The rockefeller university

Significance: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics. Aim: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration. Approach: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves. Results: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs. Conclusions: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License.

Nutrient limitation drives competition for resources across organisms. However, much is unknown about how selective pressures resulting from nutrient limitation shape microbial coding sequences. Here, we study this "resource-driven selection" by using metagenomic and single-cell data of marine microbes, alongside environmental measurements. We show that a significant portion of the selection exerted on microbes is explained by the environment and is associated with nitrogen availability. Notably, this resource conservation optimization is encoded in the structure of the standard genetic code, providing robustness against mutations that increase carbon and nitrogen incorporation into protein sequences. This robustness generalizes to codon choices from multiple taxa across all domains of life, including the human genome.

Early-life stress involved in the programming of stress-related illnesses can have a toxic influence on the functioning of the nigrostriatal motor system during aging. We examined the effects of perinatal stress (PRS) on the neurochemical, electrophysiological, histological, neuroimaging, and behavioral correlates of striatal motor function in adult (4 months of age) and old (21 months of age) male rats. Adult PRS offspring rats showed reduced dopamine (DA) release in the striatum associated with reductions in tyrosine hydroxylase-positive (TH+) cells and DA transporter (DAT) levels, with no loss of striatal dopaminergic terminals as assessed by positron emission tomography analysis with fluorine-18-l-dihydroxyphenylalanine. Striatal levels of DA and its metabolites were increased in PRS rats. In contrast, D-2 DA receptor signaling was reduced and A(2A) adenosine receptor signaling was increased in the striatum of adult PRS rats. This indicated enhanced activity of the indirect pathway of the basal ganglia motor circuit. Adult PRS rats also showed poorer performance in the grip strength test and motor learning tasks. The aged PRS rats also showed a persistent reduction in striatal DA release and defective motor skills in the pasta matrix and ladder rung walking tests. In addition, the old rats showed large increases in the levels of SNAP-25 and synaptophysin, which are synaptic vesicle-related proteins in the striatum, and in the PRS group only, reductions in Syntaxin-1 and Rab3a protein levels were observed. Our findings indicated that the age-dependent threshold for motor dysfunction was lowered in PRS rats. This area of research is underdeveloped, and our study suggests that early-life stress can contribute to an increased understanding of how aging diseases are programmed in early-life.

Affecting basic tenets of human existence such as health, economic as well as personal security and, of course, reproduction, the COVID-19 pandemic transcended medical specialties and professional disciplines. Yet, six months into the pandemic, there still exists no consensus on how to combat the virus in absence of a vaccine. Facing unprecedented circumstances, and in absence of real evidence on how to proceed, our organization early in the pandemic decided to act independently from often seemingly irrational guidance and, instead, to carefully follow a quickly evolving COVID-19 literature. Here described is the, likely, unique journey of a fertility center that maintained services during peaks of COVID-19 and political unrest that followed. Closely following publicly available data, we recognized relatively early that New York City and other East Coast regions, which during the initial COVID-19 wave between March and May represented the hardest-hit areas in the country, during the second wave, beginning in June and still in progress, remained almost completely unaffected. In contrast, south western regions, almost completely unaffected by the initial wave, were severely affected in the second wave. These two distinctively different infectious phenotypes suggested two likely explanations: The country was witnessing infections with two different SARS-CoV-2 viruses and NYC (along with the East Coast) acquired during the first wave much better immunity to the virus than south western regions. Both hypotheses since have been confirmed: East and West Coasts, indeed, were initially infected by two distinctively different lineages of the virus, with the East Coast lineage being 10-times more infectious. In addition, immunologists discovered an up to this point unknown long-term anti-viral innate (cellular) immune response which offers additional and much broader anti-viral immunity than the classical adaptive immunity via immobilizing antibodies that has been known for decades. Consequently, we predict that in the U.S., even in absence of an available vaccine, COVID-19, by September-October, will be at similarly low levels as are currently seen in NYC and other East Coast regions (generally < 1% test-positivity). We, furthermore, predict that, if current mitigation measures are maintained and no newly aggressive mutation of the virus enters the country, a significant fall-wave of COVID-19, in combination with the usual fall wave of influenza, appears unlikely. To continue serving patients uninterrupted throughout the pandemic, turned for all of our center's staff into a highly rewarding experience, garnered respect and appreciation from patients, and turned into an absolutely unique learning experience.

Gene and cell therapy products approved over the past decade in Europe and North America have provided new therapeutic options for single gene disorders and for hematologic malignancies. Lessons learned, and limitations identified, are reviewed.

Recent years have seen a surge in methods to track and analyze animal behavior. Nevertheless, tracking individuals in closely interacting, group-living organisms remains a challenge. Here, we present anTraX, an algorithm and software package for high-throughput video tracking of color-tagged insects. anTraX combines neural network classification of animals with a novel approach for representing tracking data as a graph, enabling individual tracking even in cases where it is difficult to segment animals from one another, or where tags are obscured. The use of color tags, a well-established and robust method for marking individual insects in groups, relaxes requirements for image size and quality, and makes the software broadly applicable. anTraX is readily integrated into existing tools and methods for automated image analysis of behavior to further augment its output. anTraX can handle large-scale experiments with minimal human involvement, allowing researchers to simultaneously monitor many social groups over long time periods.

