An additive algorithm for origami design.

Inspired by the allure of additive fabrication, we pose the problem of origami design from a different perspective: How can we grow a folded surface in three dimensions from a seed so that it is guaranteed to be isometric to the plane? We solve this problem in two steps: by first identifying the geometric conditions for the compatible completion of two separate folds into a single developable fourfold vertex, and then showing how this foundation allows us to grow a geometrically compatible front at the boundary of a given folded seed. This yields a complete marching, or additive, algorithm for the inverse design of the complete space of developable quad origami patterns that can be folded from flat sheets. We illustrate the flexibility of our approach by growing ordered, disordered, straight, and curved-folded origami and fitting surfaces of given curvature with folded approximants. Overall, our simple shift in perspective from a global search to a local rule has the potential to transform origami-based metastructure design.

Two is not necessarily better than one: A double lens in a pre-metamorphic adult axolotl (Ambystoma mexicanum).

An 8-year-old female pre-metamorphic axolotl (Ambystoma mexicanum) was examined for a suspected anterior lens luxation. Slit-lamp biomicroscopy revealed two lens-like structures in the anterior chamber of the right eye (OD), each with cataractous change. Ultrasound biomicroscopy and optical coherence tomography (OCT) were performed without sedation, and revealed small lenticular structures each with distinct nuclei and cortices. Although a distinct connection of the two lenticular structures could not be definitively ruled out, the structures appeared separate. Each of the lenticular structures was closely associated with its respective iris leaflet. This report demonstrates application of advanced imaging for diagnostic use in axolotl ophthalmology, showing that imaging of the lens can be performed without sedation, topical anesthetic, nor contact gel with high diagnostic quality. Although two distinct lenses were diagnosed with no historical evidence of trauma, the small sizes of each lenticular structure, with no detectable connection between them, are suggestive of a possible regenerative abnormality. This report opens discussion for the regenerative capabilities of the pre-metamorphic adult axolotl and possible implementations of their use in regenerative medicine research for the development of future therapies.

Endoscopic-guided diagnosis of and interventional stent placement for nasolacrimal duct obstruction in a horse.

OBJECTIVE: To describe the successful use of endoscopy to visualize and place a soft canine ureteral stent to relieve a chronic nasolacrimal duct (NLD) obstruction in a horse. ANIMAL STUDIED: A 7-year-old, Quarter horse gelding. PROCEDURE: Under general anesthesia, retrograde nasolacrimal endoscopy was performed using an 8.5 Fr Storz Flex XC ureteroscope through the nasal punctum (NP). An obstructive web of fibrous tissue was visualized approximately 20 cm proximal to the NP. A 0.035″/150 cm hydrophilic guidewire was passed normograde from the ventral lacrimal punctum and used to puncture the stenotic tissue. Then, a 5.0Fr/70 cm open-end ureteral catheter was threaded normograde over the guidewire and NLD patency was re-established. The catheter confirmed a NLD length of 30 cm and was then removed. A 5.0Fr/22-32 cm Universa© Soft Ureteral Stent was threaded normograde over the guidewire until the loops of the stent were exposed at each end. The guidewire was removed and the stent loops were sutured in place. RESULTS: The stent was withdrawn 1 month after the procedure. Telephone follow-up with the client reported significant improvement in the amount of ocular discharge and decreased sensitivity around the face and ears. CONCLUSION: Endoscopy is a safe and effective procedure allowing for definitive diagnosis of NLD obstruction and to assist in interventional procedures. Placement of a canine indwelling ureteral stent seems to be an effective alternative treatment option for equine NLD obstruction compared to conventional invasive surgical procedures.

The crosstalk between bone metabolism, lncRNAs, microRNAs and mRNAs in coronary artery calcification.

