cssi/SciSciGPT-SciSciNet huggingface dataset:
Avian Epidermal Lipids: Functional Considerations and Relationship to Feathering1

SYNOPSIS. The avian epidermis is composed of unique sebokeratinocytes that elaborate and secrete sebum-like lipids as they cornify. In addition to the lipid droplets, the avian epidermis elaborates, but rarely secretes, lipid—enriched organelles, the multigranular bodies. The multigranular bodies are analogous to the lamellar bodies of mammals (Menon et al., 1991), the secretion of which results in formation of occlusive lipid bilayers characteristic of mammalian stratum corneum and providing the permeability barrier. However, in contrast to mammals, the avian multigranular bodies form the reserve barrier mechanism. In the basal state, when multigranular bodies are not secreted, the avian cutaneous barrier is deficient, but allows evaporative cooling for thermoregulation. However, under conditions of water deficit, multigranular body secretion allows for rapid facultative waterproofing, as shown in zebra finches ( guttata). In certain glabrous regions of the skin, such as the maxillary rictus, interdigital web, and combs and wattles in the domestic fowl, there is a high degree of epidermal lipid secretion. Also specialized feathers such as powder downs elaborate lipid rich material, which can be classified as secretion. Additionally, an inverse relation between epidermal lipogenesis and the degree of feathering has been demonstrated, as in temporarily bare areas (e.g., brood patches) and following permanent feather loss from the head accompanying attainment of maturity in certain ibises and storks. In the latter, the neo-apteria often hold large reserves of carotenoids dissolved in the lipid droplets, possibly related to an altered gradient of retinoids influencing feather morphogenesis. Unusual secondary functions of epidermal lipids include cosmetic coloration (e.g., in the Japanese Crested Ibis) and chemical defense (e.g., in the Pitohui).
Studies on the structure of rabbit muscle aldolase. I. Cleavage with cyanogen bromide: an approach to the determination of the total primary structure.

Abstract S -Carboxymethylated aldolase was treated with CNBr to cleave the methionyl bonds and the products were separated by chromatography on Sephadex G-75. Five fractions were obtained, designated CnI to CnV according to their order of elution. All fractions except CnI were homogeneous in both N -terminal and C -terminal analyses. CnI was present only in 10% yield and appeared to be an aggregate of peptides. CnII had the N -terminal sequence Pro-His-, and was derived from the N -terminus of aldolase. CnIII, containing C -terminal tyrosine, was the only fragment devoid of homoserine, and was derived from the C -terminus of the enzyme. CnIV contained the Schiff base-forming lysine residue. CnV, with N -terminal sequence Val-Thr-Pro-, represented the overlapping peptide at the COOH-terminal side of this lysine (9). The sequence of the four fragments in the aldolase molecule has thus been deduced as: (NH 2 ) CnII-CnIV-CnV-CnIII (OH). Since aldolase contains 12 methionine residues, the present results confirm the 4-subunit structure of the enzyme. Fraction CnIII has been shown to contain 2 peptides derived from the C -termini of the α and β chains, and may represent the only region in which the 2 chains differ. The procedure has provided a means to locate in the molecule the functional groups involved in the manifestation of aldolase activity. The significance of this approach to the determination of the total primary structure of the enzyme is discussed.
And Then There Is This Thing Called the Curriculum Organization, Imagination, and Mind

Despite the long history of curriculum studies in the American Educational Research Association, few past presidents have used their presidential addresses to speak about the curriculum and its importance in education research and teaching. In this essay, I examined the presidential addresses (and paper) of three well-known curriculum theorists—Harold Rugg, Maxine Greene, and Eliot Eisner—to share their perspectives on the curriculum as a vehicle for public discourse and democratic engagement. The essay ends with a challenge to AERA members to continue to use the study of curriculum as a vehicle for democracy, civic participation, and a more equitable and just society.
Immunomodulatory Effects of Vitamin A on Balance of Th1/Th2 in Children with Type 1 Diabetes Mellitus

Objective To explore the influence of retinoic acid(RA),the metabolic product of vitamin A in vivo,on the balance of Th1/Th2 in children with type 1 diabetes mellitus(T1DM).Methods Totally 32 children with T1DM were taken as T1DM group,and 28 healthy children as healthy control group.Peripheral blood mononuclear cells(PBMC) were isolated from venous blood and made into cells suspension.PBMC of T1DM children were divided into 2 groups: T1DM group and vitamin A group.The supernatant was collected after 48 h.The levels of IFN-γ and IL-4 in the supernatant were determined by enzyme-linked immunosorbent assay(ELISA).SPSS 11.5 software was used to analyze the data.Results 1.IFN-γ level produced from PBMC in T1DM group was higher than that in healthy control group(P0.01),IFN-γ/IL-4 ratio was higher than that in healthy control group(P0.01),and there were no significant differences of the level of IL-4 between the 2 groups(P0.05).2.The level of IFN-γ produced from PBMC in vitamin A group was lower than that in T1DM group(P0.01),IFN-γ/IL-4 ratio was lower than that in T1DM group(P0.01),and the level of IL-4 was higher than that in T1DM group,but the difference was not statistically significant(P0.05).Conclusion Through inhibiting the function of Th1,vitamin A can restore the balance of Th1/Th2 in children with T1DM.
All together now: how and why scientific communities should develop best practice guidelines

