Wenjie Wang, Robert Aseltine, Kun Chen, Jun Yan.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 51--73.

Abstract:
The concept of integrating data from disparate sources to accelerate scientific discovery has generated tremendous excitement in many fields. The potential benefits from data integration, however, may be compromised by the uncertainty due to incomplete/imperfect record linkage. Motivated by a suicide risk study, we propose an approach for analyzing survival data with uncertain event times arising from data integration. Specifically, in our problem deaths identified from the hospital discharge records together with reported suicidal deaths determined by the Office of Medical Examiner may still not include all the death events of patients, and the missing deaths can be recovered from a complete database of death records. Since the hospital discharge data can only be linked to the death record data by matching basic patient characteristics, a patient with a censored death time from the first dataset could be linked to multiple potential event records in the second dataset. We develop an integrative Cox proportional hazards regression in which the uncertainty in the matched event times is modeled probabilistically. The estimation procedure combines the ideas of profile likelihood and the expectation conditional maximization algorithm (ECM). Simulation studies demonstrate that under realistic settings of imperfect data linkage the proposed method outperforms several competing approaches including multiple imputation. A marginal screening analysis using the proposed integrative Cox model is performed to identify risk factors associated with death following suicide-related hospitalization in Connecticut. The identified diagnostics codes are consistent with existing literature and provide several new insights on suicide risk, prediction and prevention.

Li Zhu, Zhiguang Huo, Tianzhou Ma, Steffi Oesterreich, George C. Tseng.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2611--2636.

Abstract:
Variable selection is a pervasive problem in modern high-dimensional data analysis where the number of features often exceeds the sample size (a.k.a. small-n-large-p problem). Incorporation of group structure knowledge to improve variable selection has been widely studied. Here, we consider prior knowledge of a hierarchical overlapping group structure to improve variable selection in regression setting. In genomics applications, for instance, a biological pathway contains tens to hundreds of genes and a gene can be mapped to multiple experimentally measured features (such as its mRNA expression, copy number variation and methylation levels of possibly multiple sites). In addition to the hierarchical structure, the groups at the same level may overlap (e.g., two pathways can share common genes). Incorporating such hierarchical overlapping groups in traditional penalized regression setting remains a difficult optimization problem. Alternatively, we propose a Bayesian indicator model that can elegantly serve the purpose. We evaluate the model in simulations and two breast cancer examples, and demonstrate its superior performance over existing models. The result not only enhances prediction accuracy but also improves variable selection and model interpretation that lead to deeper biological insight of the disease.

Hongbin Zhang, Lang Wu.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2140--2157.

Abstract:
For a time-to-event outcome with censored time-varying covariates, a joint Cox model with a linear mixed effects model is the standard modeling approach. In some applications such as AIDS studies, mechanistic nonlinear models are available for some covariate process such as viral load during anti-HIV treatments, derived from the underlying data-generation mechanisms and disease progression. Such a mechanistic nonlinear covariate model may provide better-predicted values when the covariates are left censored or mismeasured. When the focus is on the impact of the time-varying covariate process on the survival outcome, an accelerated failure time (AFT) model provides an excellent alternative to the Cox proportional hazard model since an AFT model is formulated to allow the influence of the outcome by the entire covariate process. In this article, we consider a nonlinear mixed effects model for the censored covariates in an AFT model, implemented using a Monte Carlo EM algorithm, under the framework of a joint model for simultaneous inference. We apply the joint model to an HIV/AIDS data to gain insights for assessing the association between viral load and immunological restoration during antiretroviral therapy. Simulation is conducted to compare model performance when the covariate model and the survival model are misspecified.

Jason Xu, Samson Koelle, Peter Guttorp, Chuanfeng Wu, Cynthia Dunbar, Janis L. Abkowitz, Vladimir N. Minin.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2091--2119.