The association between Coronary Artery Calcification (CAC) and osteoporosis has been reported but not fully understood. Therefore, using an original bioinformatic framework we analyzed transcriptomic profiles of 20 elderly women with high CAC score and 31 age- and sex-matching controls from São Paulo Ageing & Health study (SPAH). We integrated differentially expressed microRNA (miRNA) and long-noncoding RNA (lncRNA) interactions with coding genes associated with CAC, in the context of bone-metabolism genes mined from literature. Top non-coding regulators of bone metabolism in CAC included miRNA 497-5p/195 and 106a-5p, and lncRNA FAM197Y7. Top non-coding RNAs revealed significant interplay between genes regulating bone metabolism, vascularization-related processes, chromatin organization, prostaglandin and calcium co-signaling. Prostaglandin E2 receptor 3 (PTGER3), Fibroblasts Growth Factor Receptor 1 (FGFR1), and One Cut Homeobox 2 (ONECUT2) were identified as the most susceptible to regulation by the top non-coding RNAs. This study provides a flexible transcriptomic framework including non-coding regulation for biomarker-related studies.

IDLY INFECTED: A REVIEW OF INFECTIOUS AGENTS IN POPULATIONS OF TWO- AND THREE-TOED SLOTHS (CHOLOEPUS SPECIES AND BRADYPUS SPECIES).

Two- and three-toed sloths (Choloepus spp. and Bradypus spp.) have become popular animals in American culture and in American zoos, where they are frequently used as animal ambassadors. Despite the increased focus on sloth species, the prevalence of infectious diseases in sloth populations and the associated clinical consequences are relatively unknown. This study reviewed all published literature from 1809 to 2019 that examined infectious agents in both captive and wild populations of either two- or three-toed sloths. Online databases were electronically searched for relevant manuscripts using strings of inclusion and exclusion terms, resulting in an initial identification of 5,364 articles. After removing duplications and conducting two relevance screenings, 57 manuscripts were included in the full review. A total of 1,769 individual two-toed sloths and 879 individual three-toed sloths were accounted for in the included studies, with evidence of infection or exposure to infectious agents in 647 (36.6%) and 222 (25.3%) individual two- and three-toed sloths, respectively. Approximately 74% of documented infections were cryptic fungal, parasitic, and viral infections. The remaining 26% of infections represent those that were associated with clinical signs of disease. The infectious agents reported were bacterial (84), parasitic (20), viral (9), and fungal (4). Significant knowledge gaps remain regarding clinical and subclinical infectious disease prevalence and impact in both free-ranging and captive sloths.

Programming shape using kirigami tessellations.

Kirigami tessellations, regular planar patterns formed by partially cutting flat, thin sheets, allow compact shapes to morph into open structures with rich geometries and unusual material properties. However, geometric and topological constraints make the design of such structures challenging. Here we pose and solve the inverse problem of determining the number, size and orientation of cuts that enables the deployment of a closed, compact regular kirigami tessellation to conform approximately to any prescribed target shape in two or three dimensions. We first identify the constraints on the lengths and angles of generalized kirigami tessellations that guarantee that their reconfigured face geometries can be contracted from a non-trivial deployed shape to a compact, non-overlapping planar cut pattern. We then encode these conditions into a flexible constrained optimization framework to obtain generalized kirigami patterns derived from various periodic tesselations of the plane that can be deployed into a wide variety of prescribed shapes. A simple mechanical analysis of the resulting structure allows us to determine and control the stability of the deployed state and control the deployment path. Finally, we fabricate physical models that deploy in two and three dimensions to validate this inverse design approach. Altogether, our approach, combining geometry, topology and optimization, highlights the potential for generalized kirigami tessellations as building blocks for shape-morphing mechanical metamaterials.

Programming curvature using origami tessellations.

Origami describes rules for creating folded structures from patterns on a flat sheet, but does not prescribe how patterns can be designed to fit target shapes. Here, starting from the simplest periodic origami pattern that yields one-degree-of-freedom collapsible structures-we show that scale-independent elementary geometric constructions and constrained optimization algorithms can be used to determine spatially modulated patterns that yield approximations to given surfaces of constant or varying curvature. Paper models confirm the feasibility of our calculations. We also assess the difficulty of realizing these geometric structures by quantifying the energetic barrier that separates the metastable flat and folded states. Moreover, we characterize the trade-off between the accuracy to which the pattern conforms to the target surface, and the effort associated with creating finer folds. Our approach enables the tailoring of origami patterns to drape complex surfaces independent of absolute scale, as well as the quantification of the energetic and material cost of doing so.

