Biology subjects

Martin, L.

Publications and source records attributed to Martin, L..

8 recordsLinked to original sources

bioRxiv2018

A comprehensive analysis of the usability and archival stability of omics computational tools and resources

Developing new software tools for analysis of large-scale biological data is a key component of advancing modern biomedical research. Scientific reproduction of published findings requires running computational tools on data generated by such studies, yet little attention is presently allocated to the installability and archival stability of computational software tools. Scientific journals require data and code sharing, but none currently require authors to guarantee the continuing functionality of newly published tools. We have estimated the archival stability of computational biology software tools by performing an empirical analysis of the internet presence for 36,702 omics software resources published from 2005 to 2017. We found that almost 28% of all resources are currently not accessible through URLs published in the paper they first appeared in. Among the 98 software tools selected for our installability test, 51% were deemed \"easy to install,\" and 28% of the tools failed to be installed at all due to problems in the implementation. Moreover, for papers introducing new software, we found that the number of citations significantly increased when authors provided an easy installation process. We propose for incorporation into journal policy several practical solutions for increasing the widespread installability and archival stability of published bioinformatics software.

bioinformatics↗

bioRxiv2018

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F-PY-PICA, 5F-PY-PINACA, and their analogues

The structural diversity of synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) has increased since the first examples were reported a decade ago. 5F-PY-PICA and 5F-PY-PINACA were identified in 2015 as putative SCRA NPS, although nothing is known of their pharmacology. 5F-PY-PICA, 5F-PY-PINACA, and analogues intended to explore structure-activity relationships within this class of SCRAs were synthesized and characterized by nuclear magnetic resonance spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry. Using competitive binding experiments and fluorescence-based plate reader membrane potential assays, the affinities and activities of all analogues at cannabinoid type 1 and type 2 receptors (CB1 and CB2) were evaluated. All ligands showed minimal affinity for CB1 (pKi < 5), although several demonstrated moderate CB2 binding (pKi = 5.45-6.99). At 10 M none of the compounds produced an effect > 50% of CP55,950 at CB1, while several compounds showed a slightly higher relative efficacy at CB2. Unlike other SCRA NPS, 5F-PYPICA and 5F-PY-PINACA did not produce cannabimimetic effects in mice at doses up to 10 mg/kg.

pharmacology and toxicology↗

bioRxiv2018

Resource: Scalable whole genome sequencing of 40,000 single cells identifies stochastic aneuploidies, genome replication states and clonal repertoires

Essential features of cancer tissue cellular heterogeneity such as negatively selected genome topologies, sub-clonal mutation patterns and genome replication states can only effectively be studied by sequencing single-cell genomes at scale and high fidelity. Using an amplification-free single-cell genome sequencing approach implemented on commodity hardware (DLP+) coupled with a cloud-based computational platform, we define a resource of 40,000 single-cell genomes characterized by their genome states, across a wide range of tissue types and conditions. We show that shallow sequencing across thousands of genomes permits reconstruction of clonal genomes to single nucleotide resolution through aggregation analysis of cells sharing higher order genome structure. From large-scale population analysis over thousands of cells, we identify rare cells exhibiting mitotic mis-segregation of whole chromosomes. We observe that tissue derived scWGS libraries exhibit lower rates of whole chromosome anueploidy than cell lines, and loss of p53 results in a shift in event type, but not overall prevalence in breast epithelium. Finally, we demonstrate that the replication states of genomes can be identified, allowing the number and proportion of replicating cells, as well as the chromosomal pattern of replication to be unambiguously identified in single-cell genome sequencing experiments. The combined annotated resource and approach provide a re-implementable large scale platform for studying lineages and tissue heterogeneity.

genomics↗

bioRxiv2018

Evaluating analgesic efficacy and administration route following craniotomy in mice using the grimace scale