Reproducibility in science—or the lack thereof—has garnered much attention in the past few years. On March 1, 2016, Molecular Biology of the Cell (MBoC) published a Perspective by Daniel Klionsky outlining the importance of scientific communities coming together to develop guidelines that could serve as “best practices” for their field (Klionsky, 2016 ). This Perspective was invited as a direct follow-up to one of several recommendations made by the American Society for Cell Biology (ASCB) Data Reproducibility Task Force in their white paper on enhancing rigor in basic research (American Society for Cell Biology, 2015 ). Here we highlight some of the benefits of community-based standards and describe how MBoC and ASCB can assist other scientific communities in developing best practices for their specific fields.
Efficacy of psychoeducational interventions on pain, depression, and disability in people with arthritis: A meta-analysis

Meta-analysis is a technique which combines data from several properly and similarly designed controlled studies so as to increase the power of the relevant statistical analysis. Fifteen studies on the effects of psychoeducational interventions on disability, pain and depression in individuals with chronic rheumatoid arthritis or osteoarthritis were analyzed by this method. The results indicate that patient education can indeed contribute to improving the health status of such patients.
Atomoxetine for ADHD.

Atomoxetine is more effective than placebo for treating symptoms of ADHD in children and adults, based on short-term studies. Given safety concerns (growth retardation, potential adverse effects in slow metabolizers) and its high cost, atomoxetine should be considered only as an alternative for patients who are intolerant or unresponsive to stimulant medications such as methylphenidate.
Regulation of Na+,K(+)-ATPase by aldosterone.

E ARLY investigators working on the mechanism of action of aldosterone in the toad bladder originally discarded the suggestion that mineralocorticoids upregulated net Na+ transport by inducing Na+,K+-ATPase. As one example, in 1973 Hill et al’ reported that at 2.5 hours after addition of aldosterone, short-circuit current (SCC, an index of net Na+ reabsorption in this tissue) was significantly increased over baseline values, but not the V,,, Na+,K+-ATPase activity associated with deoxycholate-treated membranes. More recent studies in the toad bladder by Park and Edelman2 have extended the time course of the analysis and determined that although 5 hours of aldosterone addition increased SCC fivefold, there was no augmentation of V,,, Na+,K+ATPase activity in membranes isolated from experimental versus control bladders unless the membranes were also treated with detergent during preparation. In the latter case, the stimulatory effect was small ( 13%). These authors went on to argue,3 however, that there was evidence for some change in the performance of existing Na+ pumps following acute aldosterone addition that was not mirrored by other substances that increased Na+ entry and SCC. In their study they used PCMPS (p-chloromercuriphenylsulfonate) or aldosterone to increase luminal Nat entry and found that aldosterone but not PCMPS increased the affinity of low doses of ouabain for Na+,K+-ATPase, suggesting to them some steroid-induced conformational change in the pump. They further argued that perhaps an aldosterone-induced protein (AIP) was responsible for this modification. A similar conclusion was reached by Rick et a1.4 When they added aldosterone or antidiuretic hormone (ADH) at concentrations and for times that gave equivalent changes in SCC, granular cell Na+i was much lower and K’i much higher
An agent-based modeling approach to creating more resilient littoral combat architectures

Littoral combat is a critical component of naval warfare that has gained importance since the late 20th century due to a shift from matched blue-water combat to agile, asymmetric warfare near the coast. With the increased relevance of this type of naval combat, the ability of a networked naval warfare System-of-Systems (SoS) to operate effectively given the challenges of operations in the littoral zone becomes imperative. Resilience in an SoS in the face of a variety of threats is vital. These threats may take various forms: traditional warfare, cyber attacks, or communications breakdowns. The challenge for any SoS practitioner is identifying such architectures from a vast design space. We define an architecture as the constituent systems in the SoS and the connections among these systems. We seek to apply an agent-based modeling approach to create an architecture evaluation tool that leverages the modular nature of an SoS to quickly conduct trade studies and analyses to identify architectures that are resilient to a variety of threats. The simulation tool is built on the principles of the Open Systems Architecture put forth by the Department of Defense (DoD). We present an analysis that seeks to find a suitable SoS architecture configuration that maintains operability and performance during the loss of command authorities. This loss can be attributed to battle casualties or other forms of threats including communications failures. We demonstrate that distributing managerial control in the architecture improves, to some extent, SoS performance in terms of time to threat elimination. This single analysis demonstrates how SoS practitioners can use agent-based models to quickly construct and evaluate potential architectures against a variety of threats and disruptions, ultimately building resilient SoS architectures that perform to prescribed levels even in the face of network failures and attacks.
A peptide-retrieval strategy enables significant improvement of quantitative performance without compromising confidence of identification

