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Current yeast interactome network maps contain several hundred molecular complexes with limited and somewhat controversial representation of direct binary interactions. We carried out a comparative quality assessment of current yeast interactome data sets, demonstrating that high-throughput yeast two-hybrid (Y2H) screening provides high-quality binary interaction information. Because a large fraction of the yeast binary interactome remains to be mapped, we developed an empirically controlled mapping framework to produce a \"second-generation\" high-quality, high-throughput Y2H data set covering ~20% of all yeast binary interactions. Both Y2H and affinity purification followed by mass spectrometry (AP/MS) data are of equally high quality but of a fundamentally different and complementary nature, resulting in networks with different topological and biological properties. Compared to co-complex interactome models, this binary map is enriched for transient signaling interactions and intercomplex connections with a highly significant clustering between essential proteins. Rather than correlating with essentiality, protein connectivity correlates with genetic pleiotropy.

The complexity of the immune system creates challenges in exploring its importance and robustness. To date, there have been few techniques developed to manipulate individual components of the immune system in an in vivo environment. Here we show a light-based dendritic cell (DC) activation allowing spatial and temporal control of immune activation in vivo . Additionally, we show time dependent changes in RNA profiles of the draining lymph node, suggesting a change in cell profile following DC migration and indicating that the cells migrating have been activated towards antigen presentation.

This trial aimed to identify the effects of providing pharmacogenomic (PGx) results and recommendations for patients with chronic pain treated in primary care practices compared to standard care. An open‐label, prospective, largely virtual, type‐2 hybrid effectiveness trial randomized participants to PGx or standard care arms. Adults with pain ≥ 3 months who were treated with tramadol, codeine, or hydrocodone enrolled. Alternative analgesics were recommended for CYP2D6 intermediate or poor metabolizers (IM/PMs). Prescribing decisions were at providers' discretion. The trial randomized 253 participants. A modified intent‐to‐treat primary analysis assessed change in pain intensity over 3 months among IM/PMs (PGx: 49; Standard care: 57). The PGx and standard care arms showed no difference in pain intensity change (−0.10 ± 0.63 vs. −0.21 ± 0.75 standard deviation; p = 0.74) or PGx‐aligned care (69% vs. 63%; standardized difference [SD] = 0.13). In IM/PMs, secondary analyses of pain intensity change suggested improvements with PGx‐aligned (n = 70; −0.21 ± 0.70) vs. unaligned care (n = 36; −0.06 ± 0.69) (SD = −0.22), with this difference increasing when examining IM/PMs with an analgesic change (aligned: n = 31, −0.28 ± 0.76; unaligned: n = 36, −0.06 ± 0.69; SD = −0.31). This approach to PGx implementation for chronic pain was not associated with different prescribing (i.e., similar proportions of PGx‐aligned care) or clinical outcomes. Secondary analyses suggest that prescribing aligned with PGx recommendations showed a small improvement in pain intensity. However, the proportion of patients with a clinically meaningful improvement (≥ 30%) in pain intensity was similar. Future efforts should identify effective implementation methods.

Background: To analyze the pain modulation capacity profile in a Brazilian population, the relationship between opioid receptor ( OPRM1 ) and Catechol-O-methyltransferase ( COMT ) 1polymorphisms and pain modulation capacity was determined through preoperative pain modulation tests and acute postoperative pain control evaluation, swelling, and trismus in 200 volunteers undergoing lower third molar removal. Methods: Psychologic and clinical parameters were measured. Patient DNA was sequenced for single nucleotide polymorphisms in OPRM1 and COMT , and the salivary concentration of interleukin (IL)-2 (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was evaluated. Primary outcomes were the influence of all predictors on the fluctuation of pain intensity using a visual analogue scale (VAS), and swelling and trismus on the 2nd and 7th postoperative days. Preoperative pain modulation capacity (CPM), pain catastrophizing scale (PCS), body mass index (BMI), and surgery duration and difficulty were evaluated. Results: Salivary concentration of IFN-γ and IL-2 as well as the duration of surgery influenced the fluctuation of postoperative pain in the VAS, and in the sum of the differences in pain intensity test at 8, 48, and 96 h. BMI influenced swelling, while both BMI and COMT haplotype influenced trismus on the 2nd postoperative day. Conclusion: Polymorphisms in COMT , salivary concentrations of IL-2 and IFN-γ, BMI, and duration of surgery were predictors for pain fluctuation, swelling, and trismus on the 2nd day after lower third molar extraction. This therapy was effective in controlling inflammatory symptomatology after lower third molar extraction and ibuprofen was well tolerated by patients. Clinical Trial Registration: www.ClinicalTrials.gov , identifier NCT03169127.

Background Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. Methods Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. Results Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty‐four participants (85%) were carriers of a recessive or X‐linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. Conclusion Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS. Genome sequencing (GS) of individuals without a medical indication is referred to as elective GS. Among 52 individuals undergoing elective GS, 11.5% (6/52) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history, 19% (10/52) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential, 85% (44/52) were carriers of a recessive or X‐linked disorder, and 100% of individuals with pharmacogenetic testing had variants that affected current and/or future medications.

