Certified Multi-Fidelity Zeroth-Order Optimization

We consider the problem of multi-fidelity zeroth-order optimization, where one can evaluate a function $f$ at various approximation levels (of varying costs), and the goal is to optimize $f$ with the cheapest evaluations possible. In this paper, we study \emph{certified} algorithms, which are additionally required to output a data-driven upper bound on the optimization error. We first formalize the problem in terms of a min-max game between an algorithm and an evaluation environment. We then propose a certified variant of the MFDOO algorithm and derive a bound on its cost complexity for any Lipschitz function $f$. We also prove an $f$-dependent lower bound showing that this algorithm has a near-optimal cost complexity. We close the paper by addressing the special case of noisy (stochastic) evaluations as a direct example

Adaptive approximation of monotone functions

We study the classical problem of approximating a non-decreasing function $f: \mathcal{X} \to \mathcal{Y}$ in $L^p(\mu)$ norm by sequentially querying its values, for known compact real intervals $\mathcal{X}$, $\mathcal{Y}$ and a known probability measure $\mu$ on \cX. For any function~$f$ we characterize the minimum number of evaluations of $f$ that algorithms need to guarantee an approximation $\hat{f}$ with an $L^p(\mu)$ error below $\epsilon$ after stopping. Unlike worst-case results that hold uniformly over all $f$, our complexity measure is dependent on each specific function $f$. To address this problem, we introduce GreedyBox, a generalization of an algorithm originally proposed by Novak (1992) for numerical integration. We prove that GreedyBox achieves an optimal sample complexity for any function $f$, up to logarithmic factors. Additionally, we uncover results regarding piecewise-smooth functions. Perhaps as expected, the $L^p(\mu)$ error of GreedyBox decreases much faster for piecewise-$C^2$ functions than predicted by the algorithm (without any knowledge on the smoothness of $f$). A simple modification even achieves optimal minimax approximation rates for such functions, which we compute explicitly. In particular, our findings highlight multiple performance gaps between adaptive and non-adaptive algorithms, smooth and piecewise-smooth functions, as well as monotone or non-monotone functions. Finally, we provide numerical experiments to support our theoretical results

Estudios sobre la reforma constitucional de Mendoza : una revisión necesaria

El trabajo de construcción social y dialógica de conocimiento que dio lugar a la presente obra fue tan intenso como desafiante. Intenso, porque los encuentros tuvieron lugar semana a semana, durante varios meses, pero no de manera aislada, sino que estuvieron acompañados de numerosas actividades destinadas a pensar la misma cuestión mediante debates territoriales, audiencias públicas, coloquios, encuestas, mesas de debate, jornadas, recepción continua y abierta de propuestas ciudadanas, entre otras. De manera tal que se trató de una conversación extendida, abierta, dispersante, inclusiva, igualitaria y persistente en el tiempo. También desafiante, porque dichas actividades, motivadas por una particular concepción de la democracia,como es la deliberativa, no encajan en los modelos de las prácticas tradicionales de llevar a cabo la labor política. Por lo general, y salvo contadas excepciones, antes que la inclusión de la ciudadanía se propicia su expulsión hacia las márgenes de los centros de toma de decisiones. Esa pretensión viene desde los orígenes del constitucionalismo

Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways

The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins

Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.

BACKGROUND: Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains. NEW METHOD: We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke. RESULTS: Sex, background strain, source breeder and genotype all affected whisker movements. All mouse models, apart from Parkinson's disease, revealed differences in whisker movements during locomotion. R6/2 CAG250 Huntington's disease mice had the strongest behavioural phenotype. Robo3R3-5-CKO and RIM-DKOSert mouse models have abnormal somatosensory cortex development and revealed significant changes in whisker movements during object exploration. COMPARISON WITH EXISTING METHOD(S): Our results have good agreement with past studies, which indicates the robustness and reliability of measuring whisking. We recommend that differences in whisker movements of mice with motor deficits can be captured in open field arenas, but that mice with impairments to sensory or cognitive functioning should also be filmed investigating objects. Scoring clips qualitatively before tracking will help to structure later analyses. CONCLUSIONS: Studying whisker movements provides a quantitative measure of sensing, motor control and exploration. However, the effect of background strain, sex and age on whisker movements needs to be better understood

Mouse Apolipoprotein B Editing Complex 3 (APOBEC3) Is Expressed in Germ Cells and Interacts with Dead-End (DND1)

encoded protein, DND1, is able to bind to the 3′-untranslated region (UTR) of messenger RNAs (mRNAs) to displace micro-RNA (miRNA) interaction with mRNA. Thus, one function of DND1 is to prevent miRNA mediated repression of mRNA. We report that DND1 interacts specifically with APOBEC3. APOBEC3 is a multi-functional protein. It inhibits retroviral replication. In addition, recent studies show that APOBEC3 interacts with cellular RNA-binding proteins and to mRNA to inhibit miRNA-mediated repression of mRNA.Here we show that DND1 specifically interacts with another cellular protein, APOBEC3. We present our data which shows that DND1 co-immunoprecipitates APOBEC3 from mammalian cells and also endogenous APOBEC3 from mouse gonads. Whether the two proteins interact directly remains to be elucidated. We show that both DND1 and APOBEC3 are expressed in germ cells and in the early gonads of mouse embryo. Expression of fluorescently-tagged DND1 and APOBEC3 indicate they localize to the cytoplasm and when DND1 and APOBEC3 are expressed together in cells, they sequester near peri-nuclear sites.The 3′-UTR of mRNAs generally encode multiple miRNA binding sites as well as binding sites for a variety of RNA binding proteins. In light of our findings of DND1-APOBEC3 interaction and taking into consideration reports that DND1 and APOBEC3 bind to mRNA to inhibit miRNA mediated repression, our studies implicate a possible role of DND1-APOBEC3 interaction in modulating miRNA-mediated mRNA repression. The interaction of DND1 and APOBEC3 could be one mechanism for maintaining viability of germ cells and for preventing germ cell tumor development

Tracheostomy care and decannulation during the COVID-19 pandemic. A multidisciplinary clinical practice guideline.

PURPOSE: Traditional critical care dogma regarding the benefits of early tracheostomy during invasive ventilation has had to be revisited due to the risk of COVID-19 to patients and healthcare staff. Standard practises that have evolved to minimise the risks associated with tracheostomy must be comprehensively reviewed in light of the numerous potential episodes for aerosol generating procedures. We meet the urgent need for safe practise standards by presenting the experience of two major London teaching hospitals, and synthesise our findings into an evidence-based guideline for multidisciplinary care of the tracheostomy patient. METHODS: This is a narrative review presenting the extensive experience of over 120 patients with tracheostomy, with a pragmatic analysis of currently available evidence for safe tracheostomy care in COVID-19 patients. RESULTS: Tracheostomy care involves many potentially aerosol generating procedures which may pose a risk of viral transmission to staff and patients. We make a series of recommendations to ameliorate this risk through infection control strategies, equipment modification, and individualised decannulation protocols. In addition, we discuss the multidisciplinary collaboration that is absolutely fundamental to safe and effective practise. CONCLUSION: COVID-19 requires a radical rethink of many tenets of tracheostomy care, and controversy continues to exist regarding the optimal techniques to minimise risk to patients and healthcare workers. Safe practise requires a coordinated multidisciplinary team approach to infection control, weaning and decannulation, with integrated processes for continuous prospective data collection and audit