Abstract Reliable quantification of low-abundance proteins in complex proteomes is challenging largely owing to the limited number of spectra/peptides identified. In this study we developed a straightforward method to improve the quantitative accuracy and precision of proteins by strategically retrieving the less confident peptides that were previously filtered out using the standard target-decoy search strategy. The filtered-out MS/MS spectra matched to confidently-identified proteins were recovered, and the peptide-spectrum-match FDR were re-calculated and controlled at a confident level of FDR ≤ 1%, while protein FDR maintained at ~ 1%. We evaluated the performance of this strategy in both spectral count- and ion current-based methods. > 60% increase of total quantified spectra/peptides was respectively achieved for analyzing a spike-in sample set and a public dataset from CPTAC. Incorporating the peptide retrieval strategy significantly improved the quantitative accuracy and precision, especially for low-abundance proteins (e.g. one-hit proteins). Moreover, the capacity of confidently discovering significantly-altered proteins was also enhanced substantially, as demonstrated with two spike-in datasets. In summary, improved quantitative performance was achieved by this peptide recovery strategy without compromising confidence of protein identification, which can be readily implemented in a broad range of quantitative proteomics techniques including label-free or labeling approaches. Significance We hypothesize that more quantifiable spectra and peptides in a protein, even including less confident peptides, could help reduce variations and improve protein quantification. Hence the peptide retrieval strategy was developed and evaluated in two spike-in sample sets with different LC-MS/MS variations using both MS1- and MS2-based quantitative approach. The list of confidently identified proteins using the standard target-decoy search strategy was fixed and more spectra/peptides with less confidence matched to confident proteins were retrieved. However, the total peptide-spectrum-match false discovery rate (PSM FDR) after retrieval analysis was still controlled at a confident level of FDR ≤ 1%. As expected, the penalty for occasionally incorporating incorrect peptide identifications is negligible by comparison with the improvements in quantitative performance. More quantifiable peptides, lower missing value rate, better quantitative accuracy and precision were significantly achieved for the same protein identifications by this simple strategy. This strategy is theoretically applicable for any quantitative approaches in proteomics and thereby provides more quantitative information, especially on low-abundance proteins.
714. Gene Therapy Rescues Cone Function and Viability in an Rp2 Knockout Mouse Model for X-Linked Retinitis Pigmentosa Over a Wide Dose Range and a Broad Therapeutic Time Window

Retinitis pigmentosa (RP) refers to a diverse group of inherited retinal dystrophies characterized by a progressive loss of photoreceptors, resulting in vision impairment or blindness. The prevalence of the disease is 1 in 3,500 to 4,000 worldwide. X-linked RP (XLRP) accounts for ~15% of all RP cases and is one of the most severe forms of retinal degeneration. About 10% of the total XLRP cases are caused by mutations in the RP2 gene. A recently developed Rp2 knockout (Rp2-KO) mouse model exhibits early onset, progressive cone photoreceptor dysfunction and degeneration, mimicking early cone involvement in patients with RP2 mutations. To develop gene therapy for the disease, we generated and characterized a self-complementary AAV8 vector carrying the human RP2 expression cassette (AAV8-scRK-RP2), and examined its efficacy in the Rp2-KO mice. Our initial results demonstrated successful cone function rescue following subretinal administration of the vector to the mice (ASGCT 2014, poster#122). In the present study, we continued to examine the long term safety and efficacy of the vector using a broader dose range. Four to six week-old Rp2-KO mice received unilateral subretinal injections of the vector with doses ranging from 5×107 to 1×109 vector genomes (vg)/eye. The fellow eyes were injected with vehicle as controls. Retinal function was assessed by electroretinography (ERG) and optomotor test up to 18 months of age. Our results revealed significantly higher amplitude and faster recovery of cone ERG in vector-treated eyes than control eyes in almost all dose groups through the duration of monitoring starting from 4 months of age. In addition, remarkably better visual acuity was observed in the vector-treated eyes at 18 months of age. The treatment also reversed M-opsin mis-localization, restored cone PDE expression and maintained cone viability. Interestingly, this rescue was achieved in the Rp2-KO mice even when treated at 10-month of age, suggesting the potential benefit of the treatment to older patients. Retinal toxicity was only observed in mice receiving the highest vector dose (1×109 vg/eye), as reflected by reduced rod ERG amplitude and thinner photoreceptor layer. We conclude that our RP2 AAV vector can rescue cone function and viability over a wide dose range and a broad therapeutic time window, which paves the way for future clinical studies.
Practical considerations for chimeric antigen receptor design and delivery.

