety and mood disorders, presumably due to increased emotional difficulties. However, precise emotional mechanisms have yet to be delineated. The current study investigated how sleep problems in adolescence are associated with different emotion regulation strategies, and how sleep and psychiatric risk may be indirectly associated via poor emotion regulation. This study utilized data from the National Comorbidity Survey-Adolescent Supplement, a nationally representative sample from the United States (N = 10,148; age range 13-18 years). A diagnostic interview determined if adolescents qualified for a mood or anxiety disorder within the past year. Participants provided reports of their sleep, emotion regulation, and current life stress. Adolescents who reported greater sleep problems were more likely to qualify for a mood or anxiety disorder and generally reported poorer emotion regulation strategy use, even when accounting for demographic characteristics and current stress. Specifically, adolescents with greater sleep problems reported less problem solving, and greater avoidance, suppression, rumination, and acceptance. Sleep problems were indirectly associated with anxiety disorders through greater suppression and rumination, and indirectly associated with mood disorders through greater rumination and lower problem solving. Although cross-sectional, this study extends current research by suggesting that certain emotion regulation strategies may be more difficult for youth struggling with sleep problems, and provides initial evidence that poor emotion regulation may be one factor contributing to sleep-based psychiatric risk. These findings can inform more efficacious intervention efforts.


Nitric Oxide Delivery Using Biocompatible Perfluorocarbon Microemulsion for Antibacterial Effect.
Nitric oxide (NO) participates in various physiological and pathophysiological processes, for example, as a cell messenger and as an antimicrobial agent of the cell-mediated immune response. The development of NO-releasing materials to carry and deliver NO for biomedical applications has gained immense attention. NO-releasing perfluorooctane (PFO) microemulsion (ME) has been prepared using a simple and time-saving method. Perfluorocarbon (PFC) liquids are halogen-substituted carbon nonpolar oils with enhanced NO gas dissolution capacity. The solubility of NO in PFC liquids is higher than that in water-based fluids. Liquid-gas solubility is governed by Henry's Law. The cytotoxicity of the NO-unloaded and NO-loaded PFO MEs toward human dermal fibroblast (HDF) was evaluated. The results showed that the NO-loaded PFO ME was highly biocompatible. On the other hand, at high concentrations the NO-releasing PFO ME accelerated the bacteria (Staphylococcus aureus) death unlike the NO-unloaded PFO ME. Hence, NO-releasing PFO MEs are suitable for biomedical applications such as wound healing and antibacterial agents.


Role of mononuclear phagocytes in expression of resistance and susceptibility to Mycobacterium avium infections in mice.
The growth of Mycobacterium avium 702 in the spleens and livers of four inbred strains of mice varied such that the mice could be separated into naturally susceptible (BALB/c and C57BL/6) and naturally resistant (A/Tru and DBA/2) strains. This phenomenon was independent of the size of the infecting inoculum of bacteria in that both low (10(4))- and high (10(7))-dose inocula of M. avium grew progressively in susceptible strains and were eliminated from the target organs of resistant strains. Resistance and susceptibility were also demonstrated in in vitro preparations of macrophages from these strains of mice. Over a 7-day period, replication of M. avium in susceptible mouse macrophages was far greater than that in resistant macrophages. Evidence was obtained to suggest that toxic oxygen metabolites were not responsible for this difference. Though no difference was found in the rate of clearance of M. avium from the blood of susceptible or resistant mice, resident macrophages from susceptible mice ingested more M. avium in vitro than did resident macrophages from resistant animals. Growth of M. avium in spleens of susceptible mice induced a large influx of phagocytes, whereas this was not observed in resistant mice. In contrast to this it was found that, after injection of a variety of inflammatory agents, influx of leukocytes into the peritoneal cavity could not be used to distinguish susceptible and resistant strains of mice.


Influence of body position on pulmonary diffusing capacity in yound and old men.
Steady-state diffusing capacity (DLCOSS2), studied in healthy nonsmokers, was significantly higher in five old men when seated than when supine, but was unchanged in five young men. However, "corrected" for the increased ventilation, it decreased in the young--but not in the old--when erect compared with when supine. The change of DLCOSS2 in the young during the first 20 min when seated was related to a change of the fractional dead space ventilation (VD/VT)mThe old showed less venous admixture when seated than when supine, whereas VD/VT and regional ventilation-perfusion index of the lung bases was the same in both positions. The decrease in venous admixture was probably due to the closing capacity (CC) being less than the functional residual capacity (FRC) when seated. The elimination of closed off regions when seated made more pulmonary capillaries available for diffusion.


Magnetic Seizure Therapy: Towards Personalized Seizure Therapy for Major Depression.
Magnetic seizure therapy (MST) is a noninvasive neuromodulation therapy under investigation for the treatment of severe neuropsychiatric disorders. MST involves inducing a therapeutic seizure under anesthesia in a setting similar to electroconvulsive therapy (ECT). To date, randomized controlled trials suggest that MST has similar antidepressant efficacy as ECT, but without significant cognitive adverse effects. Large scale clinical trials are currently underway to confirm these preliminary findings. So far, there has only been one study evaluating the clinical predictors of response to MST and more research is needed. This study found that patients with fewer episodes of depression and a positive family history of depression had a better response to MST. Overall, the ability of MST to focus the delivery of the electric field and the resultant seizure makes targeting seizure therapy to specific brain regions possible, and further research will be helpful in identifying personalized targets to maximize clinical benefit. In this review, we describe MST methodology and how it could be individualized to each patient. We also summarize the clinical and cognitive effects of MST and provide indications of which patients may be most likely to benefit. Finally, we summarize the studied neurophysiological predictors of response.


[Fibronectin receptors on the surfaces of alveolar macrophages].
The interaction of rabbit alveolar macrophages with purified homologous fibronectin bound to gelatin-Sepharose granules was studied. Gelatin-Sepharose, albumin-Sepharose and pure Sepharose 4B granules served as control. It is found that the macrophages are able to attach to fibronectin-coated surface and that the attachment is strongly dependent upon Ca2+ and, especially, upon Mg2+. Heparin partly inhibited the cell-fibronectin interaction. The gelatinized surface (i. e. Gelatin-Sepharose) also caused adhesion of macrophages but this process was, in contrast to their binding to fibronectin, enhanced by heparin. The trypsinization of cells completely inhibited both types of interaction. The data suggest that fibronectin and receptors for fibronectin (FN-receptors) may be present simultaneously on the surface of alveolar macrophages. A significant role that fibronectin plays in mononuclear phagocytosis is pointed out, and some biological properties of alveolar macrophages are explained taking into account the existence of FN-receptors.


Influence of glucogenic dietary supplementation and reproductive state of dairy cows on the composition of lipids in milk.
We studied the effects of the frequently used glucogenic dietary supplementation in dairy herds and the hormonal changes occurring during the normal estrous cycle on the composition and concentration of milk lipid components. Holstein dairy cows were synchronized with two injections of prostaglandin F2α (estrus=day 0). Animals were held as controls or drenched for 11 days (day -3 to day 8 of the cycle) with 850 ml/day liquid propylene glycol (treatment, n=13 per group). Blood and milk samples were collected on day 1 and 8 of the cycle. In both groups, plasma progesterone concentration increased ∼10-fold between 1 and 8 days post-estrus. Milk fatty acid composition was associated primarily with estrous-cycle day: polyunsaturated fatty acids increased by 16%, n-6 by 15% and n-3 by 1% from day 1 to 8 post-estrus. Polar lipid composition was also altered by cycle day: phosphatidylethanolamine concentration was 2-fold and 1.5-fold higher on day 1 v. day 8 post-estrus in the control and treatment groups, respectively. Phosphatidylserine concentration in milk was also affected by cycle day by treatment interaction (P=0.04). A progesterone level by treatment interaction influenced the triglyceride-to-phospholipid ratio in the milk (P=0.02). The results suggest that progesterone plays a role in modulating milk lipid composition and structure. Therefore, strategies designed to alter milk lipid composition should consider the cow's reproductive status.


Ursolic Acid Reduces Mycobacterium tuberculosis-Induced Nitric Oxide Release in Human Alveolar A549 cells.
Alveolar epithelial cells have been functionally implicated in Mycobacterium tuberculosis infection. This study investigated the role of ursolic acid (UA)-a triterpenoid carboxylic acid with potent antioxidant, anti-tumor, anti-inflammatory, and anti-tuberculosis properties in mycobacterial infection of alveolar epithelial A549 cells. We observed that M. tuberculosis successfully entered A549 cells. Cytotoxi-city was mediated by nitric oxide (NO). A549 toxicity peaked along with NO generation 72 h after infection. The NO generated by mycobacterial infection in A549 cells was insufficient to kill mycobacteria, as made evident by the mycobacteria growth indicator tube time to detect (MGIT TTD) and viable cell count assays. Treatment of mycobacteria-infected cells with UA reduced the expression of inducible nitric oxide synthase, NO generation, and eventually improved cell viability. Moreover, UA was found to quench the translocation of the transcription factor, nuclear factor kappa B (NF-κB), from the cytosol to the nucleus in mycobacteria-infected cells. This study is the first to demonstrate the cytotoxic role of NO in the eradication of mycobacteria and the role of UA in reducing this cytotoxicity in A549 cells.