Most research laboratories abide by guidelines and mandates set by their research institution regarding the administration of analgesics to control pain during the postoperative period. Unfortunately, measuring pain originating from the head is difficult, making adequate decisions regarding pain control following stereotaxic surgery problematic. In addition, most postsurgical analgesia protocols require multiple injections over several days, which may cause stress and distress during a critical recovery period. Here we sought to 1) assess the degree of postoperative pain following craniotomy in mice, 2) compare the efficacy of three common rodent analgesics (carprofen, meloxicam and buprenorphine) for reducing this pain and 3) determine whether the route of administration (injected or self-administered through the water supply) influenced pain relief post-craniotomy. Using the mouse grimace scale (MGS), we found that injectable analgesics were significantly more effective at relieving post-craniotomy pain, however, both routes of administration decreased pain scores in the first 24 h post-surgery. Specifically, buprenorphine administered independently of administration route was the most effective at reducing MGS scores, however, female mice showed greater sensitivity to carprofen when administered through the water supply. Although it is necessary to provide laboratory animals with analgesics after an invasive procedure, there remains a gap in the literature regarding the degree of craniotomy-related pain in rodents and the efficacy of alternative routes of administration. Our study highlights the limitations of administering drugs through the water supply, even at doses that are considered to be higher than those currently recommended by most research institutions for treating pain of mild to moderate severity.

neuroscience↗

bioRxiv2018

Clinical and MRI changes of puborectalis and iliococcygeus after a short period of intensive pelvic floor muscles training with or without instrumentation. A randomized study

PurposeThis study evaluates the impact of a 3-week period of intensive pelvic floor muscles training (PFMT), with or without instrumentation, on clinical and static magnetic resonance imaging (MRI) changes of puborectalis (PR) and iliococcygeus (IL) muscles.\n\nMethods24 healthy young 5 women were enrolled in the study and 17 achieved the 9 sessions of 30 minutes training exercises and conducted all assessments. Participants were randomly assigned in two training groups: voluntary contractions combined with hypopressive exercises (HYPO) or biofeedback exercises combined with transvaginal electrical stimulations (ELEC). Clinical and T2-weighted MRI assessments io were realized before and after training.\n\nResultsModified Oxford Grading System (MOGS) scores for left PR and perineal body significantly increased in the two groups (p=0.039, p=0.008), but MOGS score for right PR significantly increased only in HYPO (p=0.020). Muscle volumes of right and left IL significantly decreased (p=0.040, p=0.045) after training as well as signal i5 intensities of right and left PR (p=0.040, p=0.021) and thickness of right and left IL at mid-vagina location (p=0.012, p=0.011).\n\nConclusionsA short period of intensive PFMT induces clinical and morphological changes in PFMs at rest suggesting a decrease in IL volume and adipose content of PR. Given the difference in cost and accessibility between HYPO and ELEC approaches, PFMT should be based primarily on non-instrumented exercises.

physiology↗

bioRxiv2017

A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML

BackgroundDecitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints.\n\nResultsTwenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A, 14 in Arm B). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-point marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, one week prior to the patients marrow aspirate confirming non-response. Decitabine-induced effects of end-induction marrows in Arm A were reflected by changes in DNA methylation and gene expression comparison with matched paired marrow diagnostic aspirates.\n\nConclusionsThis first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML. This trial was registered at www.clinicaltrials.gov as NCT01177540.

clinical trials↗

bioRxiv2017

Addressing the digital divide in contemporary biology: Lessons from teaching UNIX

Researchers in the biomedical sciences increasingly rely on applications that lack a graphical interface and require inputting code that, such as UNIX. Scientists who are not trained in computer science face an enormous challenge in analyzing the high-throughput data their research groups generate. We present a training model for use of command-line tools when the learner has little to no prior knowledge of UNIX.

scientific communication and education↗

bioRxiv2017

Humans are colonized by many uncharacterized and highly divergent microbes

Blood circulates throughout the entire body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analysing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated.

microbiology↗