The rockefeller university

Motivations bias our responses to stimuli, producing behavioural outcomes that match our needs and goals. Here we describe a mechanism behind this phenomenon: adjusting the time over which stimulus-derived information is permitted to accumulate towards a decision. As a Drosophila copulation progresses, the male becomes less likely to continue mating through challenges1-3. We show that a set of copulation decision neurons (CDNs) flexibly integrates information about competing drives to mediate this decision. Early in mating, dopamine signalling restricts CDN integration time by potentiating Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation in response to stimulatory inputs, imposing a high threshold for changing behaviours. Later into mating, the timescale over which the CDNs integrate termination-promoting information expands, increasing the likelihood of switching behaviours. We suggest scalable windows of temporal integration at dedicated circuit nodes as a key but underappreciated variable in state-based decision-making. In Drosophila, dopamine sets motivational state during mating by regulating the integration of competing drives in copulation decision neurons, potentially indicative of a more general role for control over neuronal integration time in the regulation of behavioural decisions.

Human infectious diseases are unique in that the discovery of their environmental trigger, the microbe, was sufficient to drive the development of extraordinarily effective principles and tools for their prevention or cure. This unique medical prowess has outpaced, and perhaps even hindered, the development of scientific progress of equal magnitude in the biological understanding of infectious diseases. Indeed, the hope kindled by the germ theory of disease was rapidly subdued by the infection enigma, in need of a host solution, when it was realized that most individuals infected with most infectious agents continue to do well. The root causes of disease and death in the unhappy few remained unclear. While canonical approaches in vitro (cellular microbiology), in vivo (animal models), and in natura (clinical studies) analyzed the consequences of infection with a microbe, considered to be the cause of disease, in cells, tissues, or organisms seen as a uniform host, alternative approaches searched for preexisting causes of disease, particularly human genetic and immunological determinants in populations of diverse individuals infected with a trigger microbe.

Rodents are commonly employed to model human liver conditions, although species differences can restrict their translational relevance. To overcome some of these limitations, researchers have long pursued human hepatocyte transplantation into rodents. More than 20 years ago, the first primary human hepatocyte transplantations into immunodeficient mice with liver injury were able to support hepatitis B and C virus infections, as these viruses cannot replicate in murine hepatocytes. Since then, hepatocyte chimeric mouse models have transitioned into mainstream preclinical research and are now employed in a diverse array of liver conditions beyond viral hepatitis, including malaria, drug metabolism, liver-targeting gene therapy, metabolic dysfunction-associated steatotic liver disease, lipoprotein and bile acid biology, and others. Concurrently, endeavors to cotransplant other cell types and humanize immune and other nonparenchymal compartments have seen growing success. Looking ahead, several challenges remain. These include enhancing immune functionality in mice doubly humanized with hepatocytes and immune systems, efficiently creating mice with genetically altered grafts and reliably humanizing chimeric mice with renewable cell sources such as patient-specific induced pluripotent stem cells. In conclusion, hepatocyte chimeric mice have evolved into vital preclinical models that address many limitations of traditional rodent models. Continued improvements may further expand their applications.

Assisted migration consists of the introduction of a species to previously inhabited areas or to new suitable regions. Such introductions have been touted as a viable tool for conserving the earth's biodiversity. However, both the likely success of assisted migrations and the impacts on local communities are hotly debated. Empirical data on the local impacts of assisted migration are particularly lacking. We examined the short and long time-scale effects of herbivory on Lonicera involucrata (Richards) Banks ex. Spreng (Caprifoliaceae) after an introduction of Euphydryas gillettii Barnes (Lepidoptera: Nymphalidae, Melitaeini) to Gunnison County, Colorado, USA, via an assisted migration in 1977. The plant is the primary larval host plant for the butterfly. We quantified plant seed production, plant survival, and population stage structure in two sets of observational experiments. We found that herbivory by E. gillettii increased L. involucrata reproduction on an annual time scale, independent of plant size and local microhabitat characteristics. Over the time since the butterfly's introduction, herbivory by E. gillettii resulted in a plant population structure biased toward smaller plants in the butterfly introduction and satellite sites compared with sites without the butterfly. Our results highlight the importance of studying the effects of assisted migrations on native populations at different temporal scales. As assisted migration becomes an indispensable tool for species conservation, our work adds to the understanding of the multi-trophic impacts of assisted introductions on local populations and communities.

