Exploiting protein family and protein network data to identify novel drug targets for bladder cancer

Bladder cancer remains one of the most common forms of cancer and yet there are limited small molecule targeted therapies. Here, we present a computational platform to identify new potential targets for bladder cancer therapy. Our method initially exploited a set of known driver genes for bladder cancer combined with predicted bladder cancer genes from mutationally enriched protein domain families. We enriched this initial set of genes using protein network data to identify a comprehensive set of 323 putative bladder cancer targets. Pathway and cancer hallmarks analyses highlighted putative mechanisms in agreement with those previously reported for this cancer and revealed protein network modules highly enriched in potential drivers likely to be good targets for targeted therapies. 21 of our potential drug targets are targeted by FDA approved drugs for other diseases - some of them are known drivers or are already being targeted for bladder cancer (FGFR3, ERBB3, HDAC3, EGFR). A further 4 potential drug targets were identified by inheriting drug mappings across our in-house CATH domain functional families (FunFams). Our FunFam data also allowed us to identify drug targets in families that are less prone to side effects i.e., where structurally similar protein domain relatives are less dispersed across the human protein network. We provide information on our novel potential cancer driver genes, together with information on pathways, network modules and hallmarks associated with the predicted and known bladder cancer drivers and we highlight those drivers we predict to be likely drug targets

Effect of β-glucan and black tea in a functional bread on short chain fatty acid production by the gut microbiota in a gut digestion/fermentation model

β-Glucan and black tea are fermented by the colonic microbiota producing short chain fatty acids (SCFA) and phenolic acids (PA). We hypothesized that the addition of β-glucan, a dietary fiber, and tea polyphenols to a food matrix like bread will also affect starch digestion in the upper gut and thus further influence colonic fermentation and SCFA production. This study investigated SCFA and PA production from locally developed breads: white bread (WB), black tea bread (BT), β-glucan bread (βG), β-glucan plus black tea bread (βGBT). Each bread was incubated in an in vitro system mimicking human digestion and colonic fermentation. Digestion with α-amylase significantly (p = 0.0001) increased total polyphenol and polyphenolic metabolites from BT bread compared with WB, βG, and βGBT. Total polyphenols in βGBT remained higher (p = 0.016; 1.3-fold) after digestion with pepsin and pancreatin compared with WB. Fermentations containing βG and βGBT produced similar propionate concentrations ranging from 17.5 to 18.6 mmol/L and total SCFA from 46.0 to 48.9 mmol/L compared with control WB (14.0 and 37.4 mmol/L, respectively). This study suggests that combination of black tea with β-glucan in this functional bread did not impact on SCFA production. A higher dose of black tea and β-glucan or in combination with other fibers may be needed to increase SCFA production

Diagnosis of immune thrombocytopenia, including secondary forms, and selection of second-line treatment

This article summarizes our approach to the diagnosis of immune thrombocytopenia (ITP), its secondary forms, and choice of second-line treatment options. We very briefly summarize first-line treatment and then utilize a case-based approach. We first explore persistent, chronic ITP in a younger female. We consider many possibilities beyond primary ITP e.g., hypogammaglobulinemia, chronic infection, and anemia, and how to approach their diagnosis and management. The journey continues throughout pregnancy and the post-partum period and eventually includes fourth-line treatment after a late relapse. We then consider an older male, emphasizing differences in diagnostic considerations and management. The focus is on initiation and continuation of second-line treatment, the pros and cons of each option, and briefly the impact of treatment choices related to the endemic presence of severe acute respiratory syndrome coronavirus 2. During the review of potential second-line treatment options, we also briefly touch upon novel treatments. Finally, there is a short section on refractory disease drawn from our previous extensive review published in February 2020.1 The clinical nature of the discussions, replete with figures and tables and with the interspersion of pearls regarding efficacy and toxicity at different ages and genders, will serve the reader in the management of “typical” adult patients who develop persistent and chronic ITP

FOOT STRIKE PATTERN trends in sub-elite half marathon runners

The purpose of this study was to examine the changes in foot strike patterns throughout a sub elite half-marathon and examine the relationship between foot strike pattern and race performance. Race participants were filmed at mile 2, 5.5 and 12.5. Video was analysed to determine if participants used a forefoot, mid-foot strike or rear foot strike pattern at each camera. Furthermore participants were broken down in performance groups of 50 based off of time taken to reach each camera. At mile 5.5 and 12.5 significant difference in foot strike pattern (

The Mass Function of Super Giant Molecular Complexes and Implications for Forming Young Massive Star Clusters in the Antennae (NGC 4038/39)

We have used previously published observations of the CO emission from the Antennae (NGC 4038/39) to study the detailed properties of the super giant molecular complexes with the goal of understanding the formation of young massive star clusters. Over a mass range from 5E6 to 9E8 solar masses, the molecular complexes follow a power-law mass function with a slope of -1.4 +/- 0.1, which is very similar to the slope seen at lower masses in molecular clouds and cloud cores in the Galaxy. Compared to the spiral galaxy M51, which has a similar surface density and total mass of molecular gas, the Antennae contain clouds that are an order of magnitude more massive. Many of the youngest star clusters lie in the gas-rich overlap region, where extinctions as high as Av~100 imply that the clusters must lie in front of the gas. Combining data on the young clusters, thermal and nonthermal radio sources, and the molecular gas suggests that young massive clusters could have formed at a constant rate in the Antennae over the last 160 Myr and that sufficient gas exists to sustain this cluster formation rate well into the future. However, this conclusion requires that a very high fraction of the massive clusters that form initially in the Antennae do not survive as long as 100 Myr. Finally, we compare our data with two models for massive star cluster formation and conclude that the model where young massive star clusters form from dense cores within the observed super giant molecular complexes is most consistent with our current understanding of this merging system. (abbreviated)Comment: 40 pages, four figures; accepted for publication in Ap

