PREDICT: a method for inferring novel drug indications with application to personalized medicine

Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large‐scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug–drug and disease–disease similarity measures for the prediction task. On cross‐validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue‐specific expression information on the drug targets. We further show that disease‐specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease‐specific signatures.     

Predictors and Outcomes of Infection-Related Hospital Admissions of Heart Failure Patients

Background

Infections are one of the most common causes for hospitalization of patients with heart failure (HF). Yet, little is known regarding the prevalence and predictors of different types of acute infections as well as their impact on outcome among this growing population.

Methods and Results

We identified all patients aged 50 or older with a major diagnosis of HF and at least one echocardiography examination who had been hospitalized over a 10-year period (January 2000 and December 2009). Infection-associated admissions were identified according to discharge diagnoses. Among 9,335 HF patients, 3530 (38%) were hospitalized at least once due to infections. The most frequent diagnoses were respiratory infection (52.6%) and sepsis/bacteremia (23.6%) followed by urinary (15.7%) and skin and soft tissue infections (7.8%). Hospitalizations due to infections compared to other indications were associated with increased 30-day mortality (13% vs. 8%, p<0.0001). These higher mortality rates were predominately related to respiratory infections (OR 1.28 [95% CI 1.09, 1.5]) and sepsis\bacteremia (OR 3.13 [95% CI 2.6, 3.7]). Important predictors for these serious infections included female gender, chronic obstructive pulmonary disease, past myocardial infarction and echocardiography-defined significant right (RV) but not left ventricular dysfunction.

Conclusions

Major infection-related hospitalizations are frequent among patients with HF and are associated with increased mortality rates. Elderly female patients with multiple comorbidities and those with severe RV dysfunction are at higher risk for these infections.     

On the contribution of water-mediated interactions to protein-complex stability

Protein-water interactions have long been recognized as a major determinant of chain folding, conformational stability, binding specificity and catalysis. However, the detailed effects of water on stabilizing protein-protein interactions remain elusive. A way to test experimentally the contribution of water-mediated interactions is by applying double mutant cycle analysis on pairs of residues that do not form direct interactions, but are bridged by water. Seven such interactions within the interface between TEM1 and BLIP proteins were evaluated. No significant interaction free energy was found between either of them. Water can bridge interactions, but also stabilize the structure of the monomer. To distinguish between these, we performed a bioinformatic analysis using AQUAPROT (http://bioinfo.weizmann.ac.il/aquaprot) to determine the degree of water conservation between the bound and unbound states. 29 structures of twelve complexes and 20 related monomers were analyzed. Of the 262 water molecules located within the interfaces, 145 were conserved between the unbound and bound structures. Strikingly, all 50 buried or partially buried waters in the monomer structures were conserved at the same location in the bound structures. Thus, buried waters have an important role in stabilizing the monomer fold rather than contributing to protein-protein binding, and are not replaced by residues from the incoming protein. Taking together the experimental and bioinformatics evidence suggests that exposed waters within the interface may be good sites for protein engineering, while buried or mostly buried waters should be left unchanged.     

Documented Utility and Biocultural Value of <Emphasis Type="Italic">Aloe</Emphasis> L. (Asphodelaceae): A Review

Documented Utility and Biocultural Value of Aloe L. (Asphodelaceae): A Review. The genus Aloe L. (Asphodelaceae) comprises 548 accepted species, of which at least one-third are documented as having some utilitarian value. The group is of conservation concern due to habitat loss and being extensively collected from the wild for horticulture and natural products. Cultural value is increasingly important in the effective conservation of biodiversity. The present study evaluated the biocultural value of the known uses of Aloe, excluding the domesticated and commercially cultivated A. vera. Over 1,400 use records representing 173 species were collated from the literature and through personal observation; this paper presents a synopsis of uses in each of 11 use categories. Medicinal uses of Aloe were described by 74% of the use records, followed by social and environmental uses (both 5%). Species yielding natural products, notably A. ferox and A. perryi, were most frequently cited in the literature. Consensus ratios indicate that the most valued uses of Aloe are in medicine and pest control against arthropods and other invertebrates.     