Abstract:
Single-cell lineage tracking strategies enabled by recent experimental technologies have produced significant insights into cell fate decisions, but lack the quantitative framework necessary for rigorous statistical analysis of mechanistic models describing cell division and differentiation. In this paper, we develop such a framework with corresponding moment-based parameter estimation techniques for continuous-time, multi-type branching processes. Such processes provide a probabilistic model of how cells divide and differentiate, and we apply our method to study hematopoiesis , the mechanism of blood cell production. We derive closed-form expressions for higher moments in a general class of such models. These analytical results allow us to efficiently estimate parameters of much richer statistical models of hematopoiesis than those used in previous statistical studies. To our knowledge, the method provides the first rate inference procedure for fitting such models to time series data generated from cellular barcoding experiments. After validating the methodology in simulation studies, we apply our estimator to hematopoietic lineage tracking data from rhesus macaques. Our analysis provides a more complete understanding of cell fate decisions during hematopoiesis in nonhuman primates, which may be more relevant to human biology and clinical strategies than previous findings from murine studies. For example, in addition to previously estimated hematopoietic stem cell self-renewal rate, we are able to estimate fate decision probabilities and to compare structurally distinct models of hematopoiesis using cross validation. These estimates of fate decision probabilities and our model selection results should help biologists compare competing hypotheses about how progenitor cells differentiate. The methodology is transferrable to a large class of stochastic compartmental and multi-type branching models, commonly used in studies of cancer progression, epidemiology and many other fields.

Bret Zeldow, Vincent Lo Re III, Jason Roy.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1989--2010.

Abstract:
Bayesian Additive Regression Trees (BART) is a flexible machine learning algorithm capable of capturing nonlinearities between an outcome and covariates and interactions among covariates. We extend BART to a semiparametric regression framework in which the conditional expectation of an outcome is a function of treatment, its effect modifiers, and confounders. The confounders are allowed to have unspecified functional form, while treatment and effect modifiers that are directly related to the research question are given a linear form. The result is a Bayesian semiparametric linear regression model where the posterior distribution of the parameters of the linear part can be interpreted as in parametric Bayesian regression. This is useful in situations where a subset of the variables are of substantive interest and the others are nuisance variables that we would like to control for. An example of this occurs in causal modeling with the structural mean model (SMM). Under certain causal assumptions, our method can be used as a Bayesian SMM. Our methods are demonstrated with simulation studies and an application to dataset involving adults with HIV/Hepatitis C coinfection who newly initiate antiretroviral therapy. The methods are available in an R package called semibart.

Jessica K. Hargreaves, Marina I. Knight, Jon W. Pitchford, Rachael J. Oakenfull, Sangeeta Chawla, Jack Munns, Seth J. Davis.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1817--1846.

Abstract:
Rhythmic data are ubiquitous in the life sciences. Biologists need reliable statistical tests to identify whether a particular experimental treatment has caused a significant change in a rhythmic signal. When these signals display nonstationary behaviour, as is common in many biological systems, the established methodologies may be misleading. Therefore, there is a real need for new methodology that enables the formal comparison of nonstationary processes. As circadian behaviour is best understood in the spectral domain, here we develop novel hypothesis testing procedures in the (wavelet) spectral domain, embedding replicate information when available. The data are modelled as realisations of locally stationary wavelet processes, allowing us to define and rigorously estimate their evolutionary wavelet spectra. Motivated by three complementary applications in circadian biology, our new methodology allows the identification of three specific types of spectral difference. We demonstrate the advantages of our methodology over alternative approaches, by means of a comprehensive simulation study and real data applications, using both published and newly generated circadian datasets. In contrast to the current standard methodologies, our method successfully identifies differences within the motivating circadian datasets, and facilitates wider ranging analyses of rhythmic biological data in general.

Seong-Hwan Jun, Samuel W. K. Wong, James V. Zidek, Alexandre Bouchard-Côté.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1678--1707.

Abstract:
In this paper, we consider the knot-matching problem arising in computational forestry. The knot-matching problem is an important problem that needs to be solved to advance the state of the art in automatic strength prediction of lumber. We show that this problem can be formulated as a quadripartite matching problem and develop a sequential decision model that admits efficient parameter estimation along with a sequential Monte Carlo sampler on graph matching that can be utilized for rapid sampling of graph matching. We demonstrate the effectiveness of our methods on 30 manually annotated boards and present findings from various simulation studies to provide further evidence supporting the efficacy of our methods.

Jesús D. Arroyo Relión, Daniel Kessler, Elizaveta Levina, Stephan F. Taylor.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1648--1677.

