cssi/SciSciGPT-SciSciNet huggingface dataset:
An analysis of venom ontogeny and prey-specific toxicity in the Monocled Cobra (Naja kaouthia).

Venoms of snakes of the family Elapidae (cobras, kraits, mambas, and relatives) are predominantly composed of numerous phospholipases A2 (PLA2s) and three-finger toxins (3FTxs), some of which are lethal while others are not significantly toxic. Currently, the only identified prey-specific toxins are several nonconventional 3FTxs, and given the large diversity of 3FTxs within Monocled Cobra (Naja kaouthia) venom, it was hypothesized that several 3FTxs, previously found to be non-toxic or weakly toxic 3FTxs in murine models, could potentially be toxic towards non-murine prey. Additionally, it was hypothesized that ontogenetic dietary shifts will be correlated with observable changes in specific 3FTx isoform abundance. Adult and juvenile N. kaouthia venom composition was investigated using ion-exchange FPLC, 1D and 2D SDS-PAGE, mass spectrometry, and various enzymatic and LD50 assays. Alpha-cobratoxin (α-elapitoxin) was the only significantly toxic (LD50 < 1 μg/g) 3FTx found in N. kaouthia venom and was equally toxic toward both lizard and mouse models. The abundance and diversity of 3FTxs and most enzyme activities did not vary between adult and juvenile cobra venoms; however, total venom PLA2 activity and specific PLA2 isoforms did vary, with juveniles lacking several of the least acidic PLA2s, and these differences could have both biological (related to predation) and clinical (antivenom efficacy) implications. Nevertheless, the ubiquitous presence of α-cobratoxin in both adult and juvenile cobra venoms, with high toxicity toward both reptiles and mammals, represents a venom compositional strategy wherein a single potent toxin effectively immobilizes a variety of prey types encountered across life history stages.
Is it enough to drain the heaviest bottlenecks

This paper takes a philosophically new approach to throughput-optimal scheduling queueing systems with interference. All existing popular approaches (e.g. max-weight, greedy, ”pick-and-compare” etc.) focus on the weights of individual queues. We take an alternative approach, by focusing instead on the aggregate queues of bottlenecks. A bottleneck is a set of mutually-interfering queues; a schedule drains a bottleneck if it removes a packet from any one of its queues. We consider (the standard) switch scheduling problem, where the bottlenecks are the nodes. We establish the following phasetransition (1) ensuring only that the very heaviest nodes are drained is not enough for throughput optimality, but (2) ensuring scheduling for all nodes with weight within (1 − α) of the heaviest is enough for throughput optimality, for any α>0. The proof uses a new Lyapunov function: the weight of the critical bottleneck. Our alternate node-focused view also enables the development of new algorithms for scheduling. We show (a) how any policy can be made throughput-optimal by doing a small number of extra operations, (b) a new algorithm — Maximum Vertex-weighted Matching (MVM) — has (empirical) delay performance better than the current state of the art, and lower complexity than Max-(edge)weighted Matching, and (c) a class o f throughput-optimal policies that trade off between complexity and delay.
Notions of centrality in consensus protocols with structured uncertainties

We introduce new insights into the network centrality based not only on the network topology but also on the network dynamics. The focus of this paper is on the class of uncertain linear consensus networks in continuous time, where the network uncertainty is modeled by structured additive Gaussian white noise input on the update dynamics of each agent. The performance of the network is measured by the expected dispersion of its states in steady-state. This measure is equal to the square of the ℍ 2 -norm of the network, and it quantifies the extent by which its state is away from the consensus state in steady-state. We show that this performance measure can be explicitly expressed as a function of the Laplacian matrix of the network and the covariance matrix of the noise input. We investigate several structures for the noise input and provide engineering insights on how each uncertainty structure can be relevant in real-world settings. Then, a new centrality index is defined to assess the influence of each agent or link on the network performance. For each noise structure, the value of the centrality index is calculated explicitly, and it is shown that how it depends on the network topology as well as the noise structure. Our results assert that agents or links can be ranked according to this centrality index and their rank can drastically change from the lowest to the highest, or vice versa, depending on the noise structure.
The role of ancillary tests in the evaluation and management of patients with negative and non‐diagnostic pancreatic cyst aspirates