ABSTRACTIntroduction: The development of chimeric antigen receptor (CAR)-modified immune cells has become a highly active field of research since the introduction of this approach in 1989. New ideas are constantly being proposed and tested, resulting in CARs that are more effective and specialized.Areas covered: Many aspects of CAR design and administration can be varied in order to achieve the best possible outcomes; optimization of this therapeutic schema is an active area of research. Here, the authors summarize the work that has been carried out thus far to assess different adaptations for each portion of the CAR itself. They also discuss the various methods used for CAR transgene transfer into effector cells.Expert opinion: While the field has made significant advancements in terms of expansion and testing of the variations available for CAR therapy, it remains difficult to ascertain which options are truly superior and under what conditions. Continued research in this area, as well as in aspects suc...
Mechanical dyssynchrony of the left atrium during sinus rhythm is associated with history of stroke in patients with atrial fibrillation.

Aims We sought to evaluate the relationship between left atrial (LA) mechanical dyssynchrony and history of stroke or transient ischaemic attack (TIA) in patients with atrial fibrillation (AF). We hypothesized that mechanical dyssynchrony of the LA is associated with history of stroke/TIA independent of LA function and Cardiac failure, Hypertension, Age, Diabetes, Stroke/transient ischaemic attack (TIA), VAscular disease, and Sex category (CHA2DS2-VASc) score in patients with AF. Methods and results We conducted a cross-sectional study of 246 patients with a history of AF (59 ± 10 years, 29% female, 26% non-paroxysmal AF) referred for catheter ablation to treat drug-refractory AF who underwent preablation cardiac magnetic resonance (CMR) in sinus rhythm. Using tissue-tracking CMR, we measured the LA longitudinal strain and strain rate in each of 12 equal-length segments in two- and four-chamber views. We defined indices of LA mechanical dyssynchrony, including the standard deviation of the time to the peak longitudinal strain (SD-TPS). Patients with a prior history of stroke or TIA (n = 23) had significantly higher SD-TPS than those without (n = 223) (39.9 vs. 23.4 ms, P < 0.001). Multivariable analysis showed that SD-TPS was associated with stroke/TIA after adjusting for the CHA2DS2-VASc score, LA minimum index volume, and the peak LA longitudinal strain (P < 0.001). The receiver-operating characteristics curve showed that SD-TPS identified patients with stroke/TIA more accurately than CHA2DS2-VASc score alone (c-statistics: 0.82 vs. 0.75, P < 0.001). Conclusion Higher mechanical dyssynchrony of the LA during sinus rhythm is associated with a history of stroke/TIA in patients with AF.
Isometry-Aware Preconditioning for Mesh Parameterization

This paper presents a new preconditioning technique for large-scale geometric optimization problems, inspired by applications in mesh parameterization. Our positive semi-definite preconditioner acts on the gradients of optimization problems whose variables are positions of the vertices of a triangle mesh in ℝ2 or of a tetrahedral mesh in ℝ3, converting localized distortion gradients into the velocity of a globally near-rigid motion via a linear solve. We pose our preconditioning tool in terms of the Killing energy of a deformation field and provide new efficient formulas for constructing Killing operators on triangle and tetrahedral meshes. We demonstrate that our method is competitive with state-of-the-art algorithms for locally injective parameterization using a variety of optimization objectives and show applications to two- and three-dimensional mesh deformation.
Oral shedding of herpesviruses in HIV-infected patients with varying degrees of immune status.

Objective:Herpesvirus shedding in the oral cavity was analyzed to determine if presence in the oral compartment correlates with systemic changes in HIV-associated immune deficiency as measured by CD4+ cell counts, plasma HIV viral load and presence of AIDS-defining events.Design:A5254 is a multicent
Ischemic Stroke After Emergency Department Discharge for Symptoms of Transient Neurological Attack.

Background and Purpose:The significance of transient neurological attack (TNA) symptoms is unclear. We sought to determine the risk of ischemic stroke after discharge from the emergency department ...
Best PEEP trials are dependent on tidal volume.

Determining the optimal positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome remains an area of active investigation. Most trials individualizing PEEP optimize one physiologic parameter (e.g., driving pressure) by titrating PEEP while holding other ventilator settings constant. Optimal PEEP, however, may depend on the tidal volume, and changing the tidal volume with which a best PEEP trial is performed may lead to different best PEEP settings in the same patient. ClinicalTrials.gov, NCT02871102. Registered on 12 August 2016.
Translational Research Unit: Development of Nursing Standards and Practice Within a Specialized Unit for Participants in Early Phase Clinical Trials.

BACKGROUND A growing need exists to ensure safe and skilled oncology nursing care for an increasing number of patients enrolled in phases 1 and 1/2 clinical trials and to provide detailed adherence to protocol administration. This can be best accomplished in a dedicated area for patients in early phase clinical trials. OBJECTIVES Nursing standards and practice within a newly established translational research unit at an academic medical center were developed. METHODS A portion of an existing outpatient infusion room composed of 13 beds and a sub-waiting room with 2 chairs was designated for placement of patients enrolled in early phase clinical trials. The functional and safety requirements needed to successfully care for these patients while meeting the demands of the trial protocol drove the creation of this dedicated unit. FINDINGS Development of dedicated space provided opportunities to define the role of the nurse and hardwire patient and staff safety practices that assisted in reducing study deviations.
Primary biliary cirrhosis and systemic amyloidosis, a new association.