Mentored Training to Increase Diversity among Faculty in the Biomedical Sciences: The NHLBI Summer Institute Programs to Increase Diversity (SIPID) and the Programs to Increase Diversity among Individuals Engaged in Health-related Research (PRIDE).

OBJECTIVE: To report baseline characteristics of junior-level faculty participants in the Summer Institute Programs to Increase Diversity (SIPID) and the Programs to Increase Diversity among individuals engaged in Health-Related Research (PRIDE), which aim to facilitate participants' career development as independent investigators in heart, lung, blood, and sleep research. DESIGN AND SETTING: Junior faculty from groups underrepresented in the biomedical-research workforce attended two, 2-3 week, annual summer research-education programs at one of six sites. Programs provided didactic and/or laboratory courses, workshops to develop research, writing and career-development skills, as well as a mentoring component, with regular contact maintained via phone, email and webinar conferences. Between summer institutes, trainees participated in a short mid-year meeting and an annual scientific meeting. Participants were surveyed during and after SIPID/PRIDE to evaluate program components. PARTICIPANTS: Junior faculty from underrepresented populations across the United States and Puerto Rico participated in one of three SIPID (2007-2010) or six PRIDE programs (2011-2014). RESULTS: Of 204 SIPID/PRIDE participants, 68% were female; 67% African American and 27% Hispanic/Latino; at enrollment, 75% were assistant professors and 15% instructors, with most (96%) on non-tenure track. Fifty-eight percent had research doctorates (PhD, ScD) and 42% had medical (MD, DO) degrees. Mentees' feedback about the program indicated skills development (eg, manuscript and grant writing), access to networking, and mentoring were the most beneficial elements of SIPID and PRIDE programs. Grant awards shifted from primarily mentored research mechanisms to primarily independent investigator awards after training. CONCLUSIONS: Mentees reported their career development benefited from SIPID and PRIDE participation.

A Perspective on Promoting Diversity in the Biomedical Research Workforce: The National Heart, Lung, and Blood Institute's PRIDE Program.

Aspiring junior investigators from groups underrepresented in the biomedical sciences face various challenges as they pursue research independence. However, the biomedical research enterprise needs their participation to effectively address critical research issues such as health disparities and health inequities. In this article, we share a research education and mentoring initiative that seeks to address this challenge: Programs to Increase Diversity among Individuals Engaged in Health Related Research (PRIDE), funded by the National Heart, Lung, and Blood Institute (NHLBI). This longitudinal research-education and mentoring program occurs through summer institute programs located at US-based academic institutions. Recruited participants are exposed to didactic and lab-based research-skill enhancement experiences, with year-round mentoring over the course of two years. Mentor-mentee matching is based on shared research interests to promote congruence and to enhance skill acquisition. Program descriptions and sample narratives of participants' perceptions of PRIDE's impact on their career progress are showcased. Additionally, we highlight the overall program design and structure of four of seven funded summer institutes that focus on cardiovascular disease, related conditions, and health disparities. Mentees' testimonials about the value of the PRIDE mentoring approach in facilitating career development are also noted. Meeting the clinical and research needs of an increasingly diverse US population is an issue of national concern. The PRIDE initiative, which focuses on increasing research preparedness and professional development of groups underrepresented in the biomedical research workforce, with an emphasis on mentoring as the critical approach, provides a robust model that is impacting the careers of future investigators.

An additive framework for kirigami design.

We present an additive approach for the inverse design of kirigami-based mechanical metamaterials by focusing on the empty (negative) spaces instead of the solid tiles. By considering each negative space as a four-bar linkage, we identify a simple recursive relationship between adjacent linkages, yielding an efficient method for creating kirigami patterns. This allows us to solve the kirigami design problem using elementary linear algebra, with compatibility, reconfigurability and rigid-deployability encoded into an iterative procedure involving simple matrix multiplications. The resulting linear design strategy circumvents the solution of a non-convex global optimization problem and allows us to control the degrees of freedom in the deployment angle field, linkage offsets and boundary conditions. We demonstrate this by creating a large variety of rigid-deployable, compact, reconfigurable kirigami patterns. We then realize our kirigami designs physically using two simple but effective fabrication strategies with very different materials. Altogether, our additive approaches present routes for efficient mechanical metamaterial design and fabrication based on ori/kirigami art forms.