Background Fine needle aspiration of pancreatic cystic lesions has its limitations as the cytology is often paucicellular to acellular. This study reports on the value of ancillary tests, amylase and carcinoembryonic, in the evaluation and management of patients with negative and non-diagnostic pancreatic cysts. Methods From January 1, 2010 through December 31, 2015, the Cytopathology Laboratory processed 119 pancreatic cyst aspirates of which 51(43%) were negative and 52(44%) were non-diagnostic and form the basis of this study. The 103 patients, 66 men and 37 women underwent endoscopic ultrasound with fine needle aspiration and biochemical and biomarker analysis; amylase and carcinoembryonic antigen, of cyst contents. In this study, the cytologic findings were interpreted independent of the cyst fluid analysis. Results Of the 51 patients with negative pancreatic cyst aspirates, combined endoscopic ultrasound/cytology/cyst fluid analysis findings were compatible with 37 (72%) pseudocysts, 11 (22%) serous cystadenomas, and 3 (6%) intraductal papillary mucinous neoplasms. Of the 52 patients with non-diagnostic pancreatic cyst aspirates, combined endoscopic ultrasound/cyst fluid analysis findings were compatible with 17 (33%) pseudocysts, 17 (33%) serous cystadenomas, 14 (27%) intraductal papillary mucinous neoplasms, and 4 (7%) mucinous cystic neoplasms. Eight patients underwent surgical resection and the remaining 95 patients were managed medically with repeat imaging. Conclusion Ancillary tests are of added benefit in the evaluation and management of patients with negative and non-diagnostic pancreatic cyst aspirates. Diagn. Cytopathol. 2017;45:303-307. © 2016 Wiley Periodicals, Inc.
A History of Acute Care Surgery (Emergency Surgery)

The broader field of surgery has made significant strides over the past two decades in both the understanding of surgical disease as well as in the technical conduct of operations. However, a significant portion of surgical patients present with “time-sensitive surgical disease” requiring immediate evaluation and management, often at times of the day or in clinical settings in which a specialist is not immediately available [1]. As the number of surgeons trained and willing to provide comprehensive care for this population has declined while the clinical need continues to increase, the specialty of Acute Care Surgery (ACS; referred to as Emergency Surgery in Europe) was proposed by the American Association for the Surgery of Trauma (AAST). At its inception, ACS was initially comprised of trauma, emergency general surgery, and critical care. As the specialty has begun to mature, it has expanded its focus to include elective general surgery and surgical rescue (Fig. 2.1).
Gender Differences in Psychiatry

There are important gender differences in the epidemiology of psychiatric disorders and in the effects of drugs used to treat these disorders. Women are major consumers of psychotropic drugs, but they have often been excluded from drug trials that establish tolerability and dose parameters. Because women have a higher proportion of adipose tissue than men, higher plasma drug concentrations and longer elimination half-lives can occur in women. In this review, gender differences are examined for the most prevalent diagnoses with a tradition of pharmacological responsivity. Anxiety disorders are generally more common in women, although social phobia and post-traumatic stress dis order may have an equal gender distribution. Obsessive-compulsive disorder has a slight preponderance in women, while patients with generalised anxiety disorder and panic disorder are predominantly women. Benzodiazepines that undergo conjugation appear to have a longer elimination time in women, and concomitant administration of oral contraceptives can decrease clearance of these drugs. Women are twice as likely to have a major depression and equally likely to have bipolar disorder as men. However, women are overrepresented in the rapid cycling variant of bipolar disorder. Gender data on antidepressant response are mixed, but women are more vulnerable to lithium-induced hypothyroidism. Men and women have equal risk for schizophrenia, but vary in terms of clinical features such as premorbid functioning, age of onset and outcome. Women tend to require lower dosages of antipsychotics, experience a greater improvement in symptoms when receiving these drugs, but are at a higher risk of developing tardive dyskinesia. The incidence of eating disorders (anorexia nervosa and bulimia nervosa) is higher in females than in males. Future attention to gender differences will improve the diagnosis of, allow for more accurate prognosis of, and promote individually designed interventions for psychiatric disorders.
Interactions, Transformations, and Bioavailability of Nano-Copper Exposed to Root Exudates

Due to the potential for interactions between crop plants and engineered nanomaterials (ENMs), there is increasing interest in understanding the bioavailability and effects of ENMs released into soil systems. Here, we investigate the influence of root exudates on the fate of ENMs from a thermodynamic perspective. Nano isothermal titration calorimetry was applied to determine thermodynamic parameters for the interaction between nanocopper (nCu) and synthetic root exudate (SRE) and its components (including sugars, organic acids, amino acids, and phenolic acids), as well as Cu2+ and SRE. The measured binding constant (Kd = 5.645 × 103 M–1) indicated strong interactions between nCu particles and SRE, as well as with individual organic acids. The interaction between Cu2+ and SRE was stronger (Kd = 7.181 × 104 M–1) but varies for the individual SRE components. nCu dissolution in the presence of SRE was the predominant interaction. In addition, SRE resulted in a complex transformation of nCu, where Cu2+, Cu+, a...
Infliximab Pharmacokinetics are Influenced by Intravenous Immunoglobulin Administration in Patients with Kawasaki Disease.

