The rockefeller university

Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and an SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4. Here, we demonstrate that the classical nonhomologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS, coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in COCA7- and HELLS-deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of gamma H2AX signals. Although less prominent, cells with mutations in the other ICF genes DNMT3B and ZBTB24 (responsible for ICF types 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis.

We report crystal structures of the antibacterial lasso peptides microcin J25 (MccJ25) and capistruin (Cap) bound to their natural enzymatic target, the bacterial RNA polymerase (RNAP). Both peptides bind within the RNAP secondary channel, through which NTP substrates enter the RNAP active site, and sterically block trigger-loop folding, which is essential for efficient catalysis by the RNAP. MccJ25 binds deep within the secondary channel in a manner expected to interfere with NTP substrate binding, explaining the partial competitive mechanism of inhibition with respect to NTPs found previously [Mukhopadhyay J, Sineva E, Knight J, Levy RM, Ebright RH (2004) Mol Cell 14:739-751]. The Cap binding determinant on RNAP overlaps, but is not identical to, that of MccJ25. Cap binds further from the RNAP active site and does not sterically interfere with NTP binding, and we show that Cap inhibition is partially noncompetitive with respect to NTPs. This work lays the groundwork for structure determination of other lasso peptides that target the bacterial RNAP and provides a structural foundation to guide lasso peptide antimicrobial engineering approaches.

A major function of the nervous system is to transmit information between the body and the brain. The vagus nerve, also known as the tenth cranial nerve, is an important conduit for brain-body communication and has been identified as a focus of bioelectronic therapies. Current neuromodulation therapies, such as vagus nerve stimulation (VNS), lack fiber-and molecular-specificity as they involve electrical stimulation of the entire nerve bundle. This results in recruitment of fiber types based on electrical properties rather than molecular specificity. To better understand the contributions of different fiber subtypes in the vagus nerve, we utilized optogenetics to record light-evoked compound actions potentials (CAPs) in TRPV1-ChR2-YFP and ChAT-ChR2-YFP mice. We found that direct photostimulation of TRPV1-ChR2 on the vagus nerve evoked large amplitude CAPs, while the same light stimulation in ChAT-ChR2 mice produced smaller amplitude CAPs. We also found that the amplitude of light-evoked CAPs decreased at a higher photostimulation frequency (25 Hz). Our results show that fiber-specific activation of the sensory afferent and motor efferent pathways in the vagus nerve produce discrete evoked CAPs. This can be used to decipher different neurotransmitter contributions in vagus nerve signaling for both the afferent and efferent pathways, thereby opening an avenue for potential selective, fiber-specific neuromodulation of the vagus nerve.

Glia are abundant components of animal nervous systems. Recognized 170

Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional "one-size-fits-all" therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation.

The mean and variance of a sum of a random number of random variables are well known when the number of summands is independent of each summand and when the summands are independent and identically distributed (iid), or when all summands are identical. In scientific and financial applications, the preceding conditions are often too restrictive. Here, we calculate the mean and variance of a sum of a random number of random summands when the mean and variance of each summand depend on the number of summands and when every pair of summands has the same correlation. This article shows that the variance increases with the correlation between summands and equals the variance in the iid or identical cases when the correlation is zero or one.

N-6-methyladenosine (m(6)A) is the most prevalent internal methylation in messenger RNA (mRNA). This biochemically reversible modification is deposited by m(6)A methyltransferases, removed by m(6)A demethylases and recognized by different RNA-binding proteins. Depending on the localization of m(6)A and its reader proteins, an array of cellular processes ranging from RNA maturation and export in nucleus, to degradation and translation in cytoplasm, can be affected and consequently lead to diverse cell fates. The essential role of m(6)A in normal tissue development as well as tumor progression has been revealed in the past few years, emphasizing an additional layer of gene expression regulation.

Besides failing for the reasons Brette gives, codes fail to help us understand brain function because codes imply algorithms that compute outputs without reference to the signals' meanings. Algorithms cannot be found in the brain, only manipulations that operate on meaningful signals and that cannot be described as computations, that is, sequences of predefined operations.