Amyloidosis is a heterogeneous group of disorders characterized by the extracellular deposition of proteins in an abnormal fibrillar pattern with pathognomonic applegreen birefringence under polarized light when stained with Congo red (1). Historically, these have been classified as “primary” or “secondary” amyloidosis. Primary amyloidosis (AL) represents the most common form of systemic amyloid deposition in the Western world and is typically associated with immunocyte dyscrasias such as multiple myeloma, lymphomas, macroglobulinemia, and “benign” monoclonal gammopathies (2). Secondary amyloidosis (AA) is associated with longstanding infectious or noninfectious inflammatory disorders and, less frequently, neoplastic disorders. Associated disorders include adult rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Reiter’s syndrome, systemic lupus erythematosus, systemic sclerosis, tuberculosis, leprosy, Castleman’s disease, bronchiectasis, cystic fibrosis, osteomyelitis, heroin abuse, psoriasis, inflammatory bowel disease, and Whipple’s disease (1, 2). Despite a strong association with chronic inflammatory disorders and AA, an extensive literature review did not reveal a previously reported association between primary biliary cirrhosis (PBC) and AA. In this case review, we report the first association of these two entities.
The Economic Community of West African States, Its Achievements and Prospects as Well As Challenges for the Future

This study looks at the factors that favored the economic integration under the auspices of Economic Community of West African States (ECOWAS). The information used in this study dates back to the inception of this regional trade agreement in May of 1975. In addition, the study also looks at the accomplishments and prospects as well as challenges for the future by investigating the political issues involved between the English speaking and French speaking member countries and the efforts made toward establishing a monetary union in West Africa. Finally, the statistical model utilized in this study embodied some of the previous findings of Linnermann (1966) and Deme (1995). It also embodied the statistical findings of Amponsah (2002) and Masson and Patillo (2001).
Breaking Free of Chevron's Constraints: Zuni Public School District et al. v. U.S. Department of Justice

Breaking Free of Chevron's Constraints: Zuni Public School District 89, et al. v. U.S. Department of Education analyzes the Supreme Court's latest review of an administrative interpretation under Chevron review, and concludes that the doctrine's exclusive focus on deciding "who gets to decide" led to a complete failure by the Court to consider the consequences of the agency interpretation at issue. Such a failure rendered the Court unprepared to accurately determine whether the agency interpretation was "permissible" under the second prong of Chevron review. As a solution, the article advocates for the replacement of Chevron's second prong with the more consequence-oriented arbitrary and capricious review. Although such a replacement limits agency discretion, it serves Chevron's underlying goal of ensuring that agency actions reflect Congressional intent. In light of the Court's recent administrative law decisions clarifying the parameters of Chevron review, the Zuni case offers an opportunity to consider the outer limits of the review doctrine and its accompanying deference. The article uses a case that highlights the intersection between administrative law and public education to further the debate about those parameters, and to present a situation in which decreased agency deference is particularly appropriate. Finally, the article draws attention not only to the necessity of a more rigorous review when the provision of adequate public education is at stake, but to the broader implications of a review schema that is overly deferential to agency action
Development of a Primary Human Cell Model for the Study of Human Cytomegalovirus Replication and Spread within Salivary Epithelium.

ABSTRACT Various aspects of human cytomegalovirus (HCMV) pathogenesis, including its ability to replicate in specific cells and tissues and the mechanism(s) of horizontal transmission, are not well understood, predominantly because of the strict species specificity exhibited by HCMV. Murine CMV (MCMV), which contains numerous gene segments highly similar to those of HCMV, has been useful for modeling some aspects of CMV pathogenesis; however, it remains essential to build relevant human cell-based systems to investigate how the HCMV counterparts function. The salivary gland epithelium is a site of persistence for both human and murine cytomegaloviruses, and salivary secretions appear to play an important role in horizontal transmission. Therefore, it is important to understand how HCMV is replicating within the glandular epithelial cells so that it might be possible to therapeutically prevent transmission. In the present study, we describe the development of a salivary epithelial model derived from primary human “salispheres.” Initial infection of these primary salivary cells with HCMV occurs in a manner similar to that reported for established epithelial lines, in that gH/gL/UL128/UL130/UL131A (pentamer)-positive strains can infect and replicate, while laboratory-adapted pentamer-null strains do not. However, while HCMV enters the lytic phase and produces virus in salivary epithelial cells, it fails to exhibit robust spread throughout the culture and persists in a low percentage of salivary cells. The present study demonstrates the utility of these primary tissue-derived cells for studying HCMV replication in salivary epithelial cells in vitro . IMPORTANCE Human cytomegalovirus (HCMV) infects the majority of the world’s population, and although it typically establishes a quiescent infection with little to no disease in most individuals, the virus is responsible for a variety of devastating sequelae in immunocompromised adults and in developing fetuses. Therefore, identifying the viral properties essential for replication, spread, and horizontal transmission is an important area of medical science. Our studies use novel human salivary gland-derived cellular models to investigate the molecular details by which HCMV replicates in salivary epithelial cells and provide insight into the mechanisms by which the virus persists in the salivary epithelium, where it gains access to fluids centrally important for horizontal transmission.
Guided delivery of the “alarming” cytokine IL-33 to tumor by chimeric antigen receptor T cells