Infliximab, a monoclonal antibody directed against tumor necrosis factor-α, is being evaluated as adjunctive therapy to intravenous immunoglobulin (IVIG) for treatment of young children with acute Kawasaki disease (KD). The aim of this study was to develop a population pharmacokinetic (PopPK) model for infliximab in children with KD, and to evaluate the impact of covariates on infliximab disposition. Specifically, we wanted to investigate the effect of body weight and IVIG administration on PK parameters. In the current PopPK analysis, 70 subjects with a median (interquartile range) age of 2.9 years (1.3–4.4) were included from two randomized controlled trials. Infliximab concentration–time data were best described by a two-compartment model with first-order elimination using non-linear mixed-effects modeling (NONMEM 7.3). The clearance, volume of distribution of the central (V1) and peripheral (V2) compartment, and intercompartmental clearance estimates (95% confidence interval) from the PopPK analysis were 0.117 (0.091–0.134) L/day, 0.801 (0.545–0.960) L, 0.962 (0.733–1.759) L, and 0.692 (0.482–1.779) L/day, respectively. Allometric body weight was included on all parameters of the structural model and a covariate analysis revealed that administering infliximab after IVIG, as opposed to before, resulted in a 50% decrease in V2. Our study shows that the timing of infliximab administration relative to IVIG administration affects the disposition of the monoclonal antibody. These results may have important implications for other monoclonal antibodies administered in combination with IVIG for treating inflammatory diseases.
Multitasking roles of the mammalian deacetylase SIRT6

Abstract Sirtuins (SIRT) are highly conserved proteins first described as nicotinamide adenine dinucleotide (NAD+)-dependent type III histone deacetylases. They are the mammalian homologs of the SIR2 gene found in yeast. Seven homologs (SIRT1–7) have been described, all sharing an NAD+ binding catalytic domain comprising 275 amino acids and variable N and C termini. This difference in their terminal domains dictates distant roles and cellular localization of the members of the sirtuin family. In this review, we will focus on the chromatin deacetylase SIRT6, a multitasking protein with various roles in metabolism, development, DNA repair, and cancer. We will provide current knowledge in the context of its structure, enzymatic activity, and regulation. We will discuss its role in genomic stability and DNA repair, metabolism, and development. Finally, we will review SIRT6’s involvement in several diseases.
On Unknown Opportunities and Perils: Reflections on Carrier and Minniti's 'Biologics: The New Antitrust Frontier'

In their forthcoming article "Biologics: The New Antitrust Frontier," Michael Carrier and Carl Minniti predict what antitrust problems will arise from conduct on the part of biologic and biosimilar drug manufacturers in the near future, and how these problems will differ (in terms of frequency and severity) from the more familiar issues arising from the discovery, regulation, and marketing of small-molecule compounds. In this responsive essay I argue that, while there are certain types of cases the frequency of which in this context we can predict with a fair degree of confidence, and for which courts have more-or-less standard analytical frameworks available, precisely how various possible threats to innovation and competition will play out in the years to come remains to some degree both unknown and unknowable. The frontier beyond the frontier remains ever elusive.
The Role of Syntax and the Lexicon in Phonology

This chapter discusses two factors that control the application of a phonological rule: the phonetic properties comprising the feature matrixes of segments and the derivational source of a segment. There are other essentially nonphonetic factors that may govern the application of a rule and play a significant role in forming the phonological structure of a language. The nonphonetic factors influencing the application of a phonological rule fall into two broad categories. First, there are extra-grammatical factors because they fall outside of “grammar” as this term has been normally understood in generative as well as in most other theories of linguistics. Although most linguists have acknowledged the importance of these factors, they have been studied least of all. The second nonphonetic factor influencing the application of phonological rules is grammatical information, which is divided into two broad categories—syntactic/morphological versus lexical. The former represents information that is independently needed in the grammar to describe the syntactic or morphological structure of morphemes and words, while the latter represents information that, while not independently motivated, is required to provide a full description of the phonological behavior of a morpheme.
On Conceptual and Technical Integrity in Psychoanalysis and Behavior Therapy

American psychology has long been polarized with respect to the nature and role of unconscious mental processes. If early metaphysical behaviorists steadfastly rejected both unconsciousness and consciousness, psychoanalysts resolutely continued to espouse a complex structure of unconscious mental processes (Shevrin & Dickman, 1980). At the intellectual level, it is reasonable to conclude that the mutual antagonism between behavior therapy and psychoanalysis that characterized the early development of behavior therapy stemmed in part from this dichotomy. At a more pragmatic level, there were other driving forces.
For Labor, Race, and Liberty: George Edwin Taylor, His Historic Run for the White House, and the Making of Independent Black Politics

Review of: "For Labor, Race, and Liberty: George Edwin Taylor, His Historic Run for the White House, and the Making of Independent Black Politics," by Bruce L. Mouser.
Extreme Ultraviolet Emission from Neutron Stars

