Large-scale optical compression of free-space using an experimental three-lens spaceplate.

Recently introduced, spaceplates achieve the propagation of light for a distance greater than their thickness. In this way, they compress optical space, reducing the required distance between optical elements in an imaging system. Here we introduce a spaceplate based on conventional optics in a 4-f arrangement, mimicking the transfer function of free-space in a thinner system - we term this device a three-lens spaceplate. It is broadband, polarization-independent, and can be used for meter-scale space compression. We experimentally measure compression ratios up to 15.6, replacing up to 4.4 meters of free-space, three orders of magnitude greater than current optical spaceplates. We demonstrate that three-lens spaceplates reduce the length of a full-color imaging system, albeit with reductions in resolution and contrast. We present theoretical limits on the numerical aperture and the compression ratio. Our design presents a simple, accessible, cost-effective method for optically compressing large amounts of space.

Do you need a roadmap or can someone give you directions: When school-focused possible identities change so do academic trajectories.

INTRODUCTION: Despite the assumed importance of school-focused possible identities for academic motivation and outcomes, interventions rarely assess the effect of intervention on possible identities. This may be due to difficulty coding open-ended text at scale but leaves open a number of questions: 1) how do school-focused possible identities change over the course of the school year, 2) whether these changes are associated with changes in school outcomes, and 3) whether a machine coding approach is viable. METHODS: In Study 1 (n = 247 Chicago 8th-graders) we assess fall-to-spring change in school-focused possible identities. We test whether change in school-focused possible identities predicts 8th-grade academic outcomes. We include robustness checks. Then we examine school context effects. In Study 2 (n = 1006 Chicago 8th-graders) we address the problem of coding at scale, using a separate data set to train a machine-learning algorithm. RESULTS: On average, school-focused possible identities decline over the school year. But nearly a third of students have increasing school-focused possible identity scores. Increase is associated with improved grades. School context influences whether linked strategies matter. Our machine-learning algorithm accurately classifies school-focused possible identities in our original sample and this school-focused classification reliably predicts academic trajectories. CONCLUSIONS: Change in school-focused possible identities is normative over the course of the school year, interventions should take this into account. On average, students have fewer school-focused possible identities by spring. This decline is associated with declining academic trajectories. However, when school-focused possible identities increase, so do grades. Whether strategies matter is context dependent.

Comparative Histopathology of Bovine Acute Interstitial Pneumonia and Bovine Respiratory Syncytial Virus-Associated Interstitial Pneumonia.

Acute interstitial pneumonia (AIP) is a significant disease of cattle and many aetiologies have been implicated on the basis of the characteristic pathological lesions. Bovine respiratory syncytial virus (BRSV) is one of the key aetiological factors in bovine respiratory disease complex and several studies have suggested, controversially, that BRSV may be an underlying cause of bovine AIP. BRSV infection is known to cause several distinctive histopathological changes, including epithelial syncytia formation and intracytoplasmic viral inclusions. However, distinguishing bovine AIP from BRSV-related pneumonia by clinical presentation, gross pathology or histopathology can sometimes be challenging. In order to identify the potential distinguishing features, we compared the histopathological findings of AIP that were, and were not, associated with BRSV infection in naturally occurring cases. We found that multinucleated giant cells were more frequently identified in cattle with AIP while bronchiolitis was more common in BRSV-infected cattle. However, this was not considered a sole indicator of either disease group. Statistically, we identified that a combination of several histopathological features, including alveolar septal necrosis, presence of multinucleated giant cells and bronchiolitis, can serve as an excellent indicator for distinguishing between idiopathic AIP and BRSV-related pneumonia, with a strong statistical significance (P = 0.0004). Based on the results of this retrospective study, we present a histopathological scoring system for predicting BRSV-associated AIP.

Connecting and separating mind-sets: culture as situated cognition.

People perceive meaningful wholes and later separate out constituent parts (D. Navon, 1977). Yet there are cross-national differences in whether a focal target or integrated whole is first perceived. Rather than construe these differences as fixed, the proposed culture-as-situated-cognition model explains these differences as due to whether a collective or individual mind-set is cued at the moment of observation. Eight studies demonstrated that when cultural mind-set and task demands are congruent, easier tasks are accomplished more quickly and more difficult or time-constrained tasks are accomplished more accurately ( STUDY 1: Koreans, Korean Americans; STUDY 2: Hong Kong Chinese; STUDY 3: European- and Asian-heritage Americans; STUDY 4: Americans; STUDY: 5 Hong Kong Chinese; STUDY 6: Americans; STUDY 7: Norwegians; STUDY 8: African-, European-, and Asian-heritage Americans). Meta-analyses (d = .34) demonstrated homogeneous effects across geographic place (East-West), racial-ethnic group, task, and sensory mode-differences are cued in the moment. Contrast and separation are salient individual mind-set procedures, resulting in focus on a single target or main point. Assimilation and connection are salient collective mind-set procedures, resulting in focus on multiplicity and integration.