Chimeras in phase oscillator networks locally coupled through an auxiliary field: Stability and bifurcations.
We study networks in the form of a lattice of nodes with a large number of phase oscillators and an auxiliary variable at each node. The only interactions between nodes are nearest-neighbor. The Ott/Antonsen ansatz is used to derive equations for the order parameters of the phase oscillators at each node, resulting in a set of coupled ordinary differential equations. Chimeras are steady states of these equations, and we follow them as parameters are varied, determining their stability and bifurcations. In two-dimensional domains, we find that spiral wave chimeras and rotating waves have significantly different properties than those in networks with nonlocal coupling.


Cutoffs of isokinetic strength ratio and hamstring strain prediction in professional soccer players.
Hamstring strain injuries frequently occur during professional soccer practice. Low hamstring strength represents an intrinsic modifiable risk factor but cutoffs of isokinetic knee strength ratios are controversial to predict hamstring strain in professional soccer players. We aimed to predict hamstring strain in accordance with cutoffs of isokinetic knee strength ratios. Bilateral, conventional, and functional isokinetic strength ratios were calculated in 194 professional soccer players at the beginning of 15 consecutive seasons. 36 soccer players presented a moderate hamstring strain and 158 were not injured. The different calculated isokinetic ratios were compared with the right and left limb of the uninjured population. Different usual cutoffs were tested: at 0.85 and 0.90 for the bilateral concentric and eccentric hamstring-to-hamstring ratio, at 0.60 and 0.47 for the conventional hamstring-to-quadriceps ratio and at 0.80 and 1 for the mixed hamstring-to-quadriceps ratio. The specific ratios for the studied population were also determined by the 10th percentile and then tested. Hamstring strain prediction was established in terms of odds ratios. No cutoff with bilateral, conventional, or functional isokinetic strength ratio was predictive of hamstring strain after univariate analysis. Specific cutoffs determined from the studied population were not more predictive. Very few injured soccer players presented values under the cutoffs at 0.47 for the conventional ratio and at 0.80 for the mixed ratio. Regardless of their values, cutoffs of isokinetic strength ratios were not predictive of hamstring injuries. The use of isokinetic cutoffs is not recommended to predict hamstring muscle strain in professional soccer players.


Potential role of A2A adenosine receptor in traumatic optic neuropathy.
In traumatic optic neuropathy (TON), apoptosis of retinal ganglion cells is closely related to the local production of reactive oxygen species and inflammatory mediators from activated microglial cells. Adenosine receptor A2A (A2AAR) has been shown to possess anti-inflammatory properties that have not been studied in TON. In the present study, we examined the role of A2AAR in retinal complications associated with TON. Initial studies in wild-type mice revealed that treatment with the A2AAR agonist resulted in marked decreases in the TON-induced microglial activation, retinal cell death and releases of reactive oxygen species and pro-inflammatory cytokines TNF-α and IL-6. To further assess the role of A2AAR in TON, we studied the effects of A2AAR ablation on the TON-induced retinal abnormalities. A2AAR-/- mice with TON showed a significantly higher mRNA level of TNF-α, Iba1-1 in retinal tissue, and ICAM-1 expression in retinal sections compared with wild-type mice with TON. To explore a potential mechanism by which A2AAR-signaling regulates inflammation in TON, we performed additional studies using hypoxia- or LPS-treated microglial cells as an in vitro model for TON. Activation of A2AAR attenuates hypoxia or LPS-induced TNF-α release and significantly repressed the inflammatory signaling, ERK in the activated microglia. Collectively, this work provides pharmacological and genetic evidence for A2AAR signaling as a control point of cell death in TON and suggests that the retinal protective effect of A2AAR is mediated by attenuating the inflammatory response that occurs in microglia via interaction with MAPKinase pathway.


Androgen insensitivity with mental retardation: a contiguous gene syndrome?
We present data to suggest the existence of a mental retardation (MR) locus at Xq11.2-q12 between DXS1 and DXS905, identified in two subjects with complete androgen insensitivity syndrome (CAIS) and MR. Androgen insensitivity syndrome is a disorder of male sexual differentiation caused by a defect in the androgen receptor (AR) gene (Xq11-q12). Two subjects with CAIS resulting from a complete deletion of the AR gene have previously been reported, one of whom also has MR. We have identified another mentally retarded person with a complete deletion of the AR gene. The deletion in the two patients with CAIS and MR extends past the AR gene and includes several marker loci both proximal and distal to the AR gene, the limits of the deletions being DXS1 and DXS905. The deletions in the CAIS patients who do not have MR do not include any of the markers outside the AR gene itself. These data suggest that located close to the AR gene is a gene which is implicated in non-specific MR.


Guest Editorial-Special Collection Topic: Statistical Systems Theory in Cancer Modeling, Diagnosis, and Therapy.
Cancer is a systems disease involving mutations and altered regulation. This supplement treats cancer research as it pertains to 3 systems issues of an inherently statistical nature: regulatory modeling and information processing, diagnostic classification, and therapeutic intervention and control. Topics of interest include (but are not limited to) multiscale modeling, gene/protein transcriptional regulation, dynamical systems, pharmacokinetic/pharmacodynamic modeling, compensatory regulation, feedback, apoptotic and proliferative control, copy number-expression interaction, integration of different feature types, error estimation, and reproducibility. We are especially interested in how the above issues relate to the extremely high-dimensional data sets and small- to moderate-sized data sets typically involved in cancer research, for instance, their effect on statistical power, inference accuracy, and multiple comparisons.


Hypertension Trends and White Matter Brain Injury in the Offspring Framingham Heart Study Cohorts.
Hypertension is the most potent stroke risk factor and is also related to cerebral small vessel disease. We studied the relation between mid-to-late-life hypertension trends and cerebral white matter injury in community-dwelling individuals from the FHS (Framingham Heart Study). FHS Offspring cohort participants with available mid-life and late-life blood pressure measurements and brain magnetic resonance imaging were included. Multiple regression analyses were used to relate hypertension trends (normotension-normotension [reference], normotension-hypertension, and hypertension-hypertension) to white matter injury metrics on diffusion tensor imaging (free water, fractional anisotropy, and peak skeletonized mean diffusivity) and FLAIR (white matter hyperintensity volume) by different blood pressure cutoffs (130/80, 140/90, and 150/90 mm Hg). We included 1018 participants (mean age 47.3±7.4 years at mid-life and 73.2±7.3 at late-life). At the 140/90 mm Hg cutoff, the hypertension-hypertension trend was associated with higher free water (β, 0.16 [95% CI, 0.03-0.30]; P=0.021) and peak skeletonized mean diffusivity (β, 0.15 [95% CI, 0.01-0.29]; P=0.033). At a 130/80 mm Hg cutoff, the hypertension-hypertension trend had significantly higher free water (β, 0.16 [95% CI, 0.01-0.30]; P=0.035); and the normotension-hypertension (β, 0.24 [95% CI, 0.03-0.44]; P=0.027) and hypertension-hypertension (β, 0.22 [95% CI, 0.04-0.41]; P=0.022) trends had significantly increased white matter hyperintensity volume. Exploratory stratified analysis showed effect modifications by APOE ɛ4 allele and age. Mid-to-late-life hypertension exposure is significantly associated with microstructural and to a lesser extent, visible white matter injury; the effects are observed at both conventional and lower blood pressure cutoffs and are associated with longer duration of hypertension.


Optimized single-layer MoS2 field-effect transistors by non-covalent functionalisation.
Field-effect transistors (FETs) with non-covalently functionalised molybdenum disulfide (MoS2) channels grown by chemical vapour deposition (CVD) on SiO2 are reported. The dangling-bond-free surface of MoS2 was functionalised with a perylene bisimide derivative to allow for the deposition of Al2O3 dielectric. This allowed the fabrication of top-gated, fully encapsulated MoS2 FETs. Furthermore, by the definition of vertical contacts on MoS2, devices, in which the channel area was never exposed to polymers, were fabricated. The MoS2 FETs showed some of the highest mobilities for transistors fabricated on SiO2 with Al2O3 as the top-gate dielectric reported so far. Thus, gate-stack engineering using innovative chemistry is a promising approach for the fabrication of reliable electronic devices based on 2D materials.


Effects of peer review on outpatient psychotherapy: therapist and patient follow-up survey.
Interviews with 80 therapists and 50 patients at a community mental health center revealed that peer review effectively monitored the appropriateness of treatment and allocated limited treatment funds without unduly interfering with established treatment patterns, relationships, or outcomes. Most therapists reported receiving helpful consultation from the peer review committee, and the process encouraged them to focus more clearly on treatment goals. On the other hand, patients were concerned about the committee's role in making decisions about their treatment. Therapists noted as a problem the lack of certainty in establishing a treatment contract prior to peer review since the contract with the patient must remain fluid during the evaluation period. The therapists and patients demonstrated remarkable agreement in their assessment of treatment progress and whether further therapy was needed.


Recurrent recruitment of the THAP DNA-binding domain and molecular domestication of the P-transposable element.
The recently described THAP domain motif characterizes a DNA-binding domain (DBD) that is widely conserved in human and in animals. It presents a similarity with the DBD of the P element transposase of D. melanogaster. We show here that the P Drosophila neogenes derived from P-transposable elements conserve the THAP domain. Moreover, secondary rearrangements by exon shuffling indicate the recurrent recruitment of this domain by the host genome. As P sequences and THAP genes are found together in many animal genomes, we discuss the possibility that the THAP proteins have acquired their domain as a result of recurrent molecular domestication of P-transposable elements.