Current immune checkpoint-based cancer therapy is limited by low levels of spontaneous antitumor T cells and immune suppressive microenvironment (TME). Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines and is released by damaged tissue cells or activated innate immune cells such as macrophages upon tissue damage or infection. Thus, IL-33 is thought to serve as an endogenous “alarming signal”, which triggers inflammation and cell-mediated immune responses in affected tissues. We have found that IL-33 is expressed in many normal human lining tissue cells but drastically down-regulated in advanced cancer cells indicating the role of IL-33 in inhibiting tumor progression. Thus, IL-33 is a candidate cytokine whose down-regulation is an important mechanism for tumor “immune ignorance”, which is crucial for immune evasion by cancer cells. Consistent with this idea, we have furthered shown that expression of IL-33 in tumor cells inhibit tumor growth. Thus, tumoral delivery of IL-33 can serve as a novel therapy for immune therapy of cancer. In the current study, we “armed” CAR T cells with IL-33 expression cassette, which allows guided IL-33 expression in the tumor site specifically. The antitumor efficacy and toxicity of such strategy is evaluated in a humanized mouse model. The data will show whether and how tumor-site delivery of IL-33 increases efficacy of CAR T cells and immunogenicity of the TME.
Internal Financial Expertise on the Board: Implications for Corporate Capital Structure

Corporate boards advise management on key strategic decisions of the firm including the firm’s financing policies. However, the degree to which they can perform this task hinges upon their level of access to and their understanding of firm-specific financial information. In this study, I examine the relations between firm financing decisions and whether or not their boards have an internal financial expert. I find larger firms and those with fewer growth options, where value creation through sophisticated management of capital structure is relatively more important, are more likely to have an internal financial expert on their board. Firms with internal financial expertise on their board exhibit greater financial flexibility as evident in their association with greater changes in leverage, higher frequency of debt issues and the greater use of short-term debt financing. I find no evidence these firms engage in greater M&A activity, though they are more likely to finance acquisitions with 100% cash. Finally, shareholders react favorably to the news of an internal financial expert’s appointment to their board. These findings illustrate the value of board internal financial expertise in managing firm capital structure and financing decisions in a manner beneficial to shareholders. This is especially important in the post-Sarbanes-Oxley era where firms are mandated to increase board outside financial expertise and, at least implicitly, forced to reduce the role of internal financial expertise on their boards.
Dual-band infrared imaging using stacked colloidal quantum dot photodiodes

Infrared multispectral imaging is attracting great interest with the increasing demand for sensitive, low-cost and scalable devices that can distinguish coincident spectral information. However, the widespread use of such detectors is still limited by the high cost of epitaxial semiconductors. In contrast, the solution processability and wide spectral tunability of colloidal quantum dots (CQDs) have inspired various inexpensive, high-performance optoelectronic devices. Here, we demonstrate a two-terminal CQD dual-band detector, which provides a bias-switchable spectral response in two distinct bands. A vertical stack of two rectifying junctions in a back-to-back diode configuration is created by engineering a strong and spatially stable doping process. By controlling the bias polarity and magnitude, the detector can be rapidly switched between short-wave infrared and mid-wave infrared at modulation frequencies up to 100 kHz with D* above 1010 jones at cryogenic temperature. The detector performance is illustrated by dual-band infrared imaging and remote temperature monitoring. Colloidal quantum dot detectors, switchable between short-wave infrared and mid-wave infrared, are demonstrated.
The slow-motion catastrophe of antimicrobial resistance and practical interventions for all prescribers.

All medical and surgical specialties depend on the pool of effective antibiotics that continues to evaporate because of the increasing prevalence of drug-resistant bacteria. Antimicrobial-resistant infections kill 700,000 patients every year. By 2050, they are projected to cause 10 million deaths per year at a cumulative global cost of $100 trillion. Professional societies and international health agencies, including the United Nations, have declared escalating antimicrobial resistance as one of the gravest and most urgent threats to global public health and issued calls for action. The propensity of bacteria to mobilize and share genetic resistance determinants across species and genera, record levels of conflict-driven human population displacement, and the dearth of new antibiotics and rapid diagnostic tests, along with climate change and the epidemic of opioid addiction, exacerbate the antimicrobial resistance crisis. The predominant cause of antibiotic resistance is exposure to antibiotics through appropriate and inappropriate use. Mindfulness, nudging by peers, and adjuncts and alternatives to antibiotics, such as phage therapies, microbiome-based therapies, and novel medical informatics applications, could help reduce antibiotic use. This article describes the antimicrobial resistance crisis and highlights points in the continuum of care in which clinicians can readily implement practical, no-cost changes to minimize antibiotic exposure.
In vivo synergy between trastuzumab (herceptin ® ) and larotaxel (RPR 109881A), a new taxoid.