The Methylosome, a 20S Complex Containing JBP1 and pICln, Produces Dimethylarginine-Modified Sm Proteins

snRNPs, integral components of the pre-mRNA splicing machinery, consist of seven Sm proteins which assemble in the cytoplasm as a ring structure on the snRNAs U1, U2, U4, and U5. The survival motor neuron (SMN) protein, the spinal muscular atrophy disease gene product, is crucial for snRNP core particle assembly in vivo. SMN binds preferentially and directly to the symmetrical dimethylarginine (sDMA)-modified arginine- and glycine-rich (RG-rich) domains of SmD1 and SmD3. We found that the unmodified, but not the sDMA-modified, RG domains of SmD1 and SmD3 associate with a 20S methyltransferase complex, termed the methylosome, that contains the methyltransferase JBP1 and a JBP1-interacting protein, pICln. JBP1 binds SmD1 and SmD3 via their RG domains, while pICln binds the Sm domains. JBP1 produces sDMAs in the RG domain-containing Sm proteins. We further demonstrate the existence of a 6S complex that contains pICln, SmD1, and SmD3 but not JBP1. SmD3 from the methylosome, but not that from the 6S complex, can be transferred to the SMN complex in vitro. Together with previous results, these data indicate that methylation of Sm proteins by the methylosome directs Sm proteins to the SMN complex for assembly into snRNP core particles and suggest that the methylosome can regulate snRNP assembly.     

Estimation of the National Disease Burden of Influenza-Associated Severe Acute Respiratory Illness in Kenya and Guatemala: A Novel Methodology

Background

Knowing the national disease burden of severe influenza in low-income countries can inform policy decisions around influenza treatment and prevention. We present a novel methodology using locally generated data for estimating this burden.

Methods and Findings

This method begins with calculating the hospitalized severe acute respiratory illness (SARI) incidence for children <5 years old and persons ≥5 years old from population-based surveillance in one province. This base rate of SARI is then adjusted for each province based on the prevalence of risk factors and healthcare-seeking behavior. The percentage of SARI with influenza virus detected is determined from provincial-level sentinel surveillance and applied to the adjusted provincial rates of hospitalized SARI. Healthcare-seeking data from healthcare utilization surveys is used to estimate non-hospitalized influenza-associated SARI. Rates of hospitalized and non-hospitalized influenza-associated SARI are applied to census data to calculate the national number of cases. The method was field-tested in Kenya, and validated in Guatemala, using data from August 2009–July 2011. In Kenya (2009 population 38.6 million persons), the annual number of hospitalized influenza-associated SARI cases ranged from 17,129–27,659 for children <5 years old (2.9–4.7 per 1,000 persons) and 6,882–7,836 for persons ≥5 years old (0.21–0.24 per 1,000 persons), depending on year and base rate used. In Guatemala (2011 population 14.7 million persons), the annual number of hospitalized cases of influenza-associated pneumonia ranged from 1,065–2,259 (0.5–1.0 per 1,000 persons) among children <5 years old and 779–2,252 cases (0.1–0.2 per 1,000 persons) for persons ≥5 years old, depending on year and base rate used. In both countries, the number of non-hospitalized influenza-associated cases was several-fold higher than the hospitalized cases.

Conclusions

Influenza virus was associated with a substantial amount of severe disease in Kenya and Guatemala. This method can be performed in most low and lower-middle income countries.     