Discovery of Melanocortin Ligands via a Double Simultaneous Substitution Strategy Based on the Ac-His-dPhe-Arg-Trp-NH2 Template.

The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4, as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at positions 1 and 2, (C) double simultaneous substitution at positions 1 and 4, and (D) double simultaneous substitution at positions 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency or selectivity or converting agonists into antagonists and vice versa.

Bovine viral diarrhea virus 1b fetal infection with extensive hemorrhage.

Bovine viral diarrhea virus (BVDV) 1b was isolated from tissues of a term bovine fetus with petechial hemorrhages noted throughout the body and placenta at autopsy. Fresh lung, kidney, thymus, and liver tissues were examined by direct fluorescent antibody testing and were positive for BVDV antigen and negative for bovine herpesvirus 1 antigen. An organ pool of fresh tissues was positive for noncytopathic (NCP) BVDV-1 by virus isolation. BVDV-1b was identified by sequencing of the 5'-UTR region of the genome. Fixed brain, placenta, thymus, lymph node, lung, kidney, skeletal muscle, liver, and bone marrow were positive for BVDV antigen by immunohistochemistry. Although BVDV hemorrhage and/or thrombocytopenia has been associated historically with NCP strains of BVDV-2, this case adds to more recent reports of BVDV-1 infections and hemorrhage in cattle. This BVDV-1b isolate should be investigated for its potential to cause hemorrhage in postnatal cattle.

Clinical disease and lung lesions in calves experimentally inoculated with Histophilus somni five days after metaphylactic administration of tildipirosin or tulathromycin.

OBJECTIVE: To compare clinical disease and lung lesions in calves experimentally inoculated with Histophilus somni 5 days after metaphylactic administration of tildipirosin or tulathromycin. ANIMALS Twenty-four 3-month-old Holstein and Holstein-crossbreed steers. PROCEDURES: Calves were randomly allocated to 3 groups of 8 calves. On day 0, calves in group 1 received tildipirosin (4 mg/kg, SC), calves in group 2 received tulathromycin (2.5 mg/kg, SC), and calves in group 3 received isotonic saline (0.9% NaCl) solution (1 mL/45 kg, SC; control). On day 5, calves were inoculated with 10 mL of a solution containing H somni strain 7735 (1.6 × 10(9) CFUs/mL, intrabronchially; challenge). Calves were clinically evaluated on days 5 through 8 and euthanized on day 8. The lungs were grossly evaluated for evidence of pneumonia, and bronchial secretion samples underwent bacteriologic culture. RESULTS: The mean clinical score for each group was significantly increased 12 hours after challenge, compared with that immediately before challenge, and was significantly lower for tildipirosin-treated calves on days 6, 7, and 8, compared with those for tulathromycin-treated and control calves. The mean percentage of lung consolidation for tildipirosin-treated calves was significantly lower than those for tulathromycin-treated and control calves. Histophilus somni was isolated from the bronchial secretions of some tulathromycin-treated and control calves but was not isolated from tildipirosin-treated calves. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that metaphylactic administration of tildipirosin to calves 5 days prior to H somni challenge prevented subsequent culture of the pathogen from bronchial secretions and was more effective in minimizing clinical disease and lung lesions than was metaphylactic administration of tulathromycin.

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), ß-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

Discovery of a ß-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology.

Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87-132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report AGRP-derived peptides designed to mimic the active ß-hairpin secondary structure that contains the hypothesized Arg-Phe-Phe pharmacophore. The most potent scaffold, c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro], comprised the hexa-peptide ß-hairpin loop from AGRP cyclized through a DPro-Pro motif. A 20 compound library was synthesized from this scaffold for further structure-activity relationship studies. The most potent peptide from this library was an asparagine to diaminopropionic acid substitution that possessed sub-nanomolar antagonist activity at the mMC4R and was greater than 160-fold selective for the mMC4R versus the mMC3R. The reported ligands may serve as probes to characterize the melanocortin receptors in vivo and leads in the development of novel therapeutics.

Enteric disease in postweaned beef calves associated with Bovine coronavirus clade 2.

