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A sequential quadratic optimization algorithm is proposed for solving smooth nonlinear-equality-constrained optimization problems in which the objective function is defined by an expectation. The algorithmic structure of the proposed method is based on a step decomposition strategy that is known in the literature to be widely effective in practice, wherein each search direction is computed as the sum of a normal step (toward linearized feasibility) and a tangential step (toward objective decrease in the null space of the constraint Jacobian). However, the proposed method is unique from others in the literature in that it both allows the use of stochastic objective gradient estimates and possesses convergence guarantees even in the setting in which the constraint Jacobians may be rank-deficient. The results of numerical experiments demonstrate that the algorithm offers superior performance when compared with popular alternatives. Funding: This material is based upon work supported by the U.S. National Science Foundation's Division of Computing and Communication Foundations under award [CF-1740796], by the Office of Naval Research under award [N00014-21-1-2532], and by the National Science Foundation under award [2030859] to the Computing Research Association for the CIFellows Project. [ABSTRACT FROM AUTHOR]

The evolution of the placenta is an excellent model to examine the evolutionary processes underlying adaptive complexity due to the recent, independent derivation of placentation in divergent animal lineages. In fishes, the family Poeciliidae offers the opportunity to study placental evolution with respect to variation in degree of post-fertilization maternal provisioning among closely related sister species. In this study, we present a detailed examination of a new reference transcriptome sequence for the live-bearing, matrotrophic fish, Poeciliopsis prolifica, from multiple-tissue RNA-seq data. We describe the genetic components active in liver, brain, late-stage embryo, and the maternal placental/ovarian complex, as well as associated patterns of positive selection in a suite of orthologous genes found in fishes. Results indicate the expression of many signaling transcripts, "non-coding" sequences and repetitive elements in the maternal placental/ovarian complex. Moreover, patterns of positive selection in protein sequence evolution were found associated with live-bearing fishes, generally, and the placental P. prolifica, specifically, that appear independent of the general live-bearer lifestyle. Much of the observed patterns of gene expression and positive selection are congruent with the evolution of placentation in fish functionally converging with mammalian placental evolution and with the patterns of rapid evolution facilitated by the teleost-specific whole genome duplication event.

Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts. Tau seeding clearly discriminated between AD and control brain samples. Interestingly, seeding was absent in Progressive Supranuclear Palsy (PSP) putamen, suggesting that our tau SAA did not amplify 4R tau aggregates from PSP brain. The specificity of our tau SAA for AD brain was further supported by analysis of matched hippocampus and cerebellum samples. While seeding was detected in hippocampus from Braak stages I-II, no seeding was present in AD cerebellum that is devoid of tau inclusions. Analysis of 40 middle frontal gyrus samples encompassing all Braak stages showed that tau SAA seeding activity gradually increased with Braak stage. This relationship between seeding activity and the presence of tau inclusions in AD brain was further supported by robust correlations between tau SAA results and the levels of phosphorylated tau212/214, phosphorylated tau181, aggregated tau, and sarkosyl-insoluble tau. Strikingly, we detected tau seeding in the middle frontal gyrus already at Braak stage II-III, suggesting that tau SAA can detect tau pathology earlier than conventional immunohistochemical staining. In conclusion, our data suggest a quantitative relationship between tau seeding activity and pathological forms of tau in the human brain and provides an important basis for further development of tau SAA for accessible human samples. [ABSTRACT FROM AUTHOR]

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [[sup.11]C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [[sup.11]C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [[sup.11]C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [[sup.18]F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics., Introduction Olfactory function may serve as a general marker of brain health. In neurodevelopmental disease, patients with intellectual disability, e.g., Down syndrome and idiopathic intellectual disability, or later-onset neurodevelopmental disorders, [...]

We describe a line-search algorithm which achieves the best-known worst-case complexity results for problems with a certain "strict saddle" property that has been observed to hold in low-rank matrix optimization problems. Our algorithm is adaptive, in the sense that it makes use of backtracking line searches and does not require prior knowledge of the parameters that define the strict saddle property. [ABSTRACT FROM AUTHOR]

This paper examines the effects of the nondiscretionary trading demands of volatility index (VIX) exchange‐traded products (ETPs) issuers on the prices and volumes in the VIX futures. We find that the ETPs' informationless, mechanical rebalancing of futures positions to maintain the constant maturity of the index and the promised leverage ratios of the VIX ETPs have significantly positive predictive power for end‐of‐day futures returns. We also show that the impact on price has diminished through time from increased liquidity provided by hedge funds, and the "natural" hedging of the issuers' inverse products. [ABSTRACT FROM AUTHOR]