Amh and Dmrta2 genes map to tilapia (Oreochromis spp.) linkage group 23 within quantitative trait locus regions for sex determination

Recent studies have revealed that the major genes of the mammalian sex determination pathway are also involved in sex determination of fish. Several studies have reported QTL in various species and strains of tilapia, regions contributing to sex determination have been identified on linkage groups 1, 3, and 23. Genes contributing to sex-specific mortality have been detected on linkage groups 2, 6, and 23. To test whether the same genes might control sex determination in mammals and fishes, we mapped 11 genes that are considered putative master key regulators of sex determination: Amh, Cyp19, Dax1, Dmrt2, Dmrta2, Fhl3l, Foxl2, Ixl, Lhx9, Sf1, and Sox8. We identified polymorphisms in noncoding regions of these genes and genotyped these sites for 90 individuals of an F2 mapping family. Mapping of Dax1 joined LG16 and LG21 into a single linkage group. The Amh and Dmrta2 genes were mapped to two distinct regions of LG23. The Amh gene was mapped 5 cM from UNH879 within a QTL region for sex determination and 2 cM from UNH216 within a QTL region for sex-specific mortality. Dmrta2 was mapped 4 cM from UNH848 within another QTL region for sex determination. Cyp19 was mapped to LG1 far from a previously reported QTL region for sex determination on this chromosome. Seven other candidate genes mapped to LG4, -11, -12, -14, and -17.     

Mutations of Ha-ras p21 that define important regions for the molecular mechanism of the SDC25 C-domain, a guanine nucleotide dissociation stimulator.

The SDC25 C-domain is a very active guanine nucleotide dissociation stimulator (GDS) isolated from Saccharomyces cerevisiae which acts equally well on Ha-ras p21 and yeast RAS2. These properties make the SDC25 C-domain a suitable tool to study the basic mechanism of a GDS. The action of the SDC25 C-domain was analysed by mutation of structurally important regions of p21. Substitutions that influence the coordination of Mg2+.GDP or the interaction of the guanine ring were found to stimulate the intrinsic dissociation of GDP and suppress the action of the SDC25 C-domain. No relevant effects were observed with mutations in the phosphate binding loop L1 or by deleting the last 23 C-terminal residues of p21. Substitutions in the switch region 1 (loop L2) and 2 (loop L4) of p21 strongly impaired the action of this GDS; however, we show that this effect is not related to a decreased affinity of the SDC25 C-domain for the mutated p21. No functional competition could be found between this GDS and the catalytic domain of the human GTPase activating protein (GAP). This indicates that GDS and GAP bind to different sites of the p21.nucleotide complex, even though the same mutations in loops L2 and L4 regions affect the activity of both effectors. Since these two regions appear not to be involved directly in the interaction with GDS, we conclude that the negative effect induced by their mutation is related to their function as switches of selective conformations during the GDP to GTP exchange reaction catalysed by GDS.     

Enriching small trees with artificial nest boxes cannot mimic the value of large trees for hollow‐nesting birds

Large trees support unique habitat structures (e.g. hollows) that form over centuries and cannot be provided by small trees. Large trees are also declining in human‐modified landscapes worldwide. One restoration strategy gaining popularity involves adding nest boxes to smaller trees to replicate natural hollows. However, limited empirical research has tested how hollow‐nesting fauna responds to the presence of nest boxes. We asked: can the addition of nest boxes increase tree visitation by hollow‐nesting birds? We conducted a before‐after control‐impact (BACI) experiment using 144 nest boxes and 96 sample trees comprised of three sizes (small [20–50 cm dbh], medium [51–80 cm], and large [>80 cm]) and located in four landscape contexts (reserves, pasture, urban parklands, and urban built‐up areas). We recorded a significant increase in hollow‐nesting bird abundance and richness at large trees after nest box additions. However, the same response was not observed at medium, small, or control trees. We also recorded nonsignificant increases in hollow‐nesting bird abundance and richness at trees in modified landscapes after nest box additions compared to trees in reserves and control trees. Our results suggest that adding nest boxes to smaller‐sized trees may not attract hollow‐nesting birds. Therefore, nest box management strategies may require re‐evaluation as it is often assumed that hollow supplementation will attract hollow‐using fauna and sufficiently ameliorate the loss of large, hollow‐bearing trees. We advocate that large tree retention remains crucial and should be prioritized. Large trees could be effective target structures for habitat restoration, especially in modified landscapes.