Effect of Straw Provision in Racks on Tail Lesions, Straw Availability, and Pen Hygiene in Finishing Pigs.
Unfulfilled exploratory behavior in pigs has been linked to tail biting, which causes reduced performance and welfare. Provision of straw can reduce tail biting, but large straw rations can cause poor hygiene in pens. This study examined whether provision of straw in racks, rather than on the pen floor, can enable larger straw rations without compromising hygiene. The study was conducted on a commercial farm with 458 undocked pigs in 42 pens provided with straw in racks or on the floor. Available straw and manual cleaning requirement were assessed daily, and presence of tail lesions was assessed weekly. Both treatments had a low requirement for manual cleaning (Floor: 1.7%, Rack: 1.8%). Pigs in the rack treatment had a higher incidence of lesions early in the production period, which coincided with these pigs initially not consuming straw from the rack, leading to low straw access. Late in the production period, these pigs had learned how to use the rack and had a lower incidence of lesions than pigs in the floor treatment. Delayed use of the rack may have been linked to undeveloped spatial skills in the pigs, which needs further research.


BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights.
Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view.


Exploiting agonist biased signaling of chemokines to target cancer.
As knowledge of growth-independent functions of cancer cells is expanding, exploration into the role of chemokines in modulating cancer pathogenesis, particularly metastasis, continues to develop. However, more study into the mechanisms whereby chemokines direct the migration of cancer cells is needed before specific therapies can be generated to target metastasis. Herein, we draw attention to the longstanding conundrum in the field of chemokine biology that chemokines stimulate migration in a biphasic manner; and explore this phenomenon's impact on chemokine function in the context of cancer. Typically, low concentrations of chemokines lead to chemotactic migration and higher concentrations halt migration. The signaling mechanisms that govern this phenomenon remain unclear. Over the last decade, we have defined a novel signaling mechanism for regulation of chemokine migration through ligand oligomerization and biased agonist signaling. We provide insight into this new paradigm for chemokine signaling and discuss how it will impact future exploration into chemokine function and biology. In the pursuit of producing more novel cancer therapies, we suggest a framework for pharmaceutical application of the principles of chemokine oligomerization and biased agonist signaling in cancer. © 2016 Wiley Periodicals, Inc.


Prevalence of and factors associated with Brucella sero-positivity in cattle in urban and peri-urban Gulu and Soroti towns of Uganda.
Brucellosis is a key zoonosis of major public health, animal welfare and economic significance, and is endemic in livestock in Uganda. A cross-sectional epidemiological study was carried out to estimate the sero-prevalence of brucellosis and identify factors associated with sero-positivity in cattle in urban and peri-urban Gulu and Soroti towns of Northern and Eastern Uganda, respectively. A total of 1007 sera and data on biologically plausible risk factors from 166 herds and their spatial locations, were collected from cattle reared in urban and peri-urban Gulu and Soroti towns of Uganda. The sera were analyzed using indirect ELISA and sero-positive reactors confirmed by competitive ELISA. Multivariable models were used to investigate for risk factors. The overall animal-level and herd-level sero-prevalence was 7.5% (76/1007, 95% Confidence Interval (CI): 6.15-9.4%) and 27.1% (45/166, 95% CI: 20.9-34.3%), respectively. Herd-level sero-prevalence was significantly (P<0.001) higher in Soroti than Gulu. In Gulu town, sero-positivity increased with an increase in herd size (P=0.03) and age (P=0.002), and was higher in cattle brought in from western Uganda (P<0.0001). In Soroti town, introduction of new cattle into a herd was significantly (P=0.027) associated with herd sero-positivity. There was a geographically differential risk (clustering) of Brucella sero- positivity in herds in Soroti, while sero-positivity was homogeneously distributed in Gulu. The data highlight brucellosis occurrence and major risk factors for its transmission in cattle in urban and peri-urban areas.


Changes in pupil diameter are correlated with the occurrence of pareidolias in patients with dementia with Lewy bodies.
Pareidolias are visual illusions of meaningful objects, such as faces and animals, that arise from ambiguous forms embedded in visual scenes. Pareidolias and visual hallucinations have been suggested to have a common underlying neural mechanism in patients with dementia with Lewy bodies (DLB). The aim of the present study was to find an externally observable physiological indicator of pareidolias. Using a pareidolia test developed by Uchiyama and colleagues, we evoked pareidolias in patients with DLB and recorded the resultant changes in the diameters of their pupil. The time frequencies of changes in pupil diameters preceding pareidolic utterances and correct utterances by the patients, as well as correct utterances by healthy control participants, were analyzed by a fast Fourier transform program. The power at time frequencies of 0-0.46 Hz was found to be greatest preceding pareidolic utterances in patients with DLB, followed by that preceding correct utterances in control participants, followed by that preceding correct utterances in patients with DLB. When the changes in power preceding the utterance were greater than the median value of correct utterances by the control group, the frequency of pareidolic utterances was significantly greater than that of correct utterances and when the changes were the same as or lower than the median value, the frequency of correct utterances was significantly greater than that of pareidolic utterances. Greater changes in power preceding the utterance at time frequencies of 0-0.46 Hz may thus be an externally observable physiological indicator of the occurrence of pareidolias.


Functional segregation of cortical language areas by sentence repetition.
The functional organization of the perisylvian language network was examined using a functional MRI (fMRI) adaptation paradigm with spoken sentences. In Experiment 1, a given sentence was presented every 14.4 s and repeated two, three, or four times in a row. The study of the temporal properties of the BOLD response revealed a temporal gradient along the dorsal-ventral and rostral-caudal directions: From Heschl's gyrus, where the fastest responses were recorded, responses became increasingly slower toward the posterior part of the superior temporal gyrus and toward the temporal poles and the left inferior frontal gyrus, where the slowest responses were observed. Repetition induced a decrease in amplitude and a speeding up of the BOLD response in the superior temporal sulcus (STS), while the most superior temporal regions were not affected. In Experiment 2, small blocks of six sentences were presented in which either the speaker voice or the linguistic content of the sentence, or both, were repeated. Data analyses revealed a clear asymmetry: While two clusters in the left superior temporal sulcus showed identical repetition suppression whether the sentences were produced by the same speaker or different speakers, the homologous right regions were sensitive to sentence repetition only when the speaker voice remained constant. Thus, hemispheric left regions encode linguistic content while homologous right regions encode more details about extralinguistic features like speaker voice. The results demonstrate the feasibility of using sentence-level adaptation to probe the functional organization of cortical language areas.


Studies of involvement of G-protein coupled receptor-3 in cannabidiol effects on inflammatory responses of mouse primary astrocytes and microglia.
Cannabidiol (CBD) exhibits anti-inflammatory and neuroprotective properties and is suggested to be effective in the pre-clinical and clinical treatment of illnesses of the central nervous system (CNS). Two major types of CNS glial cells, astrocytes and microglia, play critical roles in the development and pathogenesis of CNS diseases. However, the mechanisms by which CBD plays an anti-inflammatory and neuroprotective role for these glial cells have not been fully elucidated. In this study, we examined the effects of CBD on the inflammatory response of mouse primary astrocytes and microglia. We also investigated whether the effect of CBD on cytokine release is mediated by the G protein coupled receptor 3 (GPR3), which was recently identified as a novel receptor for CBD. Our results showed that CBD inhibited inflammatory responses of astrocytes and microglia stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand in vitro and in vivo. In addition, CBD reduced the phosphorylation of STAT3 and NF-κB signaling pathways in LPS-stimulated astrocytes. However, the inhibitory effect of CBD on pro-inflammatory cytokine production was independent of GPR3 expression in both types of glial cells. Thus, although CBD is effective in ameliorating the activation of astrocytes and microglia, its mechanism of action still requires further study. Our data support the concept that CBD may have therapeutic potential for neurological disorders that involve neuroinflammation.


Evidence-Based Guidelines for Screening and Management of Strongyloidiasis in Non-Endemic Countries.
Strongyloidiasis is an intestinal parasitic infection becoming increasingly important outside endemic areas, not only because of the high prevalence found in migrant populations, but also because immunosuppressed patients may suffer a potentially fatal disseminated disease. The aim of these guidelines is to provide evidence-based guidance for screening and treatment of strongyloidiasis in non-endemic areas. A panel of experts focused on three main clinical questions (who should be screened and how, how to treat), and reviewed pertinent literature available in international databases of medical literature and in documents released by relevant organizations/societies. A consensus of the experts' opinion was sought when specific issues were not covered by evidence. In particular, six systematic reviews were retrieved and constituted the main support for this work. The evidence and consensus gathered led to recommendations addressing various aspects of the main questions. Grading of evidence and strength of recommendation were attributed to assess the quality of supporting evidence. The screening of individuals at risk of the infection should be performed before they develop any clinical complication. Moreover, in immunosuppressed patients, the screening should be mandatory. The screening is based on a simple and widely accessible technology and there is now a universally accepted treatment with a high efficacy rate. Therefore, the screening could be implemented as part of a screening program for migrants although further cost-effectiveness studies are required to better evaluate this strategy from a public health point of view.