We summarize the detections of extreme ultraviolet (EUV) emission from neutron stars. Three firm detections have been made of spin-powered pulsars: the aged millisecond pulsar PSR J0437-4715, the middle-aged X-ray pulsar Geminga, and the radio pulsar PSR B0656+14. These observations allow us to evaluate both power-law and thermal-law emission models as the source of the EUV flux. For the case of PSR B0656+14 the lack of flux modulation with pulse period argues that the EUV radiation originates from the cooling neutron star surface rather than from a hot polar cap. If the emission is from a thermalized neutron star surface, then limits can be placed on the surface temperature. For the case of Geminga we can explain the observed EUV flux using thermal models that are consistent with standard neutron cooling scenarios. We also have a weak indication that the EUV emission from Geminga is pulsed in a manner consistent with the lowest energy channel observed with Rosat. For the case of the millisecond pulsar PSR J0437-4715 standard neutron star cooling models require surface re-heating. We compare different heating models to the data on this object. We rule out re-heating by crust-core friction, and find that models for the accretion from the interstellar medium, accretion from the white dwarf companion and a particle-wind nebula do not account for the EUV luminosity. Models of pulsar re-heating by magnetic monopole catalysis of nucleon decay are used to establish new limits to the flux of monopoles in the Galaxy. A single power-law source with properties derived from X-ray data cannot explain the EUV flux from PSR J0437-4715. The strongest model for explaining the EUV emission consists of a large ∼ 3 km2 polar cap heated from particle production in the pulsar magnetic field. We consider the prospects for detecting other neutron stars in the extreme ultraviolet.
Bayes/Orthodox Comparisons

Our purpose in this chapter is to compare empirically the performance of Bayes and orthodox approaches to regression and related problems. Specifically, I treat the problem of identifying the degree of a polynomial and the order of a Markov chain. When we raise the degree of a polynomial or the order of a Markov chain, we improve the model’s accuracy at the cost of some simplicity. According to the Bayesian analysis of Chapter 5, there is a well-defined rate of exchange that must be exceeded for the average likelihood (or support) of the model to increase. The exact average likelihoods are computable in both cases. It is worth stressing that the Bayesian approach to such problems is unified: one compares average likelihoods. By contrast, orthodox statistics offers us a mixed bag of tricks with no single (or simple) underlying logic.
Iodosylbenzene Coordination Chemistry Relevant to Metal–Organic Framework Catalysis

Hypervalent iodine compounds formally feature expanded valence shells at iodine. These reagents are broadly used in synthetic chemistry due to the ability to participate in well-defined oxidation–r...
Simulation of quantum many-body systems on Amazon cloud

Abstract Quantum many-body systems (QMBs) are some of the most challenging physical systems to simulate numerically. Methods involving approximations for tensor network (TN) contractions have proven to be viable alternatives to algorithms such as quantum Monte Carlo or simulated annealing. However, these methods are cumbersome, difficult to implement, and often have significant limitations in their accuracy and efficiency when considering systems in more than one dimension. In this paper, we explore the exact computation of TN contractions on two-dimensional geometries and present a heuristic improvement of TN contraction that reduces the computing time, the amount of memory, and the communication time. We run our algorithm for the Ising model using memory optimized x1.32x large instances on Amazon Web Services (AWS) Elastic Compute Cloud (EC2). Our results show that cloud computing is a viable alternative to supercomputers for this class of scientific applications.
Association of Chronic Kidney Disease with Preserved Ejection Fraction Heart Failure Is Independent of Baseline Cardiac Function.

BACKGROUND/AIMS Chronic kidney disease (CKD) is common among patients with heart failure with preserved ejection fraction (HFpEF) and is associated with worse clinical outcomes. This study aims to identify whether the association of CKD with HFpEF is independent of underlying echocardiographic abnormalities. MATERIALS We conducted a retrospective cohort study including patients without prevalent heart failure referred for echocardiography. Patients with serial echocardiograms, baseline left ventricular ejection fraction (LVEF) ≥50% and estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2 were matched 1:1 with patients with eGFR <60 mL/min/1.73 m2 for age (±5 years), sex, history of hypertension or diabetes, use of renin-angiotensin inhibitors, and LVEF (±5%). A secondary analysis included patients with preserved LVEF and normal left ventricular mass index matched for the same parameters except use of renin-angiotensin inhibitors. RESULTS Patients with CKD were at increased risk for HFpEF admission: crude hazard ratio (HR) 1.79 (95% confidence interval [CI] 1.38-2.32, p < 0.001) and adjusted HR (for coronary disease, loop diuretics, left atrial diameter) 1.64 (95% CI 1.22-2.21, p = 0.001). LVEF and left ventricular diameter decreased over time in both groups but no difference was observed in rate of dropping. Results were similar in the secondary analysis (crude HR 1.99, 95% CI 1.07-3.71, p = 0.03 and HR adjusted for left atrial diameter 1.98, 95% CI 1.05-3.75, p = 0.04). Rate of change was similar for LVEF, pulmonary artery pressure, and left ventricular mass index in both groups. CONCLUSION CKD is independently associated with incident HFpEF despite a similar change in relevant echocardiographic parameters in patients with or without CKD.
A Global Analysis of Dust Diurnal Variability Using CATS Observations