Abstract:
While statistical analysis of a single network has received a lot of attention in recent years, with a focus on social networks, analysis of a sample of networks presents its own challenges which require a different set of analytic tools. Here we study the problem of classification of networks with labeled nodes, motivated by applications in neuroimaging. Brain networks are constructed from imaging data to represent functional connectivity between regions of the brain, and previous work has shown the potential of such networks to distinguish between various brain disorders, giving rise to a network classification problem. Existing approaches tend to either treat all edge weights as a long vector, ignoring the network structure, or focus on graph topology as represented by summary measures while ignoring the edge weights. Our goal is to design a classification method that uses both the individual edge information and the network structure of the data in a computationally efficient way, and that can produce a parsimonious and interpretable representation of differences in brain connectivity patterns between classes. We propose a graph classification method that uses edge weights as predictors but incorporates the network nature of the data via penalties that promote sparsity in the number of nodes, in addition to the usual sparsity penalties that encourage selection of edges. We implement the method via efficient convex optimization and provide a detailed analysis of data from two fMRI studies of schizophrenia.

Jeng-Min Chiou, Yu-Ting Chen, Tailen Hsing.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1430--1463.

Abstract:
Motivated by the study of road segmentation partitioned by shifts in traffic conditions along a freeway, we introduce a two-stage procedure, Dynamic Segmentation and Backward Elimination (DSBE), for identifying multiple changes in the mean functions for a sequence of functional data. The Dynamic Segmentation procedure searches for all possible changepoints using the derived global optimality criterion coupled with the local strategy of at-most-one-changepoint by dividing the entire sequence into individual subsequences that are recursively adjusted until convergence. Then, the Backward Elimination procedure verifies these changepoints by iteratively testing the unlikely changes to ensure their significance until no more changepoints can be removed. By combining the local strategy with the global optimal changepoint criterion, the DSBE algorithm is conceptually simple and easy to implement and performs better than the binary segmentation-based approach at detecting small multiple changes. The consistency property of the changepoint estimators and the convergence of the algorithm are proved. We apply DSBE to detect changes in traffic streams through real freeway traffic data. The practical performance of DSBE is also investigated through intensive simulation studies for various scenarios.

Lin Liu, Yuqi Qiu, Loki Natarajan, Karen Messer.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1370--1396.

Abstract:
It is common to encounter missing data among the potential predictor variables in the setting of model selection. For example, in a recent study we attempted to improve the US guidelines for risk stratification after screening colonoscopy ( Cancer Causes Control 27 (2016) 1175–1185), with the aim to help reduce both overuse and underuse of follow-on surveillance colonoscopy. The goal was to incorporate selected additional informative variables into a neoplasia risk-prediction model, going beyond the three currently established risk factors, using a large dataset pooled from seven different prospective studies in North America. Unfortunately, not all candidate variables were collected in all studies, so that one or more important potential predictors were missing on over half of the subjects. Thus, while variable selection was a main focus of the study, it was necessary to address the substantial amount of missing data. Multiple imputation can effectively address missing data, and there are also good approaches to incorporate the variable selection process into model-based confidence intervals. However, there is not consensus on appropriate methods of inference which address both issues simultaneously. Our goal here is to study the properties of model-based confidence intervals in the setting of imputation for missing data followed by variable selection. We use both simulation and theory to compare three approaches to such post-imputation-selection inference: a multiple-imputation approach based on Rubin’s Rules for variance estimation ( Comput. Statist. Data Anal. 71 (2014) 758–770); a single imputation-selection followed by bootstrap percentile confidence intervals; and a new bootstrap model-averaging approach presented here, following Efron ( J. Amer. Statist. Assoc. 109 (2014) 991–1007). We investigate relative strengths and weaknesses of each method. The “Rubin’s Rules” multiple imputation estimator can have severe undercoverage, and is not recommended. The imputation-selection estimator with bootstrap percentile confidence intervals works well. The bootstrap-model-averaged estimator, with the “Efron’s Rules” estimated variance, may be preferred if the true effect sizes are moderate. We apply these results to the colorectal neoplasia risk-prediction problem which motivated the present work.

Javier Cárcamo, Antonio Cuevas, Luis-Alberto Rodríguez.

Source: Bernoulli, Volume 26, Number 3, 2143--2175.

Abstract:
We show that various functionals related to the supremum of a real function defined on an arbitrary set or a measure space are Hadamard directionally differentiable. We specifically consider the supremum norm, the supremum, the infimum, and the amplitude of a function. The (usually non-linear) derivatives of these maps adopt simple expressions under suitable assumptions on the underlying space. As an application, we improve and extend to the multidimensional case the results in Raghavachari ( Ann. Statist. 1 (1973) 67–73) regarding the limiting distributions of Kolmogorov–Smirnov type statistics under the alternative hypothesis. Similar results are obtained for analogous statistics associated with copulas. We additionally solve an open problem about the Berk–Jones statistic proposed by Jager and Wellner (In A Festschrift for Herman Rubin (2004) 319–331 IMS). Finally, the asymptotic distribution of maximum mean discrepancies over Donsker classes of functions is derived.