Ultrasound-Responsive Polymeric Micelles for Sonoporation-Assisted Site-Specific Therapeutic Action.
Targeting drug delivery remains a challenge in various disease treatment including cancer. The local drug deposit could be greatly enhanced by some external stimuli-responsive systems. Here we develop pluronic P123/F127 polymeric micelles (M) encapsulating curcumin (Cur) that are permeabilized directly by focused ultrasound, in which ultrasound triggers drug release. Tumor preferential accumulation and site-specific sonochemotherapy were then evaluated. Cur-loaded P123/F127 mixed micelles (Cur-M) exhibited longer circulating time and increased cellular uptake compared to free Cur. With the assistance of focused ultrasound treatment, Cur-M showed tumor-targeting deposition in a time-dependent manner following systemic administration. This was due to enhanced permeabilization of tumor regions and increased penetration of Cur-M in irradiated tumor cells by ultrasound sonoporation. Furthermore, Cur-M self-assembly could be regulated by ultrasound irradiation. In vitro Cur release from mixed micelles was greatly dependent on ultrasound intensity but not on duration, suggesting the cavitational threshold was necessary to initiate subsequent sonochemotherapy. In vivo site-specific drug release was demonstrated in dual-tumor models, which showed spatial-temporal release of entrapped drugs following intratumoral injection. The sonoporation-assisted site-specific chemotherapy significantly inhibited tumor growth and the decrease in tumor weight was approximately 6.5-fold more than without exposure to ultrasound irradiation. In conclusion, the established ultrasound-guided nanomedicine targeting deposit and local release may represent a new strategy to improve chemotherapy efficiency.


Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease.
Pruritus of end-stage renal disease (ESRD) is a multifactorial symptom of complex etiology not yet fully understood. In this study we have investigated the cerebral perfusion patterns at rest in ESRD patients on hemodialysis, compared with those in healthy volunteers. We have also studied the brain responses evoked by experimental itch induction in ESRD, after stimulating the two distinct histamine and cowhage itch pathways, and compared them with the responses evoked in healthy volunteers. To identify potential structural alterations in ESRD patients compared with a group of age-matched healthy volunteers, we calculated the density of gray matter for the entire brain using a voxel-based morphometric analysis. Our results indicated that gray matter density was significantly reduced in ESRD patients in the frontal, parietal, temporal, and occipital cortices, as well as in the S1, precuneus, and insula, whereas the brain stem, hippocampus, amygdala, midcingulate cortex, and nucleus accumbens displayed an increased gray matter density. Functionally, we found a significantly higher brain perfusion at baseline associated with ESRD pruritus in the anterior cingulate, insula, claustrum, hippocampus, and nucleus accumbens. The brain responses evoked by cowhage itch, which are mediated by protease-activated receptors (PAR2), displayed significant differences compared with responses in healthy individuals and were correlated with perceived itch intensity in a dual, complex manner. The inverse correlations in particular suggested that a negative feedback mechanism modulated itch intensity, when elicited in a preexistent chronic itch background.


Long-term outcomes of an Australian universal prevention trial of anxiety and depression symptoms in children and youth: an evaluation of the friends program.
This study evaluated the long-term effectiveness of the FRIENDS Program in reducing anxiety and depression in a sample of children from Grade 6 and Grade 9 in comparison to a control condition. Longitudinal data for Lock and Barrett's (2003) universal prevention trial is presented, along with data from 12-month follow-up to 24- and 36-month follow-up. Results of this study indicate that intervention reductions in anxiety reported in Lock and Barrett were maintained for students in Grade 6, with the intervention group reporting significantly lower ratings of anxiety at long-term follow-up. A significant Time x Intervention Group x Gender Effect on Anxiety was found, with girls in the intervention group reporting significantly lower anxiety at 12-month and 24-month follow-up but not at 36-month follow-up in comparison to the control condition. Results demonstrated a prevention effect with significantly fewer high-risk students at 36-month follow-up in the intervention condition than in the control condition. Results are discussed within the context of prevention research.


Combining tricyclic and monoamine oxidase inhibitor antidepressants.
The charts of 150 inpatients and 51 outpatients treated with a monoamine oxidase inhibitor (MAOI)-tricyclic antidepressant combination were reviewed. The incidence and severity of side effects among the patients on the combined regimen were essentially the same as those seen in the control groups. There were no deaths or strokes resulting from use of this regimen. The most frequent troublesome side effect was orthostatic hypotension. We conclude that the use of a MAOI-tricyclic combination in oral therapeutic doses is safe. However, the efficacy of this combination has not yet been proved, and it may be particularly toxic if taken in an overdose.


A radiohistochemical measure of [3H]TCP binding to the activated NMDA-receptor-gated ion channel in rat brain.
The N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor is linked to an ion channel that is blocked by the phencyclidine analog N-(1-[thienyl]cyclohexyl)piperidine (TCP). Previous studies have shown that NMDA and glycine act together to increase the access of [3H]TCP to its binding site, presumably by increasing channel opening; NMDA/glycine-enhanced [3H]TCP binding performed under non-equilibrium conditions thereby serves as a dynamic molecular marker of channel activation. In this study we tested whether NMDA and glycine regulate [3H]TCP binding in slide-mounted brain sections. Striking activation of the NMDA ion channel was observed in neo- and allocortex; dentate gyrus and strata radiatum and oriens of CA1 and CA3 of hippocampal formation; and certain amygdaloid nuclei (basomedial, basolateral, and cortical). Other nuclei of the amygdala (central, posterolateral, and medial), basal ganglia, and numerous regions within the diencephalon, brainstem and cerebellum showed relatively little activation of the NMDA ion channel. Our demonstration of enriched NMDA/glycine-stimulated [3H]TCP binding in stratum radiatum of hippocampal region CA1 but not in cerebellar granule cell layer correlates with electrophysiologic studies that showed NMDA channel ion flux in CA1 but not in cerebellar granule cell layer in adult rats. These data demonstrate that NMDA and glycine regulation of [3H]TCP binding can be quantified with a radiohistochemical method to provide a regional measure of the activated NMDA-receptor-gated ion channel. This technique is a powerful tool for functional analysis of the NMDA receptor/channel complex in both physiologic and pathologic states.


V-O Species-Doped Carbon Frameworks Loaded with Ru Nanoparticles as Highly Efficient and CO-Tolerant Catalysts for Alkaline Hydrogen Oxidation.
Efficient and CO-tolerant catalysts for alkaline hydrogen oxidation (HOR) are vital to the commercial application of anion exchange membrane fuel cells (AEMFCs). Herein, a robust Ru-based catalyst (Ru/VOC) with ultrasmall Ru nanoparticles supported on carbon frameworks with atomically dispersed V-O species is prepared elaborately. The catalyst exhibits a remarkable mass activity of 3.44 mA μgPGM, which is 31.3 times that of Ru/C and even 4.7 times higher than that of Pt/C. Moreover, the Ru/VOC anode can achieve a peak power density (PPD) of 1.194 W cm-2, much superior to that of Ru/C anode and even better than that of Pt/C anode. In addition, the catalyst also exhibits superior stability and exceptional CO tolerance. Experimental results and density functional theory (DFT) calculations demonstrate that V-O species are ideal OH- adsorption sites, which allow Ru to release more sites for hydrogen adsorption. Furthermore, the electron transfer from Ru nanoparticles to the carbon substrate regulates the electronic structure of Ru, reducing the hydrogen binding energy (HBE) and the CO adsorption energy on Ru, thus boosting the alkaline HOR performance and CO tolerance of the catalyst. This is the first report that oxophilic single atoms distributed on carbon frameworks serve as OH- adsorption sites for efficient hydrogen oxidation, opening up new guidance for the elaborate design of high-activity catalysts for the alkaline HOR.


Non-equilibrium magnetic properties of a mixed spin (1/2, 1) Ising graphene nanoisland.
Based on Glauber-type stochastic dynamics intertwined with mean field theory, we have investigated a graphene nanoisland's out-of-equilibrium magnetic and thermomagnetic behaviors with a mixed ferrimagnetic spin (1/2, 1) configuration in the presence of an oscillating magnetic field. The influence of the oscillating external magnetic field, single-ion anisotropy and temperature on the dynamic magnetic properties (dynamic phase transitions, hysteresis loop areas, correlations, and phase diagrams) of the system is studied in detail. The results illustrate that single ion anisotropy and the magnetic field play important roles in the system's dynamic order parameters, phase transitions and phase diagrams. Dynamic phase diagrams display some dynamic special points such as dynamic tricritical points, quadruple points and some sort of reentrant phenomena, which strongly depend on interaction parameters. Our predicted results may provide a reference for future experimental and theoretical studies of the nanostructures.


Reactivity differences of combined and free amino acids: quantifying the relationship between three-dimensional protein structure and singlet oxygen reaction rates.
It has long been appreciated that the photooxidation kinetics of amino acid (AA) residues in an intact protein differ from those of free AAs due to differences in the local steric microenvironment, such as its location in the three-dimensional structure. Yet there are only a few studies that have quantified the effect of protein structure on the photochemical reactivity of its residues. This is important for predicting phototransformation rates of AAs in aquatic environments where AAs in combined forms (e.g., oligopeptides and proteins) are more abundant than free AAs. In this work, the photochemical reactivity differences between free and combined AAs were assessed. Singlet oxygen ((1)O2) reaction kinetics of individual photooxidizable residues in the protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were examined. The results suggest that the (1)O2 accessibility of residues in intact GAPDH has a profound effect on their photodegradation kinetics and for histidine residues can explain most of the variation in (1)O2 reactivity. Additionally, (1)O2-accessibile surface area values of residues calculated from protein crystal structure data are useful in predicting their reaction rates in GAPDH. This work illustrates a new approach to assess the differential photochemical reactivity of AA-based biomolecules in natural environments or engineered applications.