The temporal program of gene expression during a model physiological response of human cells, the response of fibroblasts to serum, was explored with a complementary DNA microarray representing about 8600 different human genes. Genes could be clustered into groups on the basis of their temporal patterns of expression in this program. Many features of the transcriptional program appeared to be related to the physiology of wound repair, suggesting that fibroblasts play a larger and richer role in this complex multicellular response than had previously been appreciated.

Asenapine is approved for acute manic and mixed states in bipolar disorder. The objective is to review the efficacy of asenapine in bipolar disorder, with a particular focus on acceptability and adherence to treatment. FIVE CLINICAL TRIALS WERE CONDUCTED IN BIPOLAR DISORDER MANIC OR MIXED STATES: two 3-week trials (n = 976) comparing asenapine to placebo, a 9-week extension (n = 504), and a 40-week extension (n = 107). One trial was conducted comparing asenapine to placebo (n = 326) as adjunctive therapy for subjects with an incomplete response to lithium or valproate. All trials were conducted in the USA and internationally. Asenapine was found to be efficacious for manic and mixed states in bipolar disorder compared with placebo control, and compares equally well to olanzapine on efficacy measures after 3 weeks of treatment. Asenapine was not found to be efficacious for depression symptoms. Common asenapine side effects in the 40-week extension trial were sedation, insomnia, and dizziness, and 31% reported clinically significant weight gain, compared with 55% reporting clinically significant weight gain with olanzapine. Additionally, 18% had clinically significant changes in fasting blood glucose levels compared to 22% of those on olanzapine. In terms of patient acceptability, one concern may be sublingual administration requiring no liquids or food for 10 minutes after dosing and a twice-daily regimen. Suggestions about addressing barriers to adherence and acceptability are provided. Asenapine is a promising new medication in bipolar disorder. Asenapine in the long-term has a more favorable weight gain profile compared to olanzapine. No benefit was seen for depression symptoms, a major patient-reported concern. Some side effects do not remit after the short-term trials in at least 10% of patients.

Bioconjugation methods enable a variety of applications, but it remains difficult to modify many proteins in a single location with a single functional group. A serendipitous discovery of aldehyde reactivity now leads to reagents for the selective labeling of protein N termini under mild conditions. The chemical modification of proteins is an enabling technology for many scientific fields, including chemical biology, biophysics, bioengineering and materials science. These methods allow the attachment of strategically selected detection probes, polymers, drug molecules and analysis platforms. However, organic reactions that can proceed under conditions mild enough to maintain biomolecular function are limited. Even more rare are chemical strategies that can target a single site, leading to products with uniform properties and optimal function. We present a versatile method for the selective modification of protein N termini that does not require any genetic engineering of the protein target. This reaction is demonstrated for 12 different proteins, including the soluble domain of the human estrogen receptor. The function of this protein was confirmed through the binding of a fluorescent estrogen mimic, and the modified protein was explored as a prototype for the detection of endocrine-disrupting chemicals in water.

As many as 50% of patients with schizophrenia do not take oral antipsychotic medications as prescribed, yet long acting injections are rarely utilized. Community agencies that serve this population are often over-burdened and poorly funded. There are negative attitudes on the part of both physicians and consumers about injections. Transportation and logistics are often problematic. We describe the unique opportunity provided by the need for bi-weekly or monthly injections to establish a recovery-oriented group around injection visits. Our approach discusses methods and resources to help overcome some of the common barriers by establishing advocates within the agency, establishing necessary infrastructure, providing education for consumers, providers, and staff, sharing information about successful outcomes with clinic staff and working through billing issues. We also recommend public advocacy on the part of the clinic and consumers to work with state funding sources to change regulations that may limit appropriate clinical care.

The genome sequences of Caenorhabditis elegans , Drosophila melanogaster and Arabidopsis thaliana have been predicted to contain 19,000, 13,600 and 25,500 genes, respectively 1 , 2 , 3 . Before this information can be fully used for evolutionary and functional studies, several issues need to be addressed. First, the gene number estimates obtained in silico and not yet supported by any experimental data need to be verified. For example, it seems biologically paradoxical that C. elegans would have 50% more genes than Drosophilia . Second, intron/exon predictions need to be tested experimentally. Third, complete sets of open reading frames (ORFs), or “ORFeomes,” 4 need to be cloned into various expression vectors. To address these issues simultaneously, we have designed and applied to C. elegans the following strategy. Predicted ORFs are amplified by PCR from a highly representative cDNA library 4 using ORF-specific primers, cloned by Gateway recombination cloning 4 , 5 , 6 and then sequenced to generate ORF sequence tags (OSTs) as a way to verify identity and splicing. In a sample (n=1,222) of the nearly 10,000 genes predicted ab initio (that is, for which no expressed sequence tag (EST) is available so far), at least 70% were verified by OSTs. We also observed that 27% of these experimentally confirmed genes have a structure different from that predicted by GeneFinder. We now have experimental evidence that supports the existence of at least 17,300 genes in C. elegans . Hence we suggest that gene counts based primarily on ESTs may underestimate the number of genes in human and in other organisms.