Interactions between microbial symbionts influence their demography and that of their hosts. Taylor's power law (TL)-a well-established relationship between population size mean and variance across space and time-may help to unveil the factors and processes that determine symbiont multiplications. Recent studies suggest pervasive interactions between symbionts in Drosophila melanogaster. We used this system to investigate theoretical predictions regarding the effects of interspecific interactions on TL parameters. We assayed twenty natural strains of bacteria in the presence and absence of a strain of yeast using an ecologically realistic set-up with D. melanogaster larvae reared in natural fruit. Yeast presence led to a small increase in bacterial cell numbers; bacterial strain identity largely affected yeast multiplication. The spatial version of TL held among bacterial and yeast populations with slopes of 2. However, contrary to theoretical prediction, the facilitation of bacterial symbionts by yeast had no detectable effect on TL's parameters. These results shed new light on the nature of D. melanogaster's symbiosis with yeast and bacteria. They further reveal the complexity of investigating TL with microorganisms.

Immunological memory is required for protection against repeated infections and is the basis of all effective vaccines. Antibodies produced by memory B cells play an essential role in many of these responses. We have combined lineage tracing with antibody cloning from single B cells to examine the role of affinity in B cell selection into germinal centers (GCs) and the memory B cell compartment in mice immunized with an HIV-1 antigen. We find that contemporaneously developing memory and GC B cells differ in their affinity for antigen throughout the immune response. Whereas GC cells and their precursors are enriched in antigen binding, memory B cells are not. Thus, the polyclonal memory B cell compartment is composed of B cells that were activated during the immune response but whose antigen binding affinity failed to support further clonal expansion in the GC.

The synthesis of ATP, life's "universal energy currency," is the most prevalent chemical reaction in biological systems and is responsible for fueling nearly all cellular processes, from nerve impulse propagation to DNA synthesis. ATP synthases, the family of enzymes that carry out this endless task, are nearly as ubiquitous as the energy-laden molecule they are responsible for making. The F-type ATP synthase (F-ATPase) is found in every domain of life and has facilitated the survival of organisms in a wide range of habitats, ranging from the deep-sea thermal vents to the human intestine. Accordingly, there has been a large amount of work dedicated toward understanding the structural and functional details of ATP synthases in a wide range of species. Less attention, however, has been paid toward integrating these advances in ATP synthase molecular biology within the context of its evolutionary history. In this review, we present an overview of several structural and functional features of the F-type ATPases that vary across taxa and are purported to be adaptive or otherwise evolutionarily significant: ion channel selectivity, rotor ring size and stoichiometry, ATPase dimeric structure and localization in the mitochondrial inner membrane, and interactions with membrane lipids. We emphasize the importance of studying these features within the context of the enzyme's particular lipid environment. Just as the interactions between an organism and its physical environment shape its evolutionary trajectory, ATPases are impacted by the membranes within which they reside. We argue that a comprehensive understanding of the structure, function, and evolution of membrane proteins-including ATP synthase-requires such an integrative approach.

Following oxycodone (Oxy) conditioned place preference (CPP), delta opioid receptors (DORs) differentially redistribute in hippocampal CA3 pyramidal cells in female and male rats in a manner that would promote plasticity and opioid-associative learning processes. However, following chronic immobilization stress (CIS), males do not acquire Oxy-CPP and the trafficking of DORs in CA3 pyramidal neurons is attenuated. Here, we examined the subcellular distribution of DORs in CA1 pyramidal cells using electron microscopy in these same cohorts. CPP: Saline (Sal)-females compared to Sal-males have more cytoplasmic and total DORs in dendrites and more DOR-labeled spines. Following Oxy-CPP, DORs redistribute from near-plasmalemma pools in dendrites to spines in males. CIS: Control females compared to control males have more near-plasmalemmal dendritic DORs. Following CIS, dendritic DORs are elevated in the cytoplasm in females and near-plasmalemma in males. CIS plus CPP: CIS Sal-females compared to CIS Sal-males have more DORs on the plasmalemma of dendrites and in spines. After Oxy, the distribution of DORs does not change in either females or males. Conclusion: Following Oxy-CPP, DORs within CA1 pyramidal cells remain positioned in naive female rats to enhance sensitivity to DOR agonists and traffic to dendritic spines in naive males where they can promote plasticity processes. Following CIS plus behavioral enrichment, DORs are redistributed within CA1 pyramidal cells in females in a manner that could enhance sensitivity to DOR agonists. Conversely, CIS plus behavioral enrichment does not alter DORs in CA1 pyramidal cells in males, which may contribute to their diminished capacity to acquire Oxy-CPP.