Glucose oxidase incorporated collagen matrices for dermal wound repair in diabetic rat models: a biochemical study.
Impaired wound healing in diabetes is a well-documented phenomenon. Emerging data favor the involvement of free radicals in the pathogenesis of diabetic wound healing. We investigated the beneficial role of the sustained release of reactive oxygen species (ROS) in diabetic dermal wound healing. In order to achieve the sustained delivery of ROS in the wound bed, we have incorporated glucose oxidase in the collagen matrix (GOIC), which is applied to the healing diabetic wound. Our in vitro proteolysis studies on incorporated GOIC show increased stability against the proteases in the collagen matrix. In this study, GOIC film and collagen film (CF) are used as dressing material on the wound of streptozotocin-induced diabetic rats. A significant increase in ROS (p < 0.05) was observed in the fibroblast of GOIC group during the inflammation period compared to the CF and control groups. This elevated level up regulated the antioxidant status in the granulation tissue and improved cellular proliferation in the GOIC group. Interestingly, our biochemical parameters nitric oxide, hydroxyproline, uronic acid, protein, and DNA content in the healing wound showed that there is an increase in proliferation of cells in GOIC when compared to the control and CF groups. In addition, evidence from wound contraction and histology reveals faster healing in the GOIC group. Our observations document that GOIC matrices could be effectively used for diabetic wound healing therapy.


[Sensitivity of mammalian tissues to prolonged exposure to high-tension permanent magnetic fields].
The retinal epithelium, bone marrow and spermatogenic epithelium of mice exposed for 30 days to constant magnetic fields of 1.6 T were examined cytologically. During and after exposure the retinal and bone marrow epithelium showed no biologically significant deviations from normal. The mitotic changes were of small amplitude and insufficient to cause cell unbalance. No chromosome aberrations or degenerative changes in the cells were seen. In the spermatogenic epithelium the exposure to a constant magnetic field produced a destruction of mature cell elements. Due to this the total amount of spermatogenic cells was significantly lower during and immediately after exposure.


Genome-wide analysis of methylation in bovine clones by methylated DNA immunoprecipitation (MeDIP).
Methylated DNA immunoprecipitation (MeDIP), when coupled to high-throughput sequencing or microarray hybridization, allows for the identification of methylated loci at a genome-wide scale. Genomic regions affected by incomplete reprogramming after nuclear transfer can potentially be delineated by comparing the MeDIP profiles of bovine clones and non-clones. This chapter presents a MeDIP protocol largely inspired from Mohn and colleagues (Mohn et al., Methods Mol Biol 507:55-64, 2009), with PCR primers specific for cattle, and when possible, overviews of experimental designs adapted to the comparison between clones and non-clones.


A Sarcoma Masquerading as a Pseudotumor After Total Hip Arthroplasty: A Case Report.
There is an increasing emphasis on adverse reactions to metal debris around prosthetic hip implants. We present a case report of a patient with increasing pain around a previous total hip arthroplasty and magnetic resonance imaging findings consistent with a pseudotumor. Serum metal ion levels were not elevated and initial biopsy findings inconclusive. The patient was diagnosed with an extraskeletal chondrosarcoma after revision total hip arthroplasty and subsequently underwent external hemipelvectomy with negative margins. This report highlights the importance of remaining vigilant for malignant sarcomas presenting as pseudotumors around hip replacements, particularly in the absence of abnormal metal ion levels or definitive biopsy results.


Impact of Protein and Carbohydrate Supplementation on Musculoskeletal Injuries in Army Initial Entry Training Soldiers.
This project investigated whey protein and/or carbohydrate supplementation effects on musculoskeletal injury (MSI) outcomes. Four groups of Initial Entry Training soldiers consumed either: (1) one protein (38.6 g, 293 kcal); (2) one carbohydrate (63.4 g, 291 kcal); (3) two protein (77.2 g, 586 kcal); or (4) two carbohydrate servings/day (126.8 g, 582 kcal) after physical training and before bed, or before bed only. Odds Ratio, Chi-square and Wilcoxon ranked-sum test compared supplementation/no supplementation, number of servings, and protein/carbohydrate for MSI and limited/missed duty rates and limited/missed training days. Non-matched pairs group averages were compared to 2015/2016 historical data. Non-supplemented soldiers were approximately 5× more likely to sustain a MSI (χ2 = 58.48, p < 0.001) and 4× more likely to miss training (χ2 = 9.73, p = 0.003) compared to two servings. Non-supplemented soldiers missed five additional training days compared to two servings (W = 6059.5, p = 0.02). Soldiers consuming one serving were approximately 3× more likely to sustain a MSI than two servings (χ2 = 9.55, p = 0.002). There was no difference in limited/missed duty rates or limited/missed training days between consuming one or two servings. There was no difference between consuming one serving versus no supplementation or protein versus carbohydrate supplementation for any outcome variable. Soldiers consuming 2 servings/day of protein or carbohydrate had lower MSI rates, limited/missed duty rates, and limited/ missed training days compared to non-supplemented soldiers.


Liver transplantation for jejunoileal bypass-associated cirrhosis: allograft histology in the setting of an intact bypassed limb.
Jejunoileal bypass (JIB) is a well known cause of steatohepatitis, which may, on occasion, progress to cirrhosis and require liver transplantation. We report 3 patients who underwent orthotopic liver transplantation (OLT) for steatohepatitic cirrhosis secondary to JIB in which the JIB was left intact. All 3 patients have demonstrated recurrent steatosis in the graft after liver transplantation. In two of the cases, the changes are moderately severe, whereas in one case the changes are mild. All 3 patients have essentially normal liver function tests and are clinically asymptomatic; 1 of the patients has undergone removal of the JIB 2.5 years after transplantation. Control hepatic allografts in patients with primary biliary cirrhosis and primary sclerosing cholangitis show negligible fatty change, and in patients who receive transplants for alcoholic steatohepatitis, they rarely (2 of 20 patients) contain greater than 10% fat. We conclude that transplantation alone is not associated with subsequent steatosis. Presence of JIB is, therefore, a continuing risk factor for steatosis in patients who have undergone OLT. Reversal of JIB after OLT may be considered if fatty changes are severe or associated with significant fibrosis.


Real-world healthcare resource utilization and costs associated with tisagenlecleucel and axicabtagene ciloleucel among patients with diffuse large B-cell lymphoma: an analysis of hospital data in the United States.
This study compared the real-world healthcare resource utilization (HRU), costs, adverse events (AEs), and AE treatments associated with the chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel), for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Adults with DLBCL who received tisa-cel or axi-cel were identified in the Premier Healthcare Database (2017-2020). Non-CAR-T costs, HRU, and AE rates during the infusion and follow-up periods were compared between the tisa-cel and axi-cel cohorts. Of 119 patients, 33 received tisa-cel (86% as inpatient infusion) and 86 received axi-cel (100% inpatient). Tisa-cel was associated with significantly shorter mean inpatient length of stay than axi-cel during infusion (11.3 vs. 18.3 days) and follow-up ([monthly] 3.9 vs. 6.9 days). Non-CAR-T costs were significantly lower for tisa-cel compared with axi-cel during infusion ($27594.8 vs. $51378.3) and follow-up ([monthly] $28777.3 vs. $46575.7; both p< .05). Rates of AEs and AE treatments were similar.


Cytochalasin B: effects on microfilaments and movement of melanin granules within melanocytes.
The intracellular translocation of melanin granules within both epidermal and dermal melanocytes of Rana pipiens is influenced by cytochalasin B. Cytochalasin B prevents dispersion of pigment granules by melanocytestimulating hormone (MSH) and causes centripetal movement of pigment granules that have been dispersed by MSH. Microfilaments are abundant in the dendritic processes of epidermal melanocytes in which pigment granules have been dispersed by MSH. Microfilaments are dramatically reduced in number in the processes of melanocytes that have been lightened by cytochalasin B. These observations suggest that microfilaments mediate dispersion of pigment granules.


Data-Driven Tree Transforms and Metrics.
We consider the analysis of high dimensional data given in the form of a matrix with columns consisting of observations and rows consisting of features. Often the data is such that the observations do not reside on a regular grid, and the given order of the features is arbitrary and does not convey a notion of locality. Therefore, traditional transforms and metrics cannot be used for data organization and analysis. In this paper, our goal is to organize the data by defining an appropriate representation and metric such that they respect the smoothness and structure underlying the data. We also aim to generalize the joint clustering of observations and features in the case the data does not fall into clear disjoint groups. For this purpose, we propose multiscale data-driven transforms and metrics based on trees. Their construction is implemented in an iterative refinement procedure that exploits the co-dependencies between features and observations. Beyond the organization of a single dataset, our approach enables us to transfer the organization learned from one dataset to another and to integrate several datasets together. We present an application to breast cancer gene expression analysis: learning metrics on the genes to cluster the tumor samples into cancer sub-types and validating the joint organization of both the genes and the samples. We demonstrate that using our approach to combine information from multiple gene expression cohorts, acquired by different profiling technologies, improves the clustering of tumor samples.