Akio Fujiwara, Koichi Yamagata.

Source: Bernoulli, Volume 26, Number 3, 2105--2142.

Abstract:
We herein develop a theory of contiguity in the quantum domain based upon a novel quantum analogue of the Lebesgue decomposition. The theory thus formulated is pertinent to the weak quantum local asymptotic normality introduced in the previous paper [Yamagata, Fujiwara, and Gill, Ann. Statist. 41 (2013) 2197–2217], yielding substantial enlargement of the scope of quantum statistics.

Ulrike Mayer, Henryk Zähle, Zhou Zhou.

Source: Bernoulli, Volume 26, Number 3, 1891--1911.

Abstract:
We derive a functional weak limit theorem for a local empirical process of a wide class of piece-wise locally stationary (PLS) time series. The latter result is applied to derive the asymptotics of weighted empirical quantiles and weighted V-statistics of non-stationary time series. The class of admissible underlying time series is illustrated by means of PLS linear processes and PLS ARCH processes.

Holger Sambale, Arthur Sinulis.

Source: Bernoulli, Volume 26, Number 3, 1863--1890.

Abstract:
We derive sufficient conditions for a probability measure on a finite product space (a spin system ) to satisfy a (modified) logarithmic Sobolev inequality. We establish these conditions for various examples, such as the (vertex-weighted) exponential random graph model, the random coloring and the hard-core model with fugacity. This leads to two separate branches of applications. The first branch is given by mixing time estimates of the Glauber dynamics. The proofs do not rely on coupling arguments, but instead use functional inequalities. As a byproduct, this also yields exponential decay of the relative entropy along the Glauber semigroup. Secondly, we investigate the concentration of measure phenomenon (particularly of higher order) for these spin systems. We show the effect of better concentration properties by centering not around the mean, but around a stochastic term in the exponential random graph model. From there, one can deduce a central limit theorem for the number of triangles from the CLT of the edge count. In the Erdős–Rényi model the first-order approximation leads to a quantification and a proof of a central limit theorem for subgraph counts.

Stanislav Minsker, Xiaohan Wei.

Source: Bernoulli, Volume 26, Number 1, 694--727.

Abstract:
Let $Y$ be a $d$-dimensional random vector with unknown mean $mu $ and covariance matrix $Sigma $. This paper is motivated by the problem of designing an estimator of $Sigma $ that admits exponential deviation bounds in the operator norm under minimal assumptions on the underlying distribution, such as existence of only 4th moments of the coordinates of $Y$. To address this problem, we propose robust modifications of the operator-valued U-statistics, obtain non-asymptotic guarantees for their performance, and demonstrate the implications of these results to the covariance estimation problem under various structural assumptions.

Mingjie Liang, René L. Schilling, Jian Wang.

Source: Bernoulli, Volume 26, Number 1, 664--693.

Abstract:
We present a general method to construct couplings of stochastic differential equations driven by Lévy noise in terms of coupling operators. This approach covers both coupling by reflection and refined basic coupling which are often discussed in the literature. As applications, we prove regularity results for the transition semigroups and obtain successful couplings for the solutions to stochastic differential equations driven by additive Lévy noise.

Nicolas Privault, Grzegorz Serafin.

Source: Bernoulli, Volume 26, Number 1, 587--615.

Abstract:
We derive normal approximation bounds in the Kolmogorov distance for sums of discrete multiple integrals and weighted $U$-statistics made of independent Bernoulli random variables. Such bounds are applied to normal approximation for the renormalized subgraph counts in the Erdős–Rényi random graph. This approach completely solves a long-standing conjecture in the general setting of arbitrary graph counting, while recovering recent results obtained for triangles and improving other bounds in the Wasserstein distance.

Eric Beutner, Laurent Bordes, Laurent Doyen.

Source: Bernoulli, Volume 26, Number 1, 557--586.

