Institute of Science and Technology Austria

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

We study the problem of object recognition for categories for which we have no training examples, a task also called zero--data or zero-shot learning. This situation has hardly been studied in computer vision research, even though it occurs frequently; the world contains tens of thousands of different object classes, and image collections have been formed and suitably annotated for only a few of them. To tackle the problem, we introduce attribute-based classification: Objects are identified based on a high-level description that is phrased in terms of semantic attributes, such as the object's color or shape. Because the identification of each such property transcends the specific learning task at hand, the attribute classifiers can be prelearned independently, for example, from existing image data sets unrelated to the current task. Afterward, new classes can be detected based on their attribute representation, without the need for a new training phase. In this paper, we also introduce a new data set, Animals with Attributes, of over 30,000 images of 50 animal classes, annotated with 85 semantic attributes. Extensive experiments on this and two more data sets show that attribute-based classification indeed is able to categorize images without access to any training images of the target classes.

Due to the importance of zero-shot learning, i.e., classifying images where there is a lack of labeled training data, the number of proposed approaches has recently increased steadily. We argue that it is time to take a step back and to analyze the status quo of the area. The purpose of this paper is three-fold. First, given the fact that there is no agreed upon zero-shot learning benchmark, we first define a new benchmark by unifying both the evaluation protocols and data splits of publicly available datasets used for this task. This is an important contribution as published results are often not comparable and sometimes even flawed due to, e.g., pre-training on zero-shot test classes. Moreover, we propose a new zero-shot learning dataset, the Animals with Attributes 2 (AWA2) dataset which we make publicly available both in terms of image features and the images themselves. Second, we compare and analyze a significant number of the state-of-the-art methods in depth, both in the classic zero-shot setting but also in the more realistic generalized zero-shot setting. Finally, we discuss in detail the limitations of the current status of the area which can be taken as a basis for advancing it.

Background Neuronal networks in the brain include glutamatergic principal neurons and GABAergic interneurons (GABA, γ-aminobutyric acid). The latter may be a minority cell type, but they are vital for normal brain function because they regulate the activity of principal neurons. If interneuron function is impaired, higher brain function can be damaged and seizures may result. The fast-spiking, parvalbumin-positive interneurons (PV + interneurons) are readily characterized and, consequently, have been adopted as a research model for systematic and quantitative investigations. These cells contribute to feedback and feedforward inhibition and are critically involved in the generation of network oscillations. They can convert an excitatory input signal into an inhibitory output signal within a millisecond, but it is unclear how these signaling properties are implemented at the molecular and cellular levels, nor how PV + interneurons shape complex network functions. Advances Recent work sheds light on the subcellular signaling properties of PV + interneurons. PV + cells show a high degree of polarity. The weakly excitable dendrites allow PV + interneurons to sample activity in the surrounding network, whereas the highly excitable axons enable analog-to-digital conversion and fast propagation of the digital signal to a large number of target cells. Additionally, tight coupling of Ca 2+ channels and release sensors at GABAergic output synapses increases the efficacy and speed of the inhibitory output. Recent results also provide a better understanding of how PV + interneurons operate in neuronal networks. Not only are PV + interneurons involved in basic microcircuit functions, such as feedforward and feedback inhibition or gamma-frequency oscillations, but they also play a role in complex network operations, including expansion of dynamic activity range, pattern separation, modulation of place and grid field shapes, phase precession, and gain modulation of sensory responses. Thus, PV + interneurons are critically involved in advanced computations in microcircuits and neuronal networks. Outlook Parvalbumin-expressing interneurons may also play a key role in numerous brain diseases. These include epilepsy, but also complex psychiatric diseases such as schizophrenia. Thus, PV + interneurons may become important therapeutic targets in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will have a chance to successfully use PV + interneurons for therapeutic purposes.