Role of cAMP-phosphodiesterase isozymes in pathogenesis of murine nephrogenic diabetes insipidus.
To test the hypothesis that rapid adenosine 3',5'-cyclic monophosphate (cAMP) catabolism via cyclic 3',5'-nucleotide phosphodiesterase (PDE) is a cause of the unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI), we investigated properties of PDEs and other aspects of the VP-dependent cAMP-signaling system in segments of collecting ducts [inner medullary (IMCD), cortical (CCD), and outer medullary (OMCD) ducts] microdissected from control mice and mice with NDI. The activity of cAMP-PDE, but not of cGMP-PDE, was markedly higher in IMCD (+109%), and to a lesser degree in OMCD (+41%) and CCD (+27%), of NDI mice than in normal controls. The cAMP-PDE in IMCD of NDI mice was more sensitive to inhibition by the PDE isozyme-specific inhibitors rolipram and cilostamide, but not by 3-isobutyl-1-methylxanthine, than was the cAMP-PDE in controls. Levels of cAMP in intact IMCD and CCD from NDI mice completely failed to increase in response to 10(-6) M VP. Incubation with rolipram alone, but not with cilostamide alone, restored VP-dependent cAMP accumulation in IMCD of NDI mice to the levels found in control mice; addition of cilostamide further enhanced the effect of rolipram. Analogous (but quantitatively lesser) anomalies of the VP-dependent cAMP system, including the effects of PDE inhibitors, were observed also in CCD of NDI mice. However, the activity of VP-stimulated adenylate cyclase assayed in permeabilized IMCD did not differ in NDI and control mice. These results indicate that anomalously high activities of low-Km cAMP-PDE isozymes account for the failure of collecting ducts of NDI mice to increase cAMP levels in response in VP.(ABSTRACT TRUNCATED AT 250 WORDS)


Early bacterial clearance from murine lungs. Species-dependent phagocyte response.
Two sets of phagocytic cells are available to defend the lung against inhaled bacteria. Both resident alveolar macrophages and granulocytes from the circulation have been observed in pulmonary air spaces after the deposition of bacteria; their functional roles, however, have been defined. We rendered mice selectively granulocytopenic with heterologous antiserum in order to ascertain the relative contributions of these two groups of cells in intrapulmonary bacterial killing. The clearance of Staphylococcus aureus was unimpaired in granulocytopenic animals, confirming the primary role of the alveolar macrophages in the killing of these organisms. In contrast, granulocytopenic animals cleared only 10.0+/-7.0% of an inoculum of Klebsiella pneumoniae compared with 33.0+/-4.0% clearance in normal animals (P < 0.02), and Pseudomonas aeruginosa proliferated to 513% of baseline levels in granulocytopenic animals, whereas normal mice cleared 26.8+/-10.6% of the inoculum. These findings indicate that circulating granulocytes play a major role in the clearance of the latter two organisms. This variation in cellular response to different bacterial species suggests that the defense of the lung against pathogenic bacteria is more complex than has been previously assumed.


Enhanced functional potential of nucleic acid aptamer libraries patterned to increase secondary structure.
The in vitro selection of nucleic acid libraries has driven the discovery of RNA and DNA receptors (aptamers) and catalysts with tailor-made functional properties. Functional nucleic acids emerging from selections have been observed to possess an unusually high degree of secondary structure. In this study, we experimentally examined the relationship between the degree of secondary structure in a nucleic acid library and its ability to yield aptamers that bind protein targets. We designed a patterned nucleic acid library (denoted R*Y*) to enhance the formation of stem-loop structures without imposing any specific sequence or secondary structural requirement. This patterned library was predicted computationally to contain a significantly higher average folding energy compared to a standard, unpatterned N(60) library of the same length. We performed three different iterated selections for protein binding using patterned and unpatterned libraries competing in the same solution. In all three cases, the patterned R*Y* library was enriched relative to the unpatterned library over the course of the 9- to 10-round selection. Characterization of individual aptamer clones emerging from the three selections revealed that the highest affinity aptamer assayed arose from the patterned library for two protein targets, while in the third case, the highest affinity aptamers from the patterned and random libraries exhibited comparable affinity. We identified the binding motif requirements for the most active aptamers generated against two of the targets. The two binding motifs are 3.4- and 27-fold more likely to occur in the R*Y* library than in the N(60) library. Collectively, our findings suggest that researchers performing selections for nucleic acid aptamers and catalysts should consider patterned libraries rather than commonly used N(m) libraries to increase both the likelihood of isolating functional molecules and the potential activities of the resulting molecules.


5,7-Dihydroxytryptamine lesions of crayfish serotonin-containing neurons: effect on the lateral giant escape reaction.
The crayfish's lateral giant escape response, a relatively simple behavioral reaction, is readily modulated in certain situations. For example, when a crayfish is restrained, its lateral giant (LG) fibers--command neurons that mediate the escape response--are strongly inhibited (Krasne and Wine, 1975). Previous work (Glanzman and Krasne, 1983) had suggested that serotonin (5-HT) might mediate this restraint-induced inhibition of the escape response. To test this possibility, we attempted to lesion serotonergic neurons in crayfish with the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). We compared the levels of 5-HT-immunoreactive staining in nerve cords from 5,7-DHT-treated and from normal crayfish to assess 5,7-DHT's effectiveness. Levels of immunoreactive staining, as judged by ratings of the visibility of immunofluorescence, were significantly lower in nerve cords from crayfish that had received injections of 5,7-DHT (1.0-4.0 mg) than in nerve cords from normal crayfish. In addition, some serotonergic neurons in the neurotoxin-treated crayfish developed an abnormal brown pigmentation. To assess the behavioral consequence of central serotonergic lesions, we compared the responsiveness of escape in crayfish treated with 5,7-DHT (2.0-2.75 mg) and in normal crayfish. The threshold for firing the LGs was significantly lower in restrained neurotoxin-treated animals than in restrained normal animals. Furthermore, the responsiveness of the LGs in neurotoxin-treated crayfish approximated that in crayfish whose nerve cords had been severed between the thorax and abdomen, a procedure known to abolish restraint-induced inhibition (Krasne and Wine, 1975).(ABSTRACT TRUNCATED AT 250 WORDS)


75 years of dryland science: Trends and gaps in arid ecology literature.
Growth in the publication of scientific articles is occurring at an exponential rate, prompting a growing need to synthesise information in a timely manner to combat urgent environmental problems and guide future research. Here, we undertake a topic analysis of dryland literature over the last 75 years (8218 articles) to identify areas in arid ecology that are well studied and topics that are emerging. Four topics-wetlands, mammal ecology, litter decomposition and spatial modelling, were identified as 'hot topics' that showed higher than average growth in publications from 1940 to 2015. Five topics-remote sensing, climate, habitat and spatial, agriculture and soils-microbes, were identified as 'cold topics', with lower than average growth over the survey period, but higher than average numbers of publications. Topics in arid ecology clustered into seven broad groups on word-based similarity. These groups ranged from mammal ecology and population genetics, broad-scale management and ecosystem modelling, plant ecology, agriculture and ecophysiology, to populations and paleoclimate. These patterns may reflect trends in the field of ecology more broadly. We also identified two broad research gaps in arid ecology: population genetics, and habitat and spatial research. Collaborations between population genetics and ecologists and investigations of ecological processes across spatial scales would contribute profitably to the advancement of arid ecology and to ecology more broadly.


A preliminary investigation of powered prostheses for improved walking biomechanics in bilateral transfemoral amputees.
The authors conducted a preliminary investigation of the extent to which a pair of powered prostheses can provide improved gait biomechanics in bilateral transfemoral amputee walking. Specifically, a finite state-based impedance controller for level ground walking was implemented in a pair of powered knee and ankle prostheses. The efficacy of the powered prostheses and impedance-based controllers was tested on a healthy subject using able-body adapters. Motion capture data was collected while the subject performed treadmill walking with the powered prostheses. This kinematic data is compared to that of healthy subjects, and also to previously published data for bilateral transfemoral amputee gait with passive prostheses. The comparison indicates that the powered prostheses are able to provide a walking gait that is considerably more representative of healthy biomechanical gait relative to passive prostheses.


Community support as a moderator of postdisaster mental health symptoms in urban and nonurban communities.
We examined the association between disaster exposure, community support, and mental health outcomes in urban and nonurban participants of Galveston and Chambers counties after Hurricane Ike. The moderating effect of community support was evaluated as a protective factor relative to postdisaster mental health. A representative population-based sample of 157 urban and 714 nonurban adults were interviewed 12 to 17 months after the hurricane about their mental health functioning, disaster exposure, and perceptions of community support. A series of multiple regressions demonstrated that disaster exposure was associated with mental health outcomes for both groups. The strength of the association varied across population samples.Community support moderated the association between interpersonal effects of the disaster and posttraumatic stress disorder (PTSD) and depression outcomes in nonurban participants and the association between property damage and PTSD in urban participants. Community support played a larger role in reducing PTSD and depression symptoms associated with the interpersonal effects of a disaster in the nonurban sample only. Communities may play a more beneficial role in the recovery process in nonurban areas that have elevated levels of injury or death attributed to a disaster.


The sensitivity of human fibroblasts to N-acetoxy-2-acetylaminofluorene is determined by the extent of transcription-coupled repair, and/or their capability to counteract RNA synthesis inhibition.
Nucleotide excision repair (NER) mechanism is the major pathway responsible for the removal of a large variety of bulky lesions from the genome. Two different NER subpathways have been identified, i.e. the transcription-coupled and the global genome repair pathways. For DNA-damage induced by ultraviolet light both transcription-coupled repair and global genome repair are essential to confer resistance to cytotoxic effects. To gain further insight into the contribution of NER subpathways in the repair of bulky lesions and in their prevention of biological effects we measured the rate of repair of dG-C8-AF in active and inactive genes in normal human cells, XP-C cells (only transcription-coupled repair) and XP-A cells (completely NER-deficient) exposed to NA-AAF. XP-C cells are only slightly more sensitive to NA-AAF than normal cells and, like normal cells, they are able to recover RNA synthesis repressed by the treatment. In contrast, XP-A cells are sensitive to NA-AAF and unable to recover from RNA synthesis inhibition. Repair of dG-C8-AF in the active ADA gene proceeds in a biphasic way and without strand specificity, with a subclass of lesions quickly repaired during the first 8 h after treatment. Repair in the inactive 754 gene occurs more slowly than in the ADA gene. In XP-C cells, repair of dG-C8-AF in the ADA gene is confined to the transcribed strand and occurs at about half the rate of repair seen in normal cells. Repair in the inactive 754 gene in XP-C cells is virtually absent. Consistent with these results we found that repair replication in XP-C is drastically reduced when compared with normal cells and abolished by alpha-amanitin indicating that the repair in XP-C cells is mediated by transcription-coupled repair only. Our data suggest that dG-C8-AF is a target for transcription-coupled repair and that this repair pathway is the main pathway or recovery of RNA synthesis inhibition conferring resistance to cytotoxic effects of NA-AAF. In spite of this, repair of dG-C8-AF in active genes in normal cells by transcription-coupled repair and global genome repair is not additive, but dominated by global genome repair. This indicates that the subset of lesions which are capable of stalling RNA polymerase II, and are, therefore, a substrate for TCR, are also the lesions which are very efficiently recognized by the global genome repair system.