Abstract:
Virtual age models are very useful to analyse recurrent events. Among the strengths of these models is their ability to account for treatment (or intervention) effects after an event occurrence. Despite their flexibility for modeling recurrent events, the number of applications is limited. This seems to be a result of the fact that in the semiparametric setting all the existing results assume the virtual age function that describes the treatment (or intervention) effects to be known. This shortcoming can be overcome by considering semiparametric virtual age models with parametrically specified virtual age functions. Yet, fitting such a model is a difficult task. Indeed, it has recently been shown that for these models the standard profile likelihood method fails to lead to consistent estimators. Here we show that consistent estimators can be constructed by smoothing the profile log-likelihood function appropriately. We show that our general result can be applied to most of the relevant virtual age models of the literature. Our approach shows that empirical process techniques may be a worthwhile alternative to martingale methods for studying asymptotic properties of these inference methods. A simulation study is provided to illustrate our consistency results together with an application to real data.

Xiucai Ding.

Source: Bernoulli, Volume 26, Number 1, 387--417.

Abstract:
We consider the recovery of a low rank $M imes N$ matrix $S$ from its noisy observation $ ilde{S}$ in the high dimensional framework when $M$ is comparable to $N$. We propose two efficient estimators for $S$ under two different regimes. Our analysis relies on the local asymptotics of the eigenstructure of large dimensional rectangular matrices with finite rank perturbation. We derive the convergent limits and rates for the singular values and vectors for such matrices.

EdWeek Market Brief asked district officials in a nationwide survey about their most urgent assessment needs, as they cope with COVID-19 and tentatively plan for reopening schools.

The post What Districts Want From Assessments, as They Grapple With the Coronavirus appeared first on Market Brief.

Fangzheng Xie, Yanxun Xu.

Source: Bayesian Analysis, Volume 15, Number 1, 159--186.

Abstract:
We propose a kernel mixture of polynomials prior for Bayesian nonparametric regression. The regression function is modeled by local averages of polynomials with kernel mixture weights. We obtain the minimax-optimal contraction rate of the full posterior distribution up to a logarithmic factor by estimating metric entropies of certain function classes. Under the assumption that the degree of the polynomials is larger than the unknown smoothness level of the true function, the posterior contraction behavior can adapt to this smoothness level provided an upper bound is known. We also provide a frequentist sieve maximum likelihood estimator with a near-optimal convergence rate. We further investigate the application of the kernel mixture of polynomials to partial linear models and obtain both the near-optimal rate of contraction for the nonparametric component and the Bernstein-von Mises limit (i.e., asymptotic normality) of the parametric component. The proposed method is illustrated with numerical examples and shows superior performance in terms of computational efficiency, accuracy, and uncertainty quantification compared to the local polynomial regression, DiceKriging, and the robust Gaussian stochastic process.

Peter D. Hoff

Source: Bayesian Anal., Volume 6, Number 2, 179--196.

Abstract:
Modern datasets are often in the form of matrices or arrays, potentially having correlations along each set of data indices. For example, data involving repeated measurements of several variables over time may exhibit temporal correlation as well as correlation among the variables. A possible model for matrix-valued data is the class of matrix normal distributions, which is parametrized by two covariance matrices, one for each index set of the data. In this article we discuss an extension of the matrix normal model to accommodate multidimensional data arrays, or tensors. We show how a particular array-matrix product can be used to generate the class of array normal distributions having separable covariance structure. We derive some properties of these covariance structures and the corresponding array normal distributions, and show how the array-matrix product can be used to define a semi-conjugate prior distribution and calculate the corresponding posterior distribution. We illustrate the methodology in an analysis of multivariate longitudinal network data which take the form of a four-way array.

Ruosi Guo, Chunming Zhang, Zhengjun Zhang.

Source: Statistical Science, Volume 35, Number 1, 145--157.

Abstract:
In many scientific disciplines, finding hidden influential factors behind observational data is essential but challenging. The majority of existing approaches, such as the independent component analysis (${mathrm{ICA}}$), rely on linear transformation, that is, true signals are linear combinations of hidden components. Motivated from analyzing nonlinear temporal signals in neuroscience, genetics, and finance, this paper proposes the “maximum independent component analysis” (${mathrm{MaxICA}}$), based on max-linear combinations of components. In contrast to existing methods, ${mathrm{MaxICA}}$ benefits from focusing on significant major components while filtering out ignorable components. A major tool for parameter learning of ${mathrm{MaxICA}}$ is an augmented genetic algorithm, consisting of three schemes for the elite weighted sum selection, randomly combined crossover, and dynamic mutation. Extensive empirical evaluations demonstrate the effectiveness of ${mathrm{MaxICA}}$ in either extracting max-linearly combined essential sources in many applications or supplying a better approximation for nonlinearly combined source signals, such as $mathrm{EEG}$ recordings analyzed in this paper.