An Introduction and Overview of RON Receptor Tyrosine Kinase Signaling.

RON is a receptor tyrosine kinase (RTK) of the MET receptor family that is canonically involved in mediating growth and inflammatory signaling. RON is expressed at low levels in a variety of tissues, but its overexpression and activation have been associated with malignancies in multiple tissue types and worse patient outcomes. RON and its ligand HGFL demonstrate cross-talk with other growth receptors and, consequentially, positions RON at the intersection of numerous tumorigenic signaling programs. For this reason, RON is an attractive therapeutic target in cancer research. A better understanding of homeostatic and oncogenic RON activity serves to enhance clinical insights in treating RON-expressing cancers.

RON-augmented cholesterol biosynthesis in breast cancer metastatic progression and recurrence.

Recurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but preclinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and ß-catenin -dependent SREBP2 expression.

Geometric mechanics of curved crease origami.

Folding a sheet of paper along a curve can lead to structures seen in decorative art and utilitarian packing boxes. Here we present a theory for the simplest such structure: an annular circular strip that is folded along a central circular curve to form a three-dimensional buckled structure driven by geometrical frustration. We quantify this shape in terms of the radius of the circle, the dihedral angle of the fold, and the mechanical properties of the sheet of paper and the fold itself. When the sheet is isometrically deformed everywhere except along the fold itself, stiff folds result in creases with constant curvature and oscillatory torsion. However, relatively softer folds inherit the broken symmetry of the buckled shape with oscillatory curvature and torsion. Our asymptotic analysis of the isometrically deformed state is corroborated by numerical simulations that allow us to generalize our analysis to study structures with multiple curved creases.

The role of indoleamine 2, 3 dioxygenase in regulating host immunity to leishmania infection.

Pathogen persistence in immune-competent hosts represents an immunological paradox. Increasing evidence suggests that some pathogens, such as, Leishmania major (L. major) have evolved strategies and mechanisms that actively suppress host adaptive immunity. If this notion is correct conventional vaccination therapies may be ineffective in enhancing host immunity, unless natural processes that suppress host immunity are also targeted therapeutically. The key problem is that the basis of pathogen persistence in immune-competent individuals is unknown, despite decades of intense research. This fact, coupled with poor health care and a dearth of effective treatments means that these diseases will remain a scourge on humans unless a better understanding of why the immune system tolerates such infections emerges from research. Indoleamine 2,3-dioxygenase (IDO) has been shown to act as a molecular switch regulating host responses, and IDO inhibitor drugs shown to possess potential in enhancing host immunity to established leishmania infections. It is hoped that this review will help stimulate and help generate critical new knowledge pertaining to the IDO mechanism and how to exploit it to suppress T cell mediated immunity, thus offer an innovative approach to studying the basis of chronic leishmania infection in mice.

Vertically resolved measurements of nighttime radical reservoirs in Los Angeles and their contribution to the urban radical budget.

Photolabile nighttime radical reservoirs, such as nitrous acid (HONO) and nitryl chloride (ClNO(2)), contribute to the oxidizing potential of the atmosphere, particularly in early morning. We present the first vertically resolved measurements of ClNO(2), together with vertically resolved measurements of HONO. These measurements were acquired during the California Nexus (CalNex) campaign in the Los Angeles basin in spring 2010. Average profiles of ClNO(2) exhibited no significant dependence on height within the boundary layer and residual layer, although individual vertical profiles did show variability. By contrast, nitrous acid was strongly enhanced near the ground surface with much smaller concentrations aloft. These observations are consistent with a ClNO(2) source from aerosol uptake of N(2)O(5) throughout the boundary layer and a HONO source from dry deposition of NO(2) to the ground surface and subsequent chemical conversion. At ground level, daytime radical formation calculated from nighttime-accumulated HONO and ClNO(2) was approximately equal. Incorporating the different vertical distributions by integrating through the boundary and residual layers demonstrated that nighttime-accumulated ClNO(2) produced nine times as many radicals as nighttime-accumulated HONO. A comprehensive radical budget at ground level demonstrated that nighttime radical reservoirs accounted for 8% of total radicals formed and that they were the dominant radical source between sunrise and 09:00 Pacific daylight time (PDT). These data show that vertical gradients of radical precursors should be taken into account in radical budgets, particularly with respect to HONO.