Congenital aflatoxicosis, mal-detoxification genomics & ontogeny trigger immune-mediated Kotb disease biliary atresia variant: SANRA compliant review.
Biliary atresia (BA) is the most common indication for pediatric liver transplantation. We describe The BA variant: Kotb disease. Liver tissue in the Kotb disease BA is massively damaged by congenital aflatoxicosis resulting in inflammation, adhesions, fibrosis, bile duct proliferation, scarring, cholestasis, focal syncytial giant cell transformation, and typical immune response involving infiltration by CD4+, CD8+, CD68+, CD14+, neutrophil infiltration, neutrophil elastase spill, heavy loads of aflatoxin B1, accelerated cirrhosis, disruption of p53 and GSTPi, and have null glutathione S transferase M1 (GSTM1). All their mothers are heterozygous for GSTM1. This inability to detoxify aflatoxicosis results in progressive inflammatory adhesions and obliterative cholangiopathy early in life. The typical disruption of both p53 and GSTPi causes loss of fidelity of hepatic regeneration. Hence, regeneration in Kotb disease BA typically promotes accelerated cirrhosis. The immune response in Kotb disease BA is for damage control and initiation of regeneration, yet, this friendly fire incurs massive structural collateral damage. The Kotb disease BA is about actual ongoing hepatic entrapment of aflatoxins with lack of ability of safe disposal due to child detoxification-genomics disarray. The Kotb disease BA is a product of the interaction of persistent congenital aflatoxicosis, genetic lack of GSTM1 detoxification, ontogenically impaired activity of other hepatic detoxification, massive neutrophil-elastase, immune-induced damage, and disturbed regeneration. Ante-natal and neonatal screening for aflatoxicosis, avoiding cord milking, and stringent control of aflatoxicosis content of human, poultry and live-stock feeds might prove effective for prevention, prompt diagnosis and management based on our recent understanding of its patho-genomics.


Prostaglandin E2 and cyclic AMP response to vasopressin in renal medullary tubular cells.
Rat renal medullary tubular cells, prepared by collagenase dispersion and hypotonic lysis, were introduced in Teflon chambers for superfusion. Prostaglandin (PG) E2 and cyclic adenosine 5'-monophosphate (cAMP) production was measured in the effluent. Arginine vasopressin (AVP) but not 1-deamino-8-D-arginine vasopressin (dDAVP) (10(-10)-10(-6) M), induced a dose-dependent increase in PGE2 synthesis, whereas AVP and dDAVP produced a similar dose-dependent increase in cAMP synthesis. The Ca2+ ionophore A23187 (10(-6) M) stimulated PGE2 synthesis but not cAMP production. In contrast, forskolin (10(-5) M) stimulated cAMP synthesis without affecting PGE2 generation. The pressor antagonists dEt2AVP and d(CH2)5Tyr(Me)AVP (10(-5) M) completely inhibited the PGE2 response to 10(-8) M AVP, whereas d(CH2)5-D-LeuVAVP (10(-6) M), a mixed pressor-antidiuretic antagonist, inhibited incompletely. dEt2AVP did not significantly affect cAMP synthesis in response to 10(-8) M AVP, whereas d(CH2)5-D-LeuVAVP, and unexpectedly also d(CH2)5Tyr(Me)AVP, were inhibitory. dPTyr(Me)AVP (10(-7) M), a pressor antagonist, had an unexpectedly high cAMP-stimulating capacity. In Ca2+-free media containing EGTA, the PGE2 response to AVP and A23187 was inhibited. Nifedipine (10(-6) M) did not significantly inhibit the AVP-stimulated PGE2 production. Thus AVP-stimulated PGE2 synthesis is linked to a V1-receptor in renal medullary tubular cells and occurs independently to the activation of adenylate cyclase through a V2-receptor.


Continuous Flow Synthesis of ACE Inhibitors From N-Substituted l-Alanine Derivatives.
A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h-1 , all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h-1 .


[The role of oligomeric structure in the functioning of D-glyceraldehyde-3-phosphate dehydrogenase].
The review summarizes the results of a study on the functional role of subunit interactions in a tetrameric glyceraldehyde-3-phosphate dehydrogenase molecule. A conformational asymmetry preexistent in the apoenzyme was shown to be detectable with the use of fluorescent cationic probes. Experimental evidence is presented which points to an interaction of the enzyme active centers in the course of productive E-acyl-NADH complex formation in the forward reaction. The matrix immobilized oligomeric and subunit forms of the enzyme were used to demonstrate that the quaternary structure is not a prerequisite for the catalytic activity. Due to subunit interactions within the oligomeric enzyme molecule the functioning of a monomer is under the control exerted by the neighbouring subunits. An association of monomers into a dimer is sufficient to create a cooperative system; the mutual influence of subunits becomes more complex in a trimeric and a tetrameric enzyme species. An isolated dimer exhibits the effect of half-of-the-sites reactivity and catalytic cooperativity of the active centers. Both the tetrameric and dimeric enzyme forms probably catalyze the reaction of 1,3-diphosphoglycerate reductive dephosphorylation via a mechanism of the flip-flop type. The catalytic cooperativity of the enzyme active centers can be controlled by some factors of the intracellular environment (e.g., by protein-protein interactions with a functionally related enzyme). Thus, the role of subunit cooperativity in the glyceraldehyde-3-phosphate dehydrogenase molecule is suggested to constitute one of the mechanisms of regulation of the enzyme functioning.


The spoken knowledge of low literacy in patients with diabetes.
This research was planned descriptively and analytically to determine the diabetes knowledge of patients with low level of education diabetes. This study has been performed with 200 patients diagnosed with diabetes at least 3 months ago who were able to communicate, volunteered to participate in the study, had less than highschool education, and were at least 18 years of age. Data were collected through questionnaire and SKILLD (Individual Knowledge Scale), and is evaluated using ANOVA, chi-square and t-test. The mean age of the participants was 54 ± 15.104. There was difference between the time passed for the diagnosis of the diabetes and total SKILLD score averages (p = .009). SKILLD scores decreased as age and number of children increased (p = .003). SKILLD scores increased as education levels and diabetes duration increased (p < .0001). More patients with moderate level of education knew normal ranges of blood sugar and HbA1C compared to those with lower level of education (p < .0001). Besides, more patients with moderate level of education were aware of the optimum frequency to exercise, with a significant difference between the two groups (p < .0001). Diabetes knowledge increased with higher level education and younger ages, while the elderly and individuals with low level of education had insufficient knowledge on diabetes.


Dyslipidemia after pediatric renal transplantation-The impact of immunosuppressive regimens.
Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry. Data were obtained before and during the first year after RTx to analyze possible non-modifiable and modifiable risk factors. The prevalence of dyslipidemia was 95% before engraftment and 88% at 1 year post-transplant. Low estimated glomerular filtration rate at 1 year post-transplant was associated with elevated serum triglyceride levels. The use of TAC and of MPA was associated with significantly lower concentrations of all lipid parameters compared to regimens containing CsA and mTORi. Immunosuppressive regimens consisting of CsA, MPA, and steroids as well as of CsA, mTORi, and steroids were associated with a three- and 25-fold (P<.001) increased risk of having more than one pathologic lipid parameter as compared to the use of TAC, MPA, and steroids. Thus, amelioration of the cardiovascular risk profile after pediatric RTx may be attained by adaption of the immunosuppressive regimen according to the individual risk profile.


[Nutritional recommendations in gynecology].
In pregnant women, appropriate eating habits has a key role to play in the development of the foetus and is also related with the amount of labour at delivery, helping to avoid complications. In addition, correct nutrition is also necessary during the puerperium to encourage breast feeding and provide the new-born child with an adequate nutritional status without leading to any deficits in the mother.


Innovation where it counts: in the home.
Managed care and consumer preference have once again focused attention on care delivered in the home. The development of clinical technology has enabled the home care market to accept complex, "high-tech" patients. For advanced practice nurses (APNs) to have an integral part in shaping the emerging high-tech home care industry, they must have an understanding of the technology and its clinical and financial implications. APNs must define their roles in response to the needs created by the evolving home care market.


Face-Based Judgments: Accuracy, Validity, and a Potential Underlying Mechanism.
Despite the pervasiveness of facial inferences, scholars have debated whether our face reflects valid information regarding how we actually behave. Whereas previous research has largely focused on the accuracy of facial inferences, the present research examined the validity of face-based judgments. Specifically, we tested how accurate face-based judgments are, whether the accuracy of and confidence in face-based judgments are associated, and what mechanisms potentially link facial appearance to behaviors (N = 1,386 American and Korean adults). We found that although face-based judgments could accurately predict someone's behavior (Study 1), participants' confidence about their face-based judgments was not associated with their accuracy (Studies 2a and 2b). Moreover, Study 3 demonstrated that the accuracy of facial inferences is possibly due to self-fulfilling effects of facial inferences. That is, accuracy is largely driven by perceivers' beliefs rather than by the direct association between faces and behaviors.