Abstract. The current study investigates the diurnal cycle of dust loading across the global tropics, sub-tropics, and mid-latitudes by analyzing aerosol extinction and typing profiles observed by the Cloud-Aerosol Transport System (CATS) lidar aboard the International Space Station. According to the comparison with ground-based and other satellite observations, CATS aerosol and dust loading observations exhibits reasonable quality and insignificant day-night inconsistency, thereby supporting the current analysis of dust diurnal cycle using CATS data. Based on an analysis of variance analytical framework, statistically significant diurnal variability in dust loading is identified over key dust sources, including the Bodele depression, West African El Djouf, Rub-al Khali desert, and western and southern North America, confirming the previous observation-based findings regarding the diurnal cycle of dust emission and underlying meteorological processes in these regions. Insignificant annual mean dust diurnal variability is identified over the Iraqi, Thar, and Taklamakan deserts. The currently identified significant diurnal cycles in dust loading over the rainforests in Amazon and tropical southern Africa, and drylands in South America and the central Australia, are hypothesized to be driven by enhanced dust emission due to wildfires and enhanced katabatic and frontal winds, respectively.
Reducing FPGA Compile Time with Separate Compilation for FPGA Building Blocks

Today's FPGA compilation is slow because it compiles and co-optimizes the entire design in one monolithic mapping flow. This achieves high quality results but also means a long edit-compile-debug loop that slows development and limits the scope of design-space exploration. We introduce PRflow that uses partial reconfiguration and an overlay packet-switched network to separate the HLS-to-bitstream compilation problem for individual components of the FPGA design. This separation allows both incremental compilation, where a single component can be recompiled without recompiling the entire design, and parallel compilation, where all the components are compiled in parallel. Both uses reduce the compilation time. Mapping the Rosetta Benchmarks to a Xilinx XCZU9EG, we show compilation times reduce from 42 minutes to 12 minutes (one case from 160 minutes to 18 minutes) when running on top of commercial tools from Xilinx. Using Symbiflow (Project X-Ray/Yosys/VPR), we show preliminary evidence we can further reduce most compile times under 5 minutes, with some components mapping in less than 2 minutes.
Multi-modal imaging reveals differential brain volumetric, biochemical, and white matter fiber responsivity to repeated intermittent ethanol vapor exposure in male and female rats.

Abstract A generally accepted framework derived predominately from animal models asserts that repeated cycles of chronic intermittent ethanol (EtOH; CIE) exposure cause progressive brain adaptations associated with anxiety and stress that promote voluntary drinking, alcohol dependence, and further brain changes that contribute to the pathogenesis of alcoholism. The current study used CIE exposure via vapor chambers to test the hypothesis that repeated episodes of withdrawals from chronic EtOH would be associated with accrual of brain damage as quantified using in vivo magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS). The initial study group included 16 male (~325g) and 16 female (~215g) wild-type Wistar rats exposed to 3 cycles of 1-month in vapor chambers + 1 week of abstinence. Half of each group (n = 8) was given vaporized EtOH to blood alcohol levels approaching 250 mg/dL. Blood and behavior markers were also quantified. There was no evidence for dependence (i.e., increased voluntary EtOH consumption), increased anxiety, or an accumulation of pathology. Neuroimaging brain responses to exposure included increased cerebrospinal fluid (CSF) and decreased gray matter volumes, increased Choline/Creatine, and reduced fimbria-fornix fractional anisotropy (FA) with recovery seen after one or more cycles and effects in female more prominent than in male rats. These results show transient brain integrity changes in response to CIE sufficient to induce acute withdrawal but without evidence for cumulative or escalating damage. Together, the current study suggests that nutrition, age, and sex should be considered when modeling human alcoholism.
Gene signature of antigen processing and presentation machinery (APM) as highly predictive of response to checkpoint blockade in lung cancer and melanoma.

3121Background: Treatment of non-small cell lung cancer (NSCLC) with immune checkpoint blockade (ICB) has resulted in striking clinical responses, but only in a subset of patients (pts), underscori...
Cabozantinib Unlocks Efficient In Vivo Targeted Delivery of Neutrophil-Loaded Nanoparticles into Murine Prostate Tumors

A major barrier to the successful application of nanotechnology for cancer treatment is the suboptimal delivery of therapeutic payloads to metastatic tumor deposits. We previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anticancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of BSA-coated polymeric nanoparticles (BSA-NPs) into murine PTEN/p53-deficient prostate tumors. On the basis of the observation that BSA coating of NPs enhanced association and internalization by activated neutrophils by approximately 6-fold in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pretreated with cabozantinib. Flow cytometric analysis revealed an approximately 4-fold increase of neutrophil-associated BSA-NPs and an approximately 32-fold increase in mean fluorescent dye uptake following 3 days of cabozantinib/BSA-NP administration, relative to BSA-NP alone. Strikingly, neutrophil depletion with Ly6G antibody abolished dye-loaded BSA-NP accumulation within tumors to baseline levels, demonstrating targeted neutrophil-mediated intratumoral NP delivery. Furthermore, we observed an approximately 13-fold decrease in accumulation of BSA-NPs in the liver, relative to uncoated NPs, post-cabozantinib treatment, suggesting that BSA coating of NPs can significantly enhance cabozantinib-induced, neutrophil-mediated targeted intratumoral drug delivery, while mitigating off-target toxicity. Collectively, we demonstrate a novel targeted nano-immunotherapeutic strategy for enhanced intratumoral delivery of BSA-NPs, with translational potential to significantly augment therapeutic indices of cancer medicines, thereby overcoming current pharmacologic barriers commonly encountered in preclinical/early-phase drug development.
Reduced calcium storage blunts calcium signaling in Toxoplasma bradyzoites and impedes motility and egress