The goal of limiting global warming to 1.5 °C requires a drastic reduction in CO 2 emissions across many sectors of the world economy. Batteries are vital to this endeavor, whether used in electric vehicles, to store renewable electricity, or in aviation. Present lithium-ion technologies are preparing the public for this inevitable change, but their maximum theoretical specific capacity presents a limitation. Their high cost is another concern for commercial viability. Metal–air batteries have the highest theoretical energy density of all possible secondary battery technologies and could yield step changes in energy storage, if their practical difficulties could be overcome. The scope of this review is to provide an objective, comprehensive, and authoritative assessment of the intensive work invested in nonaqueous rechargeable metal–air batteries over the past few years, which identified the key problems and guides directions to solve them. We focus primarily on the challenges and outlook for Li–O 2 cells but include Na–O 2, K–O 2, and Mg–O 2 cells for comparison. Our review highlights the interdisciplinary nature of this field that involves a combination of materials chemistry, electrochemistry, computation, microscopy, spectroscopy, and surface science. The mechanisms of O 2 reduction and evolution are considered in the light of recent findings, along with developments in positive and negative electrodes, electrolytes, electrocatalysis on surfaces and in solution, and the degradative effect of singlet oxygen, which is typically formed in Li–O 2 cells.

Auxin participates in a multitude of developmental processes, as well as responses to environmental cues. Compared with other plant hormones, auxin exhibits a unique property, as it undergoes directional, cell-to-cell transport facilitated by plasma membrane-localized transport proteins. Among them, a prominent role has been ascribed to the PIN family of auxin efflux facilitators. PIN proteins direct polar auxin transport on account of their asymmetric subcellular localizations. In this review, we provide an overview of the multiple developmental roles of PIN proteins, including the atypical endoplasmic reticulum-localized members of the family, and look at the family from an evolutionary perspective. Next, we cover the cell biological and molecular aspects of PIN function, in particular the establishment of their polar subcellular localization. Hormonal and environmental inputs into the regulation of PIN action are summarized as well.

In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI:http://dx.doi.org/10.7554/eLife.00747.001.

Differential cell adhesion and cortex tension are thought to drive cell sorting by controlling cell-cell contact formation. Here, we show that cell adhesion and cortex tension have different mechanical functions in controlling progenitor cell-cell contact formation and sorting during zebrafish gastrulation. Cortex tension controls cell-cell contact expansion by modulating interfacial tension at the contact. By contrast, adhesion has little direct function in contact expansion, but instead is needed to mechanically couple the cortices of adhering cells at their contacts, allowing cortex tension to control contact expansion. The coupling function of adhesion is mediated by E-cadherin and limited by the mechanical anchoring of E-cadherin to the cortex. Thus, cell adhesion provides the mechanical scaffold for cell cortex tension to drive cell sorting during gastrulation.

Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function and are characterized by wide genetic and clinical variability. In this review, we discuss the multiple factors that influence the clinical presentation of NDDs, with particular attention to gene vulnerability, mutational load, and the two-hit model. Despite the complex architecture of mutational events associated with NDDs, the various proteins involved appear to converge on common pathways, such as synaptic plasticity/function, chromatin remodelers and the mammalian target of rapamycin (mTOR) pathway. A thorough understanding of the mechanisms behind these pathways will hopefully lead to the identification of candidates that could be targeted for treatment approaches.

Speciation results from the progressive accumulation of mutations that decrease the probability of mating between parental populations or reduce the fitness of hybrids-the so-called species barriers. The speciation genomic literature, however, is mainly a collection of case studies, each with its own approach and specificities, such that a global view of the gradual process of evolution from one to two species is currently lacking. Of primary importance is the prevalence of gene flow between diverging entities, which is central in most species concepts and has been widely discussed in recent years. Here, we explore the continuum of speciation thanks to a comparative analysis of genomic data from 61 pairs of populations/species of animals with variable levels of divergence. Gene flow between diverging gene pools is assessed under an approximate Bayesian computation (ABC) framework. We show that the intermediate "grey zone" of speciation, in which taxonomy is often controversial, spans from 0.5% to 2% of net synonymous divergence, irrespective of species life history traits or ecology. Thanks to appropriate modeling of among-locus variation in genetic drift and introgression rate, we clarify the status of the majority of ambiguous cases and uncover a number of cryptic species. Our analysis also reveals the high incidence in animals of semi-isolated species (when some but not all loci are affected by barriers to gene flow) and highlights the intrinsic difficulty, both statistical and conceptual, of delineating species in the grey zone of speciation.