Gregorio Quintana-Ortí, Amelia Simó.

Source: Statistical Science, Volume 34, Number 2, 236--252.

Abstract:
This paper is focused on kernel regression when the response variable is the shape of a 3D object represented by a configuration matrix of landmarks. Regression methods on this shape space are not trivial because this space has a complex finite-dimensional Riemannian manifold structure (non-Euclidean). Papers about it are scarce in the literature, the majority of them are restricted to the case of a single explanatory variable, and many of them are based on the approximated tangent space. In this paper, there are several methodological innovations. The first one is the adaptation of the general method for kernel regression analysis in manifold-valued data to the three-dimensional case of Kendall’s shape space. The second one is its generalization to the multivariate case and the addressing of the curse-of-dimensionality problem. Finally, we propose bootstrap confidence intervals for prediction. A simulation study is carried out to check the goodness of the procedure, and a comparison with a current approach is performed. Then, it is applied to a 3D database obtained from an anthropometric survey of the Spanish child population with a potential application to online sales of children’s wear.

Brian Zingg
Apr 15, 2020; 40:3250-3267
Systems/Circuits

The UK's plans to launch a smartphone application to track potential COVID-19 infections won't include Apple and Google. The country's National Health Service has designed its own mobile software to do contact tracing of people exposed to the coronavirus. The NHS reportedly found that its own tech works "sufficiently well." The NHS chose a centralized model for its data collection and storage.

Revealing the organization and function of neural circuits is greatly facilitated by viral tools that spread transsynaptically. Adeno-associated virus (AAV) exhibits anterograde transneuronal transport, however, the synaptic specificity of this spread and its broad application within a diverse set of circuits remains to be explored. Here, using anatomic, functional, and molecular approaches, we provide evidence for the preferential transport of AAV1 to postsynaptically connected neurons and reveal its spread is strongly dependent on synaptic transmitter release. In addition to glutamatergic pathways, AAV1 also spreads through GABAergic synapses to both excitatory and inhibitory cell types. We observed little or no transport, however, through neuromodulatory projections (e.g., serotonergic, cholinergic, and noradrenergic). In addition, we found that AAV1 can be transported through long-distance descending projections from various brain regions to effectively transduce spinal cord neurons. Combined with newly designed intersectional and sparse labeling strategies, AAV1 can be applied within a wide variety of pathways to categorize neurons according to their input sources, morphology, and molecular identities. These properties make AAV1 a promising anterograde transsynaptic tool for establishing a comprehensive cell-atlas of the brain, although its capacity for retrograde transport currently limits its use to unidirectional circuits.

SIGNIFICANCE STATEMENT The discovery of anterograde transneuronal spread of AAV1 generates great promise for its application as a unique tool for manipulating input-defined cell populations and mapping their outputs. However, several outstanding questions remain for anterograde transsynaptic approaches in the field: (1) whether AAV1 spreads exclusively or specifically to synaptically connected neurons, and (2) how broad its application could be in various types of neural circuits in the brain. This study provides several lines of evidence in terms of anatomy, functional innervation, and underlying mechanisms, to strongly support that AAV1 anterograde transneuronal spread is highly synapse specific. In addition, several potentially important applications of transsynaptic AAV1 in probing neural circuits are described.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5–72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M₂ or M₄ receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.

SIGNIFICANCE STATEMENT The major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to speculation that the septo-hippocampal cholinergic projection contributing to theta oscillation. In this article, by long-term recording of MS cholinergic neurons, we found that they show a theta state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during slow-wave sleep could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M₂ and M₄ receptors.

The "lost" apples will help restore genetic, culinary diversity to a crop North America once produced in astonishing variety

In April alone, the Sturminster Newton Mill ground more than one ton of wheat

In New York City, a desperate need among healthcare workers has pushed to the forefront the question: Is homemade equipment safe to use?

Henry Ford spent the majority of the war as a pacifist. By 1917, however, his state-of-the-art assembly line was churning out vital engine parts to feed the war machine.

Over many years, the Xenopus laevis embryo has provided a powerful model system to investigate how mechanical forces regulate cellular function. Here, we describe a system to apply reproducible tensile and compressive force to X. laevis animal cap tissue explants and to simultaneously assess cellular behavior using live confocal imaging.