Based on the primes less than 4 x 10(18), Oliveira e Silva et al. (Math. Comp., 83(288):2033-2060, 2014) conjectured an asymptotic formula for the sum of the kth power of the gaps between consecutive primes less than a large number x. We show that the conjecture of Oliveira e Silva holds if and only if the kth moment of the first n gaps is asymptotic to the kth moment of an exponential distribution with mean log n, though the distribution of gaps is not exponential. Asymptotically exponential moments imply that the gaps asymptotically obey Taylor's law of fluctuation scaling: variance of the first n gaps similar to (mean of the first n gaps)(2). If the distribution of the first n gaps is asymptotically exponential with mean log n, then the expectation of the largest of the first n gaps is asymptotic to ( log n)(2). The largest of the first n gaps is asymptotic to ( log n)(2) if and only if the Cramer-Shanks conjecture holds. Numerical counts of gaps and the maximal gap Gn among the first n gaps test these results. While most values of Gn are better approximated by ( log n)2 than by other models, seven exceptional values of n with G(n)>2e(-gamma)( log n)(2) suggest that lim sup(n ->infinity)G(n)/[2e(-gamma)( log n)(2)] may exceed 1.

Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma. The prodrug gliocidin effectively kills glioblastoma cells by targeting de novo purine synthesis, improving survival in mouse models.

Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Association Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions and even pinpoint genes that are distant from the variants implicated by GWAS. In particular, our analysis identified solute carrier family 25 member 48 (SLC25A48) as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite betaine. Integrative rare variant and polygenic score analyses in UK Biobank provide strong evidence that the SLC25A48 causal effects on human disease may in part be mediated by the effects of choline. Altogether, our study provides a discovery platform for metabolic gene function and proposes SLC25A48 as a mitochondrial choline transporter. This study presents a multiomic Gene-Metabolite Association Prediction (GeneMAP) platform for discovery of metabolic gene function and identifies SLC25A48 as a mediator of mitochondrial choline import.

Lipid droplets are fat storage organelles composed of a protein envelope and lipid-rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid-mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.

Advances in antibody technologies have resulted in the development of potent antibody-based therapeutics with proven clinical efficacy against infectious diseases. Several monoclonal antibodies (mAbs), mainly against viruses such as SARS-CoV-2, HIV-1, Ebola virus, influenza virus, and hepatitis B virus, are currently undergoing clinical testing or are already in use. Although these mAbs exhibit potent neutralizing activity that effectively blocks host cell infection, their antiviral activity results not only from Fab-mediated virus neutralization, but also from the protective effector functions mediated through the interaction of their Fc domains with Fc gamma receptors (Fc gamma Rs) on effector leukocytes. Fc-Fc gamma R interactions confer pleiotropic protective activities, including the clearance of opsonized virions and infected cells, as well as the induction of antiviral T-cell responses. However, excessive or inappropriate activation of specific Fc gamma R pathways can lead to disease enhancement and exacerbated pathology, as seen in the context of dengue virus infections. A comprehensive understanding of the diversity of Fc effector functions during infection has guided the development of engineered antiviral antibodies optimized for maximal effector activity, as well as the design of targeted therapeutic approaches to prevent antibody-dependent enhancement of disease.

Severe defects in human IFN gamma immunity predispose individuals to both Bacillus Calmette-Gu & eacute;rin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN gamma. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Gu & eacute;rin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.