Directional guidance of cells via gradients of chemokines is considered crucial for embryonic development, cancer dissemination, and immune responses. Nevertheless, the concept still lacks direct experimental confirmation in vivo. Here, we identify endogenous gradients of the chemokine CCL21 within mouse skin and show that they guide dendritic cells toward lymphatic vessels. Quantitative imaging reveals depots of CCL21 within lymphatic endothelial cells and steeply decaying gradients within the perilymphatic interstitium. These gradients match the migratory patterns of the dendritic cells, which directionally approach vessels from a distance of up to 90-micrometers. Interstitial CCL21 is immobilized to heparan sulfates, and its experimental delocalization or swamping the endogenous gradients abolishes directed migration. These findings functionally establish the concept of haptotaxis, directed migration along immobilized gradients, in tissues.

In the 1960s-1980s, determination of bacterial growth rates was an important tool in microbial genetics, biochemistry, molecular biology, and microbial physiology. The exciting technical developments of the 1990s and the 2000s eclipsed that tool; as a result, many investigators today lack experience with growth rate measurements. Recently, investigators in a number of areas have started to use measurements of bacterial growth rates for a variety of purposes. Those measurements have been greatly facilitated by the availability of microwell plate readers that permit the simultaneous measurements on up to 384 different cultures. Only the exponential (logarithmic) portions of the resulting growth curves are useful for determining growth rates, and manual determination of that portion and calculation of growth rates can be tedious for high-throughput purposes. Here, we introduce the program GrowthRates that uses plate reader output files to automatically determine the exponential portion of the curve and to automatically calculate the growth rate, the maximum culture density, and the duration of the growth lag phase. GrowthRates is freely available for Macintosh, Windows, and Linux. We discuss the effects of culture volume, the classical bacterial growth curve, and the differences between determinations in rich media and minimal (mineral salts) media. This protocol covers calibration of the plate reader, growth of culture inocula for both rich and minimal media, and experimental setup. As a guide to reliability, we report typical day-to-day variation in growth rates and variation within experiments with respect to position of wells within the plates.

Recent experiments on Rydberg-atom quantum simulators have observed surprising signatures of nonergodic quantum dynamics, which has been attributed to the emergence of ``many-body quantum scars.'' Here, the authors present a detailed study of the eigenstate properties of strongly interacting Rydberg-atom chains, identifying distinct families of quantum scarred states that are responsible for the revivals in the quench dynamics. The results show that quantum scarred states have distinct features, such as subthermal entanglement and anomalous expectation values of local observables. The presence of scarred eigenstates leaves an imprint on the rest of the many-body spectrum, leading to a weak breakdown of ergodicity.

Abstract Characterizing the prevalence and properties of faint active galactic nuclei (AGNs) in the early Universe is key for understanding the formation of supermassive black holes (SMBHs) and determining their role in cosmic reionization. We perform a spectroscopic search for broad H α emitters at z ≈ 4–6 using deep JWST/NIRCam imaging and wide field slitless spectroscopy from the EIGER and FRESCO surveys. We identify 20 H α lines at z = 4.2–5.5 that have broad components with line widths from ∼1200–3700 km s −1 , contributing ∼30%–90% of the total line flux. We interpret these broad components as being powered by accretion onto SMBHs with implied masses ∼10 7–8 M ⊙ . In the UV luminosity range M UV,AGN+host = −21 to −18, we measure number densities of ≈10 −5 cMpc −3 . This is an order of magnitude higher than expected from extrapolating quasar UV luminosity functions (LFs). Yet, such AGN are found in only <1% of star-forming galaxies at z ∼ 5. The number density discrepancy is much lower when compared to the broad H α LF. The SMBH mass function agrees with large cosmological simulations. In two objects, we detect complex H α profiles that we tentatively interpret as caused by absorption signatures from dense gas fueling SMBH growth and outflows. We may be witnessing early AGN feedback that will clear dust-free pathways through which more massive blue quasars are seen. We uncover a strong correlation between reddening and the fraction of total galaxy luminosity arising from faint AGN. This implies that early SMBH growth is highly obscured and that faint AGN are only minor contributors to cosmic reionization.