1432 Larotaxel (RPR 109881A/XRP9881) is a taxoid, that is currently in development for breast cancer and other tumor types. Like docetaxel, it stabilizes microtubules, and has a broad spectrum of antitumor activity in taxane-sensitive tumors. In addition, it is active in vitro and in vivo against taxane-resistant tumors. In tumor-bearing mice, it was found to be active by the intravenous (iv) and oral route, and to cross the blood-brain barrier with activity against intracranial tumors (Proc AACR, 2004). The in vivo combinations of larotaxel with doxorubicin, cisplatin or vinorelbine were previously found synergistic (Proc AACR, 2005). We report here the preclinical in vitro and in vivo combination data of larotaxel with trastuzumab (herceptin®), using mammary UISO BCA-1, a human tumor model expressing Her2 and refractory in vivo to docetaxel. Larotaxel was first evaluated in vitro on human mammary UISO BCA-1 cell line, after a 96-hour incubation, using 14C-thymidine incorporation read-out. The IC50 of larotaxel (~ 3nM) was not significantly modified when combined to trastuzumab. Thereafter, in nude mice bearing UISO BCA-1, a 3 arm dose-response study was performed comparing the antitumor efficacy single agents and their combination. Mice bearing measurable (125 mg) tumors were treated iv with larotaxel (12.4, 20, 32.3 and 52.1 mg/kg/day, on days 17, 21, 25 post tumor implantation), or sc with trastuzumab (2.5, 10, 25 and 40 mg/kg/day, on days 17, 21, 25, 29). In the combination, each dose of larotaxel was combined with the dose-response of trastuzumab using the same schedule of administration as the single agents alone. Therapeutic synergism was declared when superior activity by at least 1 log cell kill (log CK = tumor growth delay / 3.32 x tumor doubling time) was observed with the combination in comparison with either of the single agents. At the Highest nonToxic Dose (HNTD) of 32.3 mg/kg/day (total dose 96.9 mg/kg), larotaxel, as a single agent, induced a 5% body weight loss (bwl) and was found active with a 1.3 log CK. Trastuzumab alone, at the highest dose tested, 40 mg/kg/day (total dose 160 mg/kg), was found inactive, although UISO BCA-1 xenografts overexpressed Her2. The HNTD of the combination (larotaxel at 32.3 mg/kg/day, with herceptin at 2.5 mg/kg/day), induced a 4 % bwl and exhibited a greater antitumor activity with 2.6 log CK, 6/8 complete regressions (regression below the limit of palpation) and 2/8 tumor free survivors on day 121. A good antitumor activity was maintained at the 5 combined dosages below the HNTD. In order to further explore this synergy between both agents, mechanistic studies are ongoing. In conclusion, the larotaxel- trastuzumab combination was found synergistic in mice bearing a human breast tumor refractory to docetaxel, as well as anthracycline and other agents. These data provide a good rationale for further clinical evaluation of this combination in breast cancer with Her2 overexpression.
Play and Movement in 6-Month-Old Infants Later Diagnosed with Autism: A Pilot Study

ABSTRACTIt is important to identify Autism Spectrum Disorder (ASD) early to alleviate its developmental impact. This pilot correlational study aimed to identify subtle differences in play and movem...
Sonothrombolysis: Effect of 220kHz insonation scheme

Introduction Ultrasound-enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis is under development as an adjuvant to ischemic stroke therapy. Methods Thrombolytic efficacy was evaluated for three 220-kHz US schemes, two pulsed insonation schemes (15 cycles, 68 µs pulse duration, 33% or 62.5% duty cycle) and an intermittent continuous wave (CW) insonation scheme (50 s active, 30 s quiescent) over a 30-min treatment period. In vitro measurements with flow were performed to assess thrombolysis using time-lapse microscopy. An in silico study using a finite-difference model of transcranial US propagation was performed to estimate the intracranial acoustic field as well as the temperature rise for each insonation scheme. Results Intracranial constructive interference was not reduced with pulsed US using a pulse length of 15 cycles compared to intermittent CW US. The 33.3% duty cycle pulsed US scheme reduced heating in the temporal bone as much as 60% relative to the intermittent CW scheme. All insonation schemes promoted sustained stable cavitation in vitro and augmented thrombolysis compared to rt-PA alone (p Conclusion These findings demonstrate that a 33.3% duty cycle pulsed US scheme with a 15-cycle burst can reduce bone heating and achieve equivalent thrombolytic efficacy as an intermittent CW scheme.
Optimal Feature Selection for Distributed Data-Driven Process Monitoring