Donated human milk use and subsequent feeding pattern in neonatal units

Background: Donated human milk (DHM) is a safe alternative in the absence of mother’s own milk (MOM); however, specific clinical indications for DHM use and its impact on subsequent feeding practice remain unclear. We aimed to audit local DHM use and explore the impact of the introduction of DHM as the first enteral feed on subsequent MOM availability. Methods: We retrospectively audited DHM recipients nursed in Royal Hospital for Children, Glasgow from 2014 to 2016 against local guidelines. Data were collected from an operational electronic database. Descriptive data analysis was performed to describe DHM use. To explore the association between the first human milk feed with subsequent MOM availability Kruskal Wallis test was used. Adjustments for confounding variables were performed using analysis of variance (ANOVA). Results: A total of 165 recipients of DHM (5.3% of all admission to RHC) were identified. The majority of recipients (69%) were born < 32 weeks of gestation. The main indication for DHM was prematurity, other indications included congenital anomalies of bowel and heart. The local guideline was adhered to in 87% of cases. The median interquartile range (IQR) at DHM introduction was 6 days (3, 17) and the duration of use was 12 days (6, 22). In those born < 32 weeks of gestation the type of human milk (DHM and/ or MOM) used as first feed did not influence the subsequent median IQR days of feeding with any MOM [DHM 40 (9, 51); MOM 28 (17, 49), MOM & DHM 17 (10, 26) p value = 0.465] after adjusting for birthweight and length of hospital stay. Conclusions: In our unit, DHM is mainly used in preterm neonates in accordance with existing local guidance. Using DHM as first milk feed did not affect subsequent MOM availability

Correlation between flocculation and adsorption of cationic polyacrylamides on precipitated calcium carbonate

The study of each stage of the flocculation process is essential to better understand and predict flocculation mechanisms. The adsorption of cationic polyacrylamide derivatives (C-PAM) onto precipitated calcium carbonate (PCC) has been investigated systematically as a function of the C-PAM characteristics including molar mass, chain architecture, and charge density. The adsorption results show that, for C-PAM of similar molar mass, highly branched architectures reach the equilibrium faster than linear C-PAM. Similarly, the flocculation rate is higher for the branched C-PAM, which may be indicative of the predominance of the bridging mechanism. In terms of the molar mass, lower molar mass leads to lower adsorption rates and slower flocculation. Adsorption isotherms of C-PAM onto precipitated calcium carbonate could be described by the Langmuir isotherm model. The maximum amount of C-PAM that adsorbs on the particle surface as a monolayer, obtained from adsorption tests through the Langmuir isotherm linear fit, could be correlated with the structure of the aggregates, obtained from flocculation experiments. Moreover, a good correlation was obtained between the adsorption results and the kinetics of the first stage of the flocculation process dominated by particle aggregation

A First Look at the Nuclear Region of M31 with Chandra

We report on the first observation of the nuclear region of M31 with the Chandra X-ray Observatory. The nuclear source seen with the Einstein and ROSAT HRIs is resolved into five point sources. One of these sources is within 1'' of the M31 central super-massive black hole. As compared to the other point sources in M31, this nuclear source has an unusual x-ray spectrum. Based on the spatial coincidence we identify this source with the central black hole, and note that the unusual spectrum is a challenge to current theories. A bright transient is detected ~26'' to the west of the nucleus, which may be associated with a stellar mass black hole.Comment: Submitted to ApJ Letters, 4 pages, 4 figures. email: garcia,ssm,fap,wrf,jem,cjf, @head-cfa.harvard.ed

KinFams: De-Novo Classification of Protein Kinases Using CATH Functional Units

Protein kinases are important targets for treating human disorders, and they are the second most targeted families after G-protein coupled receptors. Several resources provide classification of kinases into evolutionary families (based on sequence homology); however, very few systematically classify functional families (FunFams) comprising evolutionary relatives that share similar functional properties. We have developed the FunFam-MARC (Multidomain ARchitecture-based Clustering) protocol, which uses multi-domain architectures of protein kinases and specificity-determining residues for functional family classification. FunFam-MARC predicts 2210 kinase functional families (KinFams), which have increased functional coherence, in terms of EC annotations, compared to the widely used KinBase classification. Our protocol provides a comprehensive classification for kinase sequences from >10,000 organisms. We associate human KinFams with diseases and drugs and identify 28 druggable human KinFams, i.e., enriched in clinically approved drugs. Since relatives in the same druggable KinFam tend to be structurally conserved, including the drug-binding site, these KinFams may be valuable for shortlisting therapeutic targets. Information on the human KinFams and associated 3D structures from AlphaFold2 are provided via our CATH FTP website and Zenodo. This gives the domain structure representative of each KinFam together with information on any drug compounds available. For 32% of the KinFams, we provide information on highly conserved residue sites that may be associated with specificity.Adeyelu T, Bordin N, Waman VP, Sadlej M, Sillitoe I, Moya-Garcia AA, Orengo CA. KinFams: De-Novo Classification of Protein Kinases Using CATH Functional Units. Biomolecules. 2023; 13(2):277. https://doi.org/10.3390/biom1302027