Bovine coronavirus (BoCV; Betacoronavirus 1) infections are associated with varied clinical presentations including neonatal diarrhea, winter dysentery in dairy cattle, and respiratory disease in various ages of cattle. The current report presents information on BoCV infections associated with enteric disease of postweaned beef cattle in Oklahoma. In 3 separate accessions from a single herd, 1 in 2012 and 2 in 2013, calves were observed with bloody diarrhea. One calf in 2012 died and was necropsied, and 2 calves from this herd died in 2013 and were necropsied. A third calf from another herd died and was necropsied. The gross and histologic diagnosis was acute, hemorrhagic colitis in all 4 cattle. Colonic tissues from all 4 animals were positive by fluorescent antibody testing and/or immunohistochemical staining for BoCV antigen. Bovine coronavirus was isolated in human rectal tumor cells from swabs of colon surfaces of all animals. The genomic information from a region of the S envelope region revealed BoCV clade 2. Detection of BoCV clade 2 in beef cattle in Oklahoma is consistent with recovery of BoCV clade 2 from the respiratory tract of postweaned beef calves that had respiratory disease signs or were healthy. Further investigations on the ecology of BoCV in cattle are important, as BoCV may be an emerging disease beyond the initial descriptions. Challenge studies are needed to determine pathogenicity of these strains, and to determine if current BoCV vaccines are efficacious against the BoCV clade 2 strains.

Identification of putative agouti-related protein(87-132)-melanocortin-4 receptor interactions by homology molecular modeling and validation using chimeric peptide ligands.

Agouti-related protein (AGRP) is one of only two naturally known antagonists of G-protein-coupled receptors (GPCRs) identified to date. Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these melanocortin receptors. Insight into putative interactions between the antagonist AGRP amino acids with the melanocortin-4 receptor (MC4R) may be important for the design of unique ligands for the treatment of obesity related diseases and is currently lacking in the literature. A three-dimensional homology molecular model of the mouse MC4 receptor complex with the hAGRP(87-132) ligand docked into the receptor has been developed to identify putative antagonist ligand-receptor interactions. Key putative AGRP-MC4R interactions include the Arg111 of hAGRP(87-132) interacting in a negatively charged pocket located in a cavity formed by transmembrane spanning (TM) helices 1, 2, 3, and 7, capped by the acidic first extracellular loop (EL1) and specifically with the conserved melanocortin receptor residues mMC4R Glu92 (TM2), mMC4R Asp114 (TM3), and mMC4R Asp118 (TM3). Additionally, Phe112 and Phe113 of hAGRP(87-132) putatively interact with an aromatic hydrophobic pocket formed by the mMC4 receptor residues Phe176 (TM4), Phe193 (TM5), Phe253 (TM6), and Phe254 (TM6). To validate the AGRP-mMC4R model complex presented herein from a ligand perspective, we generated nine chimeric peptide ligands based on a modified antagonist template of the hAGRP(109-118) (Tyr-c[Asp-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH(2)). In these chimeric ligands, the antagonist AGRP Arg-Phe-Phe residues were replaced by the melanocortin agonist His/D-Phe-Arg-Trp amino acids. These peptides resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs). The most notable results include the identification of a novel subnanomolar melanocortin peptide template Tyr-c[Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that is equipotent to alpha-MSH at the mMC1, mMC3, and mMC5 receptors but is 30-fold more potent than alpha-MSH at the mMC4R. Additionally, these studies identified a new and novel >200-fold MC4R versus MC3R selective peptide Tyr-c[Asp-D-Phe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) template. Furthermore, when the His-DPhe-Arg-Trp sequence is used to replace the hAGRP Arg-Phe-Phe residues in the "mini"-AGRP (hAGRP87-120, C105A) template, a potent nanomolar agonist resulted at the mMC1R and MC3-5Rs.

Telemedicine follow-up of burns: lessons learned from the first thousand visits.

Telemedicine is an evolving technology that is used for health education, health care administration, and health care distribution. The potential benefits of telemedicine include a decrease in travel expenses, improved continuity of care, and increased access to specialized consultants, thus meeting the needs of patients, practitioners, and communities. Telemedicine has many evolving applications, including improved access to health care in medically underserved and rural areas. Regions Burn Center assessed the efficacy and efficiency of burn visits via telemedicine and identified the barriers and benefits specific to burn care. Information regarding travel costs and financial data were evaluated from a total of 1000 burn follow-up visits with 294 patients via telemedicine during a 5-year interval. Our results indicate that telemedicine burn visits are a cost-effective clinical alternative for the patient. However, telemedicine can be a financial burden to health care systems and inefficient for health care providers.