Abstract Toxoplasma gondii has evolved different developmental stages of tachyzoites for disseminating during acute infection and bradyzoites for establishing chronic infection. Calcium ion (Ca2+) signaling tightly regulates the lytic cycle of tachyzoites by controlling microneme secretion and motility to drive egress. However, the roles of Ca2+ signaling pathways in bradyzoites remain largely unknown. Here we show that Ca2+ signals and egress by bradyzoites in response to agonists are highly restricted. Development of dual-reporter parasites revealed dampened calcium responses and minimal microneme secretion by bradyzoites induced in vitro or harvested from infected mice and tested ex vivo. Ratiometric Ca2+ imaging demonstrated lower Ca2+ basal levels, reduced magnitude, and slower Ca2+ kinetics in bradyzoites compared with tachyzoites stimulated with agonists. Diminished responses in bradyzoites were associated with down-regulation of calcium ATPases involved in intracellular Ca2+ storage in the endoplasmic reticulum (ER) and acidocalcisome. Once liberated from cysts by trypsin digestion, bradyzoites displayed weaker gliding motility associated with Ca2+ oscillations compared with tachyzoites, although gliding motility of bradyzoites was enhanced by uptake of exogenous Ca2+. Collectively, our findings indicate that bradyzoites exhibit dampened Ca2+ signaling due to a decreased amount of stored Ca2+, limiting microneme secretion and egress, likely constituting an adaptation to their long-term intracellular niche.
Resource planning for direct fabrication of customized orthopedic implants using EBM technology

Abstract Medical innovations and patient expectations are pushing healthcare toward personalized medicine. In orthopedics, the concept of patient-specific implants could be economically realized with the use of additive manufacturing. Knee and hip replacements are some of the most common musculoskeletal procedures performed in the United States. Joint replacement implants are typically offered in standard sizes and geometries. The mass customization of theses prostheses, however, can improve patient outcomes and reduce medical costs. Mass customization is not economically feasible with traditional manufacturing methods because of the high fixed tooling costs for each geometry. The freedom of design offered by additive manufacturing presents a viable production alternative for unique personal geometry. The objective of this paper is to develop two new analytic models that can be used to investigate a complex additive manufacturing supply chain. The focus of the model is to provide planning tools and a methodology for the direct production of customized orthopedic implants using electron beam melting, an additive manufacturing technology. First, a production model for an additive manufacturing-based system is created. Next, resource planning for a single customized implant system is performed using a simulation model. A queuing model is developed for rapid systems analysis. The staffing requirement predictions of the two models align closely for production of a singular, customized implant. A detailed systems analysis of an additive manufacturing supply chain is conducted to illustrate the use of these models. The queueing model is analytically tractable, so it is extended to describe the production of standard and customized versions of multiple implant families.
End-to-End Risk Budgeting Portfolio Optimization with Neural Networks

Portfolio optimization has been a central problem in finance, often approached with two steps: calibrating the parameters and then solving an optimization problem. Yet, the two-step procedure sometimes encounter the ``error maximization'' problem where inaccuracy in parameter estimation translates to unwise allocation decisions. In this paper, we combine the prediction and optimization tasks in a single feed-forward neural network and implement an end-to-end approach, where we learn the portfolio allocation directly from the input features. Two end-to-end portfolio constructions are included: a model-free network and a model-based network. The model-free approach is seen as a black-box, whereas in the model-based approach, we learn the optimal risk contribution on the assets and solve the allocation with an implicit optimization layer embedded in the neural network. The model-based end-to-end framework provides robust performance in the out-of-sample (2017-2021) tests when maximizing Sharpe ratio is used as the training objective function, achieving a Sharpe ratio of 1.16 when nominal risk parity yields 0.79 and equal-weight fix-mix yields 0.83. Noticing that risk-based portfolios can be sensitive to the underlying asset universe, we develop an asset selection mechanism embedded in the neural network with stochastic gates, in order to prevent the portfolio being hurt by the low-volatility assets with low returns. The gated end-to-end with filter outperforms the nominal risk-parity benchmarks with naive filtering mechanism, boosting the Sharpe ratio of the out-of-sample period (2017-2021) to 1.24 in the market data.
Electric Vehicles and the Electric Grid

In order to decarbonize the transport sector and to reduce the reliance on fossil fuels, it is expected that large fleets of plug-in electric vehicles (PEVs) will constitute an important share of the electricity demand in the not-so-distant future. These devices can and would behave as any regular demand if they are allowed to charge as soon as they are connected to the electric grid. If such charging process is allowed, then several adverse impacts on the power grids such as increased system-wide peak demand and early reinforcements of the distribution, transmission, and/or generation systems would be required. However, as opposed to conventional demands, these new devices are equipped with a battery that enables them deferring their needs for electric energy in time. If the pliant nature of this demand is exploited in such a way that the charging of these devices takes place when it is more convenient for the power system, then not only the adverse impacts to the system would be avoided but also a new stream of services could be offered to the electric power grid in the form of demand response, power injections in vehicle-to-grid, and regulating reserves. This article discusses the consequences of integrating significant volumes of PEVs into power systems, in both uncontrolled and controlled manners. Keywords: electric vehicle; electric grid; batteries; electricity market; power generation; CO 2 emissions
Controversies in the use of fresh frozen plasma in critically ill small animal patients.