Two methods are proposed in this article to address distributed data-driven process monitoring. The first method selects sensors and allocates these sensors among subsystems with the objective of o...
Alternative approaches for UAV dead reckoning based on the immunity paradigm

Abstract The immunity paradigm has been recently investigated as a potential solution to the problem of unmanned aerial vehicles (UAV) navigation when external sensor systems and information of opportunity are not available. The effectiveness of specialized immunity cells in memorizing the characteristics of invading antigens, as well as the characteristics of the response of the host organism, or the antibodies, represent the source of inspiration for the development of an on-board intelligent system, an artificial immune system (AIS). The AIS is expected to provide corrections to a simple dead reckoning algorithm, such that autonomous trajectory tracking control of a UAV can be maintained over extended periods of time. Variables that can characterize the dynamic state of the vehicle and can be measured exclusively with on-board sensors are assimilated to the antigens, while the antibodies consist of the adjustments applied to the integration algorithm, such that accurate estimations of vehicle position and velocity are obtained. The AIS is built as a collection of instantaneous values of antigens and corresponding antibodies, referred to as artificial memory cells. The AIS is constructed using data collected under nominal conditions, when all sensors and systems function correctly and vehicle position and velocity are available. Two alternative approaches for building and operating the AIS are implemented and investigated in this paper. One relies on providing corrections to the output and the other to the input of the integration scheme. The AIS for both scenarios have been generated and tested using the West Virginia University unmanned aerial systems simulation environment. Both alternative approaches have been demonstrated to achieve similar performance in terms of significantly improving the vehicle position and velocity estimation algorithm and leading to desirable trajectory tracking and mission completion.
A Prescriptive Model to Assess the Socio-Demographics Impacts of Resilience Improvements on Power Networks

Abstract This paper provides a prescriptive resilience modeling framework for power grids that can account for the socio-demographic impacts of system improvements in the case of hurricanes. The power infrastructure failure rate and recovery duration models are developed based on Hurricane Hermine power outage data obtained from the City of Tallahassee, FL. For the component failures, physical factors such as component type and age, and building age in the surrounding area were used. For the component restoration, factors such as component age, critical facilities, and land use characteristics are considered. Monte Carlo simulation is utilized to estimate the potential impacts of two resilience policy/investment decisions: 1) investment to renew infrastructure components, and 2) reducing the component restoration time for faster recovery. For each scenario, the time evolution of affected populations (i.e., percentage of population with power at any time) is broken into socio-economic categories such as income, age, and ethnicity. Due to significant impact of infrastructure and neighborhood age, the scenario simulation results indicated that lower income populations were affected more (i.e., higher percentage of residents lost power) due to the Hurricane Hermine. Hence, for social equity considerations, it can be recommended that policy makers should prioritize infrastructure investments over improving recovery operations within the available budget constraints. The scenario analysis results also indicate that infrastructure investments which spatially target lower income areas can provide reasonable resilience improvements across the board while significantly closing the recovery gap between lower and higher income populations.
Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1.

Background We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection. Objectives We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. Methods Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients' PBMCs. Results Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients' PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients' unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children. Conclusions Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.
Elucidating the Impact of Immunogenicity Assessment Postapproval: A Targeted Analysis of Immunogenicity Postmarketing Requirements and Commitments

Insufficient availability of data to evaluate immunogenicity incidence or clinical impact during regulatory review could require further evaluation postapproval. Through a keyword search of all postmarketing requirements and commitments (PMRs/PMCs) associated with products with their original US Food and Drug Administration (FDA) approvals between 2009 and 2018, we identified products that had PMRs/PMCs established to address concerns or uncertainty related to immunogenicity. Of the 113 relevant products, 50% had an immunogenicity-related PMR/PMC; of these, 68% were related to developing immunogenicity assays and 48% requested an assessment of clinical impact. Fifty-five percent of the products with a fulfilled PMR/PMC had a change in the immunogenicity information in their labeling immediately following fulfillment. This work highlights that there are often unknowns associated with immunogenicity incidence and/or impact at the time of approval. Earlier regulatory discussions on immunogenicity assessments in premarket development could improve the understanding and communication of the risk/benefit profile and reduce the need for some immunogenicity PMRs/PMCs.
Evaluation of udder health parameters of organic and conventional dairy herds in Minnesota

The National Organic Program emphasizes the importance of disease prevention and does not allow organic dairy herds to use antimicrobials for dry cow therapy or for treatment of clinical mastitis. At present, little is known about the impact of these regulations on udder health or management practices on organic dairies in Minnesota. The objectives of this pilot study were to describe bulk-tank somatic cell and bacteria counts, udder health variables, and milking and udder health management practices of organic and conventional dairy herds in Minnesota, and to compare udder health variables and management practices between organic and conventional herds.