γ2-Melanocyte stimulation hormone (γ2-MSH) truncation studies results in the cautionary note that γ2-MSH is not selective for the mouse MC3R over the mouse MC5R.

The melanocortin system has been implicated in a multitude of physiological pathways including obesity, satiety, energy homeostasis, sexual behavior, pigmentation, sodium regulation, hypertension, and many others. Based upon studies of the endogenous melanocortin receptor agonists at the cloned human melanocortin receptor proteins, it was concluded that the γ-MSH related agonist ligands are selective for the MC3 versus the MC4 and MC5 receptors. In attempts to understand and identify the specific amino acids of γ2-MSH important for MC3R selectivity, we have performed N- and C-terminal truncation studies and pharmacologically characterized twenty-eight ligands at the mouse MC1 and MC3-5 melanocortin receptors. The C-terminal Trp-Asp9-Arg¹°-Phe¹¹ residues are important for nM potency at the mMC3R and the Arg7-Trp8 residues are important for mMC5R nM potency. We observed the unanticipated results that several of the C-terminal truncated analogs possessed nM agonist potency at the mMC3 and mMC5Rs which lead us to perform a comparative side-by-side study of the mouse and human MC5R. These data resulted in µM γ2-MSH analog potency at the hMC5R, consistent with previous reports, however at the mMC5R, nM γ2-MSH analog potency was observed. Thus, these data support the hypothesis of important species specific differences in γ-MSH related ligand potency at the rodent versus human MC5R subtype that is critical for the interpretation of in vivo rodent physiological studies. These results prompted us to examine the affects of a peripherally administered melanocortin agonist on hypothalamic gene expression levels of the MC3R, MC4R, and MC5R. The super potent non-selective NDP-MSH agonist was administered i.p. and resulted in significantly decreased levels of mMC3R and mMC5R hypothalamic mRNA versus saline control. These data provide for the first time data demonstrating peripherally administered NDP-MSH can modify hypothalamic melanocortin receptor expression levels.

Structure-activity relationships of melanocortin agonists containing the benzimidazole scaffold.

The melanocortin system has been implicated in regulating various physiological processes including pigmentation, energy homeostasis, obesity, steroidogenesis cardiovascular, and exocrine gland function. The five melanocortin receptors that belong to the super family of G protein-coupled receptors are stimulated by naturally occurring agonists. The aim of this research was focused on the design, synthesis, and pharmacological characterization of melanocortin ligands that contain the 1,2,5-trisubstituted benzimidazole scaffold. A series of benzimidazole analogues, with three points of diversity at positions 1, 2, and 5, were designed, synthesized, pharmacologically assayed at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R and resulted in ligands possessing a range of agonist activity from nm to no stimulation at up to 100 microM concentrations. This study demonstrates that the benzimidazole structure template can be appended with key melanocortin agonist amino acids for the design melanocortin receptor agonist ligands.

Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist.

The melanocortin-4 receptor (MC4R) is a G-protein coupled receptor (GPCR) that is expressed in the central nervous system and has a role in regulating energy homeostasis and obesity. Up to a remarkable 6% of morbidly obese adults and children studied possess single nucleotide polymorphisms (SNPs) of the MC4R. Upon stimulation by agonist, the MC4R signals through the intracellular adenylate cyclase signal transduction pathway. Posttranslational modification of the pro-opiomelanocortin (POMC) gene transcript results in the generation of several endogenous melanocortin receptor agonists including alpha-, beta-, gamma-melanocyte stimulating hormones (MSH) and adrenocorticotropin (ACTH) ligands. The endogenous MC4R antagonist, agouti-related protein (AGRP), is expressed in the brain and is only one of two naturally occurring antagonists of GPCRs identified to date. Herein, we have generated 40 hMC4 polymorphic receptors and evaluated their cell surface expression by flow cytometry as well as pharmacologically characterized their functionality using the endogenous agonists alpha-MSH, beta-MSH, gamma2-MSH, ACTH(1-24), the antagonist hAGRP(87-132), and the synthetic agonists NDP-MSH and MTII. This is the first study in which polymorphic hMC4Rs have been pharmacologically characterized simultaneously with multiple endogenous ligands. Interestingly, at the N97D, L106P, and C271Y hMC4Rs beta-MSH was more potent than the other endogenous agonists alpha-MSH, gamma2-MSH, ACTH(1-24). The S58C and R165Q/W hMC4Rs possessed significantly reduced endogenous agonist potency (15- to 90-fold), but the synthetic ligands NDP-MSH and MTII possessed only 2-9-fold reduced potency as compared to the wild-type receptor, suggesting their potential as therapeutic ligands to treat individuals with these polymorphisms.