Objective To review the literature supporting or discouraging the use of fresh frozen plasma (FFP) transfusion in critically ill patients. Data Sources Human and animal publications were searched using PubMed without time limits and the following keywords were used: “fresh frozen plasma,” “coagulopathy,” “hypocoagulable state,” “hypercoagulable states,” and “critical illness.” Human Data Synthesis The commonly used tests of coagulation (eg, prothrombin time, activated partial thromboplastin time, international normalized ratio) are poorly predictive of clinical bleeding. FFP use in critically ill patients is unlikely to result in improved outcomes and may be associated with increased risks. Veterinary Data Synthesis There is insufficient evidence to make definitive conclusions regarding the use of FFP in critically ill animals, but clinical studies are underway that may provide further data that clarify the optimal use of FFP in animals. Conclusions The use of FFP in critically ill patients remains controversial. In the absence of clinical bleeding or a risk for clinical bleeding associated with a planned procedure, treatment use of FFP is not recommended in human patients. There are insufficient data in critically ill animals to enable formulation of recommendations. Further research is warranted in dogs and cats to establish evidence-based guidelines.
Motor control function of the prefrontal cortex.

The prefrontal granular cortex, with the premotor and motor areas, forms the frontal lobe. The three areas are allied by their proximity to one another and by their role in motor control. Of these three major subdivisions, the role of prefrontal cortex has been the most obscure. However, recent anatomical studies have elucidated the circuit basis for motor regulatory functions of the principal sulcus (Brodmann's area 9; Walker's area 46). In addition to well known and well worked out prominent connections with subcortical structures, e.g. the basal ganglia and deep layers of the superior colliculus, this area of prefrontal cortex is reciprocally connected to portions of the supplementary motor and premotor fields that are but one synapse removed from primary motor cortex. The principal sulcal cortex is additionally interconnected with the primary somatosensory area and the somatosensory association areas, in the frontoparietal operculum, with area PF of von Bonin and Bailey in the posterior parietal cortex, and with parts of the 'motor' thalamus. Recent behavioural and electrophysiological studies in monkeys (Macaca mulatta) demonstrate that the principal sulcus can influence delayed-responding, whether the response is a hand or an eye movement. The anatomical and functional evidence supports the thesis that prefrontal cortex has access to and can direct the output of several motor centres.
Defending Against Allegations of Fraud and Manipulation: The Role of the Economist Under the New CFTC Rules

In this paper I review the key aspects of the new anti-manipulation and anti-fraud rules of the U.S. Commodities and Futures Trading Commission implemented last summer, representing a significant expansion of the Commission’s enforcement authority. I argue that the role of the economist may consequently be increased, not only due to the expanded set of activities covered by the new rules which will likely lead to more cases, but also due to the lower burden of proof for charges of fraudulent and manipulative practices. These lower standards will require more elaborate, more in depth, and more creative economic and empirical analyses by defendants’ experts.The paper starts by reviewing some classical manipulation and alleged manipulation cases, emphasizing the role of the economist in general and of empirical analyses in particular. It then describes the power of empirical screens to flag anticompetitive behavior, and summarizes the Commission’s market screening and monitoring program. I use as an example of the power of these empirical approaches the alleged Libor manipulation and conspiracy currently under investigation by the Commission and other agencies worldwide, which was originally flagged by screens. After establishing the power of empirical screens to detect potentially illegal behavior, I proceed with two hypothetical examples of how empirical analyses may be used on the other side, to defend against allegations of fraud and manipulation. I conclude the paper with an example of an innovative approach to screening for manipulation developed by economic experts on behalf of defendants, which was successfully used to assist in establishing the lack of conclusive evidence of price artificiality and the absence of a material manipulation in a private litigation matter.
Duality in routing and scheduling systems

This paper examines duality and transformations relating routing and scheduling systems. The authors examine the finite buffer duality results of Sparaggis et. al. (1993) and generalize the framework to controlled Markov chains, deterministic and continuous flow systems, and to multiple server/multiple layer systems. As well, the authors describe various transformations relating routing and scheduling systems with a focus on threshold decision policies. >
THE POINCARE-BENDIXSON THEOREM FOR MONOTONE CYCLIC FEEDBACK SYSTEMS WITH DELAY