Juvenile systemic lupus erythematosus and dermatomyositis associated with urticarial vasculitis syndrome: a unique presentation.

To report a case of triple association of juvenile systemic lupus erythematosus (SLE), juvenile dermatomyositis and urticarial vasculitis as well as a review of the relevant literature. A 12-year-old male patient diagnosed with overlap syndrome between SLE and juvenile dermatomyositis since 2004 evolved with erythematous plaques, which were compatible with an urticarial rash. Clinical, laboratory and histopathological findings indicated a diagnosis of urticarial vasculitis. The patient previously had a C1q deficiency. Using the established treatment with methylprednisolone (1 g/day for 3 days), increasing doses of deflazacort and introduction of a dapsone, as well as mycophenolate mofetil regimen, with the suspension of azathioprine resulted in complete resolution of skin lesions. Urticarial vasculitis can present in various diseases. In SLE, presentation of urticarial vasculitis in children is rarely found. The triple association of juvenile-onset SLE, juvenile dermatomyositis and urticarial vasculitis is unusual, and this is the first case described in literature.

Leishmania major attenuates host immunity by stimulating local indoleamine 2,3-dioxygenase expression.

Inflammation stimulates immunity but can create immune privilege in some settings. Here, we show that cutaneous Leishmania major infection stimulated expression of the immune regulatory enzyme indoleamine 2,3 dioxygenase (IDO) in local lymph nodes. Induced IDO attenuated the T cell stimulatory functions of dendritic cells and suppressed local T cell responses to exogenous and nominal parasite antigens. IDO ablation reduced local inflammation and parasite burdens, as did pharmacologic inhibition of IDO in mice with established infections. IDO ablation also enhanced local expression of proinflammatory cytokines and induced some CD4(+) T cells to express interleukin (IL) 17. These findings showed that IDO induced by L. major infection attenuated innate and adaptive immune responses. Thus, IDO acts as a molecular switch regulating host responses, and IDO inhibitor drugs are a potential new approach to enhance host immunity to established leishmania infections.

Quantification of nitryl chloride at part per trillion mixing ratios by thermal dissociation cavity ring-down spectroscopy.

Nitryl chloride (ClNO(2)) is an important nocturnal nitrogen oxide reservoir species in the troposphere. Here, we report a novel method, thermal dissociation cavity ring-down spectroscopy (TD-CRDS), to quantify ClNO(2) mixing ratios with tens of parts-per-trillion by volume (pptv) sensitivity. The mixing ratios of ClNO(2) are determined by blue diode laser CRDS of NO(2), produced from quantitative thermal dissociation of ClNO(2) in an inlet heated to 450 °C, relative to NO(2) observed in an unheated reference channel. ClNO(2) was generated by passing Cl(2) gas over a slurry containing a 1:10 mixture of NaNO(2) and NaCl. The TD-CRDS response was evaluated using parallel measurements of ClNO(2) by chemical ionization mass spectrometry (CIMS) using I(-) as the reagent ion and NO(y) (= NO + NO(2) + HNO(3) + ΣRO(2)NO(2) + ΣRONO(2) + HONO + 2N(2)O(5) + ClNO(2) + ...) chemiluminescence (CL). The linear dynamic range extends from the detection limit of 20 pptv (1 σ, 1 min) to 30 parts-per-billion by volume (ppbv), the highest mixing ratio tested. The ClNO(2) TD profile overlaps with those of alkyl nitrates, which has implications for nocturnal measurements of total alkyl nitrate (ΣAN = ΣRONO(2)) abundances by thermal dissociation (with detection as NO(2)) in ambient air.