The CFL and CFL Players' Association have halted discussions on potential contingency plans for the 2020 campaign due to the COVID-19 pandemic.

The World Agricultural Supply and Demand Estimates (WASDE) report is prepared monthly and includes forecasts for U.S. and world wheat, rice, and coarse grains (corn, barley, sorghum, and oats), oilseeds (soybeans, rapeseed, palm), and cotton. U.S. coverage is extended to sugar, meat, poultry, eggs, and milk. USDA World Agricultural Outlook Board analysts chair the Interagency Commodity Estimates Committees (ICECs) comprising representatives from several key USDA agencies. The nine ICECs- one for each commodity- compile and interpret information from USDA and other domestic and foreign official sources to produce the report.

The ICECs rely on Foreign Agricultural Service (FAS) attaché reports and analysis of foreign commodity developments, Economic Research Service (ERS) domestic and foreign regional assessments, and National Agricultural Statistics Service (NASS) U.S. crop and livestock estimates. For domestic policy and market information, the Board relies on the Farm Services Agency and the Agricultural Marketing Service. WAOB and FAS use weather analysis and satellite imagery to monitor crop conditions. Additional private and public information sources are considered.

This broad information base is reviewed and analyzed by ICEC members who bring diverse expertise and perspectives to the report. To arrive at consensus forecasts, alternative assessments of domestic and foreign supply and use are vetted at the ICEC meetings. Throughout the growing season and afterwards, estimates are compared with new information on production and utilization, and historical revisions are made as necessary.

The WASDE reports a full balance sheet for each commodity. Separate estimates are made for components of supply (beginning stocks, imports, and production) and demand (domestic use, exports, and ending stocks). Domestic use is subdivided into major categories, for example corn for feed and corn for ethanol. Domestic use may be based on data from other Federal agencies: for example, U.S. wheat ground for flour, soybeans crushed for oil, and cotton mill use come from the Bureau of the Census. The demand side of the balance sheet may include a category for residual or unaccounted disappearance to balance known uses against total supplies.

The WASDE also reports forecast season-average farm prices for most items. Prices tie together both sides of the balance sheet. Market prices aid in rationing available supplies among competing uses. Prices also indicate potential supply responses, for example potential planting decisions for the upcoming year. The process of forecasting price and balance sheet items is complex and involves the interaction of expert judgment, commodity models, and in-depth research by USDA analysts on key domestic and international issues.

Penn State Mont Alto unveiled its new project and supply chain management degree in response to a local and global need.

In what could herald a course reversal for the UK's National Health Service, health officials in that country have reportedly asked a team of developers to "investigate" switching its contact tracing app to a cross-platform API provided by Apple and Google.

Apple has been hit with a class-action lawsuit claiming that the company concealed the so-called "stage lighting" issue experienced by some 2016 MacBook Pro owners.

Stoking interest in an expected second season of Apple TV+ original "For All Mankind," Apple on Wednesday shared a virtual tour of the show's fictional Jamestown lunar base.

Apple Watch extended its lead over smartwatch market competitors during the first quarter of 2020, according to new statistics from research firm Strategy Analytics, with Apple's wearable now accounting for more than 55% of the whole.

Apple's first product to integrate Mini LED display technology might see a later-than-expected launch timeline due to setbacks caused by the coronavirus pandemic, according to new research from TF Securities analyst Ming-Chi Kuo.

Apple has reopened all of its operational Apple Stores in Australia, following their closure because of the coronavirus outbreak. Each of the stores has introduced social distancing and temperature checks.

Early Thursday morning, Apple announced it is awarding $10 million from its Advanced Manufacturing Fund plus manufacturing machinery design assistance to COVID-19 test kit collection equipment manufacturer COPAN Diagnostics.

Instead of every meeting attendee staring at a flat Zoom screen, Apple is looking to the future of video conferencing with Memoji-style avatars arranged in augmented reality around each meeting attendee.

A prolific leaker has declared that Apple has a new Apple TV 4K ready to go, and it could launch the product at any time.

Apple's Jeff Williams says that supply chains are running well and that the company is optimistic about the future for the economy both for itself and for America as a whole.

It's not exactly surprising that with all of the uncertainty in the world, Apple decided that it couldn't provide useful revenue guidance for its fiscal Q3 ending in June. It is unexpected, however, that Apple felt confident in announcing a silver lining to the pandemic -- it expects to sell more Macs and iPads in the summer of 2020 compared to 2019.