Abstract We consider cyclic nearest neighbor systems of differential delay equations, in which the coupling between neighbors possesses a monotonicity property. Using a discrete (integer-valued) Lyapunov function, we prove that the Poincare–Bendixson theorem holds for such systems. We also obtain results on piecewise monotonicity and stability of periodic solutions of such systems.
Physical effects in red blood cell trauma

Red blood cell damage and destruction are important problems in the use of artificial valves, heart-lung machines, and other devices which pump or process blood. An experimental study has been made on the mechanism of cell damage. Damage was defined by three types of observations on blood which had been subjected to trauma: (a) release of hemoglobin from cells (hemolysis), (b) morphological changes observed microscopically, and (c) red cell life span studies in rabbits using a Cr51 tagging technique. Three types of physical forces which might be injurious to red cells were studied; shearing stress (of known, constant magnitudes from a concentric cylinder viscometer), pressure variations (from studies in a static pressure cell), and direct impact of solid surfaces (from studies in a device which simulates the seating action of artificial heart valves). The study shows that high shearing stress may be primarily responsible for mechanical cell damage under certain important circumstances. There is a critical shearing stress above which cell damage increases markedly. Much of the cell damage does not appear as an immediate release of hemoglobin. Many cells undergo morphological changes and exhibit shortened average life span in vivo. The morphological changes due to shearing stress are very similar to the changes observed in patients who have hemolytic anemia associated with artificial valves.
Skewed X Chromosome Inactivation and Trisomic Spontaneous Abortion: No Association

Several studies suggest that highly skewed X chromosome inactivation (HSXI) is associated with recurrent spontaneous abortion. We hypothesized that this association reflects an increased rate of trisomic conceptions due to anomalies on the X chromosome that lead both to HSXI and to a diminished oocyte pool. We compared the distribution of X chromosome inactivation (XCI) skewing percentages (range: 50%–100%) among women with spontaneous abortions in four karyotype groups—trisomy (n = 154), chromosomally normal male (n = 43), chromosomally normal female (n = 38), nontrisomic chromosomally abnormal (n = 61)—to the distribution for age-matched controls with chromosomally normal births (n = 388). In secondary analyses, we subdivided the nontrisomic chromosomally abnormal group, divided trisomies by chromosome, and classified women by reproductive history. Our data support neither an association of HSXI with all trisomies nor an association of HSXI with chromosomally normal male spontaneous abortions. We also find no association between HSXI and recurrent abortion (n = 45).
Differential Accumulation of Soybean Seed Storage Protein Subunits in Response to Sulfur and Nitrogen Nutritional Sources

AbstractSoybean (Glycine max [L.] Merr.) seed storage proteins consist of subunits that differ in amino acid profile, the β-subunit of 7S protein being essentially devoid of the S-containing amino acids, methionine and cysteine. Our objective was to examine the interaction of N and S nutrition on the relative abundance of these storage protein subunits in soybean seed. ‘Kenwood’ soybean was grown in hydroponic culture, and during vegetative growth (V2–R4.5) N was provided as 5 mM KNO3 to plants grown under sulfur-deficient (0.004 raM Na2SO4) or sulfur-sufficient (0.4 mM Na2S04) conditions. During seed fill (R4.5–R7) N was supplied as 5 mM KNO3 or 2.5 mM urea. Each N group was given S treatments of 1) no sulfur, 2) 0.4mM Na2SO4, 3) 0.2 mM L-cystine, or 4) 0.4 mM L-methionine. Effects on seed protein quality of S deficiency during vegetative growth were essentially overcome by supplying sulfate as late as R4.5. Total protein and seed storage protein were increased with urea as N source, but urea also increa...
Fourier transform infrared (FT-IR) spectroscopy and imaging of the nucleus to characterize DNA contributions in different phases of the cell cycle

Determination of neoplasia is largely dependent on the state of cell growth. Infrared (IR) spectroscopy has the potential to measure differences between normal and cancerous cells. When analyzing biopsy sections using IR spectroscopy, careful analyses become important since biochemical variations may be misinterpreted due to variations in cell cycle. Processes like DNA replication, transcription and translation to produce proteins are important in determining if the cells are actively dividing but no studies on this aspect using IR spectroscopy have been conducted on isolated cell nuclei. Nuclei hold critical information about the phase of cell and its capacity to divide, but IR spectra of nuclei are often confounded by cytoplasmic signals during data acquisition from intact cells and tissues. Therefore, we sought to separate nuclear signals from cytoplasmic signals and identify spectral differences that characterize different phases of the cell cycle. Both cells and isolated nuclei were analyzed to assess the effect of the cytoplasmic background and to identify spectral changes in nuclei in different phases of cell cycle. We observed that signals of DNA could be obtained when imaging nuclei isolated from cells in different phases of cell cycle, which is in contrast to the oft-cited case in cells wherein nuclear contributions are obscured. The differences across cell cycle phases were more pronounced in nucleic acid regions of the spectra, showing that the use of nuclear spectrum can provide additional information on cellular state. These results can aid in developing computational models that extract nuclear spectra from whole cells and tissues for more accurate assessment of biochemical variations.