Hydrolysis of ammonia borane as a hydrogen source: fundamental issues and potential solutions towards implementation.
In today's era of energy crisis and global warming, hydrogen has been projected as a sustainable alternative to depleting CO(2)-emitting fossil fuels. However, its deployment as an energy source is impeded by many issues, one of the most important being storage. Chemical hydrogen storage materials, in particular B-N compounds such as ammonia borane, with a potential storage capacity of 19.6 wt % H(2) and 0.145 kg(H2)L(-1), have been intensively studied from the standpoint of addressing the storage issues. Ammonia borane undergoes dehydrogenation through hydrolysis at room temperature in the presence of a catalyst, but its practical implementation is hindered by several problems affecting all of the chemical compounds in the reaction scheme, including ammonia borane, water, borate byproducts, and hydrogen. In this Minireview, we exhaustively survey the state of the art, discuss the fundamental problems, and, where applicable, propose solutions with the prospect of technological applications.


Novel 30 kDa protein possessing ATP-binding and chaperone activities.
A 30 kDa protein was purified from pig liver cytosol by using ATP-Sepharose and Green A column chromatography. The partial amino acid sequences of the protein (95 amino acid residues) had no similarity with any proteins recorded in data banks. The protein was able to form a stable complex with unfolded dihydrofolate reductase (DHFR). The spontaneous refolding of chemically denatured DHFR was arrested by the 30 kDa protein. This inhibition presumably results from the formation of a stable complex between the 30 kDa protein and DHFR. Bound DHFR could be released from the protein with ATP. The protein also showed protease resistance in an ATP-dependent manner. Incubation of the 30 kDa protein with 5 mM ATP resulted in its resistance to V8 protease or to trypsin treated with 1-chloro-4-phenyl-3-L-toluene-p-sulphonamidobutan-2-one. Divalent cations enhanced the ATP-protection effect. CD analysis of the 30 kDa protein showed that ATP induced an increase in the beta-pleated sheet content and a decrease in the alpha-helix content of the 30 kDa protein. These results suggest that the 30 kDa protein, a novel cytosolic protein, might have an affinity for ATP, a chaperonin activity, and and an ATP-protection effect against some proteases in vivo.


Comparison of Veterinary Student Ability to Learn 1-Handed and 2-Handed Techniques for Surgical Knot Tying.
To determine which type of surgical hand-tie trainee surgeons learn most readily in a laboratory setting, using a combination of audiovisual demonstration and one-on-one teaching. Randomized controlled learning trial. Year 4 veterinary students in their 1st year of clinical training (n = 58). Veterinary students entering clinical rotations were randomly allocated to 2 learning groups: 1-handed (28 students) or 2-handed (30 students) surgical ties. Knot tying technique was taught followed by three 15-minute practice sessions with student progress recorded by filming each student tying a square knot (2 throws). All 3 knot tying attempts were scored for technique and knot formation. Data on potential confounding factors between groups, including age and gender, were recorded. There were no significant differences between group scores for each attempt (1st attempt P = .5; 2nd P = .2; 3rd P = .19). Initially, scores indicated more rapid learning in the 1-handed group but fewer individuals achieved a perfect technique and knot after 60 minutes of learning (29/30 for 2-handed; 24/28 for 1-handed group). The 1-handed group was the most error-prone (after 45 minutes P < .01; after 60 min P < .01). Over 95% of students in the 2-handed group performed the technique and knot perfectly after 60 minutes learning time; were significantly less error-prone and fewer students continued to make corrected errors after 60 minutes. This evidence indicates that the 2-handed technique allows students to achieve success in a manageable teaching time.


Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Treatment Rates and Outcomes in Infants Born Extremely Preterm.
To assess associations between neonatal intensive care unit (NICU)-level patent ductus arteriosus (PDA) treatment rates (pharmacologic or surgical) and neonatal outcomes. This cohort study included infants born at 24-28 weeks of gestation and birth weight <1500 g in 2007-2015 in NICUs caring for ≥100 eligible infants in 6 countries. The ratio of observed/expected (O/E) PDA treatment rates was derived for each NICU by estimating the expected rate using a logistic regression model adjusted for potential confounders and network. The primary composite outcome was death or severe neurologic injury (grades III-IV intraventricular hemorrhage or periventricular leukomalacia). The associations between the NICU-level O/E PDA treatment ratio and neonatal outcomes were assessed using linear regression analyses including a quadratic effect (a square term) of the O/E PDA treatment ratio. From 139 NICUs, 39 096 infants were included. The overall PDA treatment rate was 45% in the cohort (13%-77% by NICU) and the O/E PDA treatment ratio ranged from 0.30 to 2.14. The relationship between the O/E PDA treatment ratio and primary composite outcome was U-shaped, with the nadir at a ratio of 1.13 and a significant quadratic effect (P<.001). U-shaped relationships were also identified with death, severe neurologic injury, and necrotizing enterocolitis. Both low and high PDA treatment rates were associated with death or severe neurologic injury, whereas a moderate approach was associated with optimal outcomes.


Sorting nexin 5 is localized to a subdomain of the early endosomes and is recruited to the plasma membrane following EGF stimulation.
Sorting nexins are a large family of proteins that contain the phosphoinositide-binding Phox homology (PX) domain. A number of sorting nexins are known to bind to PtdIns3P, which mediates their localization to membranes of the endocytic pathway. We show here that sorting nexin 5 (SNX5) can be recruited to two distinct membrane compartments. In non-stimulated cells, the PX domain was independently targeted to endosomal structures and colocalized with full-length SNX5. The membrane binding of the PX domain was inhibited by the PI 3-kinase inhibitor, wortmannin. Although SNX5 colocalized with a fluid-phase marker and was found predominantly within a PtdIns3P-rich endosomal domain, very little colocalization was observed between SNX5 and the PtdIns3P-binding protein, EEA1. Using liposome-based binding assays, we have shown that the PX domain of SNX5 interacts not only with PtdIns3P but also with PtdIns3,4P2. In response to EGF stimulation, either the SNX5-PX domain or full-length SNX5 was rapidly recruited to the plasma membrane. The localization of SNX1, which does not bind PtdIns3,4P2, was unaffected by EGF signalling. Therefore, SNX5 is localized to a subdomain of the early endosome distinct from EEA1 and, following EGF stimulation and elevation of PtdIns3,4P2, is also transiently recruited to the plasma membrane. These results indicate that SNX5 may have functions not only associated with endosomal sorting but also with the phosphoinositide-signalling pathway.


Psychometric properties of the Impact of Event Scale-Revised in patients one year after burn injury.
Burn injury can be a life-threatening and traumatic event. Despite considerable risk for psychological morbidity, few outcome measures have been evaluated. The aim of this study was to examine the psychometric properties of a Swedish version of the Impact of Event Scale-Revised (IES-R) in patients 1 year after burn injury (N = 147). A principal component analysis was performed, and the results supported the three-factor structure of the IES-R. High internal consistency and intelligible associations with concurrent psychological symptoms and known risk factors for distress after trauma indicate satisfactory psychometric properties. Thus, the study supports the use of the IES-R as a screening tool for measuring traumatic distress after burn.


Scalp and calvarial reconstruction.
Over the past several decades, an improved understanding of the blood supply of local flaps, increased experience with tissue expansion, and the development of techniques for microsurgical transfer of distant flaps have greatly contributed to the ability of plastic surgeons to repair scalp defects. This article will review basic anatomy, principles, and pearls of reconstruction for simple to complex scalp defects. Included will be anatomic considerations, indications and contraindications for reconstruction, and an overview of reconstructive options.


6-Shogaol Inhibits Advanced Glycation End-Products-Induced IL-6 and ICAM-1 Expression by Regulating Oxidative Responses in Human Gingival Fibroblasts.
Advanced glycation end-products (AGEs) cause diabetes mellitus (DM) complications and accumulate more highly in periodontal tissues of patients with periodontitis and DM. AGEs aggravate periodontitis with DM by increasing the expression of inflammation-related factors in periodontal tissues. 6-Shogaol, a major compound in ginger, has anti-inflammatory and anti-oxidative activities. However, the influence of shogaol on DM-associated periodontitis is not well known. In this study, the effects of 6-shogaol on AGEs-induced oxidative and anti-oxidative responses, and IL-6 and ICAM-1 expression in human gingival fibroblasts (HGFs) were investigated. When HGFs were cultured with 6-shogaol and AGEs, the activities of reactive oxygen species (ROS) and antioxidant enzymes (heme oxygenase-1 [HO-1] and NAD(P)H quinone dehydrogenase 1 [NQO1]), and IL-6 and ICAM-1 expressions were investigated. RAGE expression and phosphorylation of MAPKs and NF-κB were examined by western blotting. 6-Shogaol significantly inhibited AGEs-induced ROS activity, and increased HO-1 and NQO1 levels compared with the AGEs-treated cells. The AGEs-stimulated expression levels of receptor of AGE (RAGE), IL-6 and ICAM-1 and the phosphorylation of p38, ERK and p65 were attenuated by 6-shogaol. These results suggested that 6-shogaol inhibits AGEs-induced inflammatory responses by regulating oxidative and anti-oxidative activities and may have protective effects on periodontitis with DM.