3D amoeboid cell migration is central to many developmental and disease-related processes such as cancer metastasis. Here, we identify a unique prototypic amoeboid cell migration mode in early zebrafish embryos, termed stable-bleb migration. Stable-bleb cells display an invariant polarized balloon-like shape with exceptional migration speed and persistence. Progenitor cells can be reversibly transformed into stable-bleb cells irrespective of their primary fate and motile characteristics by increasing myosin II activity through biochemical or mechanical stimuli. Using a combination of theory and experiments, we show that, in stable-bleb cells, cortical contractility fluctuations trigger a stochastic switch into amoeboid motility, and a positive feedback between cortical flows and gradients in contractility maintains stable-bleb cell polarization. We further show that rearward cortical flows drive stable-bleb cell migration in various adhesive and non-adhesive environments, unraveling a highly versatile amoeboid migration phenotype.

During corticogenesis, distinct subtypes of neurons are sequentially born from ventricular zone progenitors. How these cells are molecularly temporally patterned is poorly understood. We used single-cell RNA sequencing at high temporal resolution to trace the lineage of the molecular identities of successive generations of apical progenitors (APs) and their daughter neurons in mouse embryos. We identified a core set of evolutionarily conserved, temporally patterned genes that drive APs from internally driven to more exteroceptive states. We found that the Polycomb repressor complex 2 (PRC2) epigenetically regulates AP temporal progression. Embryonic age-dependent AP molecular states are transmitted to their progeny as successive ground states, onto which essentially conserved early postmitotic differentiation programs are applied, and are complemented by later-occurring environment-dependent signals. Thus, epigenetically regulated temporal molecular birthmarks present in progenitors act in their postmitotic progeny to seed adult neuronal diversity.

Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ?8-9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ?1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

Thermoelectric materials allow for direct conversion between heat and electricity, offering the potential for power generation. The average dimensionless figure of merit ZT ave determines device efficiency. N-type tin selenide crystals exhibit outstanding three-dimensional charge and two-dimensional phonon transport along the out-of-plane direction, contributing to a high maximum figure of merit Z max of ~3.6 × 10 −3 per kelvin but a moderate ZT ave of ~1.1. We found an attractive high Z max of ~4.1 × 10 −3 per kelvin at 748 kelvin and a ZT ave of ~1.7 at 300 to 773 kelvin in chlorine-doped and lead-alloyed tin selenide crystals by phonon-electron decoupling. The chlorine-induced low deformation potential improved the carrier mobility. The lead-induced mass and strain fluctuations reduced the lattice thermal conductivity. Phonon-electron decoupling plays a critical role to achieve high-performance thermoelectrics.

Contractile actomyosin rings drive various fundamental morphogenetic processes ranging from cytokinesis to wound healing. Actomyosin rings are generally thought to function by circumferential contraction. Here, we show that the spreading of the enveloping cell layer (EVL) over the yolk cell during zebrafish gastrulation is driven by a contractile actomyosin ring. In contrast to previous suggestions, we find that this ring functions not only by circumferential contraction but also by a flow-friction mechanism. This generates a pulling force through resistance against retrograde actomyosin flow. EVL spreading proceeds normally in situations where circumferential contraction is unproductive, indicating that the flow-friction mechanism is sufficient. Thus, actomyosin rings can function in epithelial morphogenesis through a combination of cable-constriction and flow-friction mechanisms.

During metastasis, malignant cells escape the primary tumor, intravasate lymphatic vessels, and reach draining sentinel lymph nodes before they colonize distant organs via the blood circulation. Although lymph node metastasis in cancer patients correlates with poor prognosis, evidence is lacking as to whether and how tumor cells enter the bloodstream via lymph nodes. To investigate this question, we delivered carcinoma cells into the lymph nodes of mice by microinfusing the cells into afferent lymphatic vessels. We found that tumor cells rapidly infiltrated the lymph node parenchyma, invaded blood vessels, and seeded lung metastases without involvement of the thoracic duct. These results suggest that the lymph node blood vessels can serve as an exit route for systemic dissemination of cancer cells in experimental mouse models. Whether this form of tumor cell spreading occurs in cancer patients remains to be determined.