gebhart/patrepeval huggingface dataset:
Prospects for Generating New Antibiotics (2002)

A plethora of human pathogens are now resistant to all clinically significant antibiotics causing a crisis, in the treatment and management of infectious diseases, but also presenting a clear danger to future public health. If drug resistance is going to be tackled successfully, new antibiotics must be continually developed to counteract the processes of evolution and natural selection in these populations of pathogens. Despite the introduction of powerful new technologies such as high throughput screening platforms and combinatorial chemistry, natural products still offer structural diversity worthy of screening for biological activity. Functional genomics can revolutionise rational drug design providing new targets for antimicrobial drug discovery. The clusters of genes, encoding enzymes that form bio-synthetic pathways leading to the synthesis of many natural products including polyketides and non-ribosomal peptides, are amenable to modern genetic engineering. Repositioning, deleting and replacing genes in these biosynthetic clusters has resulted in the synthesis of many 'un-natural' natural products. This review examines the engineering of proteins involved in chain initiation on polyketide synthases culminating in the production at high yield of a biologically active erythromycin derivative.
Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non‐antimicrobial tetracycline analog (COL‐3) in a metastatic prostate cancer model (2001)

Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI(50)] < or = 5.0 ,microg/ml). Exposure of tumor cells to CMT-3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT-3. Cell cycle arrest at the G(0)/G(1) compartment was observed in CMT-3- and DC-treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT-6) to >90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27-35%) and lung metastases were observed (28.9 +/- 15.4 sites/animal [CMT-3-treated] versus 43.6 +/- 18.8 sites/animal [DC-treated] versus 59.5 +/- 13.9 [control]; p < 0.01]. A delay in tumor growth (27 +/- 9.3%, p < 0.05), reduction in metastases (58 +/- 8%) and decrease in tumor incidences (55 +/- 9%, CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers.
Systolic time intervals vs invasive predictors of fluid responsiveness after coronary artery bypass surgery† (2013)

Non-invasively measured ISTI is able to predict and monitor fluid responsiveness after cardiac surgery non-inferiorly to invasively measured haemodynamic indices.
Recombinant human bone morphogenetic protein‐4 (rhBMP‐4) enhanced posterior spinal fusion without decortication (2002)

In posterior spinal fusion, insufficient decortication may decrease the number of bone marrow derived ostoprogenitor stem cells and affect the success of bony fusion. The finding of bone formation through interaction between rhBMP-4 and non-marrow derived mesenchymal cells constituted the basis of the current study. The aim is to investigate the possibility of molecular enhancement of posterior spinal fusion by site-specific application of rhBMP-4 with or without surgical decortication. Eighteen adult rabbits underwent single level bilateral posterior intertransverse process spinal fusion at L5-L6. one side with decortication, and the other side without decortication. Two animals underwent sham operation without bone grafts, the other 16 animals were randomly allocated into three groups, using hydroxyapatite-tricalcium phosphate (HA-TCP) ceramic blocks augmented with 0, 125 and 5 micromg [corrected] of rhBMP-4 respectively. Spinal fusion morphology was evaluated with sequential X-ray, microradiography and histomorphology. At week 7, complete bony fusion was achieved in none of the groups without rhBMP-4 irrespective of whether the bony contact surface was decorticated or not. In the groups with low dose rhBMP-4, complete fusion occurred in two of six un-decorticated sites (33%) and in three of six (50%) decorticated sites. 100% complete fusion was found in the high dose rhBMP-4 group independent of surgical decortication. The dorsal cortices of the un-decorticated transverse processes were replaced by newly formed trabecular bone through biological remodeling. This study suggested that rhBMP-4 can induce non-marrow derived mesenchymal cells to differentiate into osteogenic cells and thus enhance the high success rate of pesterior spinal fusion in both the decorticated and un-decorticated model.
The study of mammary carcinoma by mammography and whole organ sectioningearly observations (1969)

The first 38 specimens in a series of carcinomas of the breast studied by correlated mammography and subserial whole organ sectioning are reported. Three specific patterns of tumor growth have been identified and their mammographic appearances described. Intramammary spread of carcinoma has been observed to occur both intraductally and by way of periductal lymphatics. Extensive neoplastic transformation of ductal epithelium and multiplicity of invasive sites have been found frequently. Diffuse or multiple origin has been clearly demonstrated in three fourths of the specimens. The skin thickening which is often noted mammographically in association with carcinoma has been shown to be the result of an increase in dermal collagen, whether or not dilatation of dermal lymphatics is also present. An increase in the collagen of stroma of the breast has also been encountered regularly and is often visible in mammograms. Three specimens containing metastases from previously removed contralateral primaries have permitted observations of the distribution of intramammary lymphatic vessels.
An Ehrlichia chaffeensis Tandem Repeat Protein Interacts with Multiple Host Targets Involved in Cell Signaling, Transcriptional Regulation, and Vesicle Trafficking (2009)

Ehrlichia chaffeensis is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes forming cytoplasmic membrane-bound microcolonies called morulae. To survive and replicate within phagocytes, E. chaffeensis exploits the host cell by modulating a number of host cell processes, but the ehrlichial effector proteins involved are unknown. In this study, we determined that p47, a secreted, differentially expressed, tandem repeat (TR) protein, interacts with multiple host proteins associated with cell signaling, transcriptional regulation, and vesicle trafficking. Yeast two-hybrid analysis revealed that p47 interacts with polycomb group ring finger 5 (PCGF5) protein, Src protein tyrosine kinase FYN (FYN), protein tyrosine phosphatase non-receptor type 2 (PTPN2), and adenylate cyclase-associated protein 1 (CAP1). p47 interaction with these proteins was further confirmed by coimmunoprecipitation assays and colocalization in HeLa cells transfected with p47-green fluorescent fusion protein (AcGFP1-p47). Moreover, confocal microscopy demonstrated p47-expressing dense-cored (DC) ehrlichiae colocalized with PCGF5, FYN, PTPN2, and CAP1. An amino-terminally truncated form of p47 containing TRs interacted only with PCGF5 and not with FYN, PTPN2, and CAP1, indicating differences in p47 domains that are involved in these interactions. These results demonstrate that p47 is involved in a complex network of interactions involving numerous host cell proteins. Furthermore, this study provides a new insight into the molecular and functional distinction of DC ehrlichiae, as well as the effector proteins involved in facilitating ehrlichial survival in mononuclear phagocytes.
Products of experts (1999)

It is possible to combine multiple probabilistic models of the same data by multiplying the probabilities together and then renormalizing. This is a very efficient way to model high-dimensional data which simultaneously satisfies many different low dimensional constraints. Each individual expert model can focus on giving high probability to data vectors that satisfy just one of the constraints. Data vectors that satisfy this one constraint but violate other constraints will be ruled out by their low probability under the other expert models. Training a product of models appears difficult because, in addition to maximizing the probabilities that the individual models assign to the observed data, it is necessary to make the models disagree on unobserved regions of the data space. However, if the individual models are tractable there is a fairly efficient way to train a product of models. This training algorithm suggests a biologically plausible way of learning neural population codes.
Chimeric Restriction Enzyme: Gal4 Fusion to Fokl Cleavage Domain (1998)

Gal4, a yeast protein, activates transcription of genes required for metabolism of galactose and melibiose. It binds as a dimer to a consensus palindromic 17-base pair DNA sequence. It is a member of the third family of proteins that contain zinc-mediated peptide loops that interact specifically with nucleic acids. Gal4 has a very distinctive zinc coordination profile and mode of DNA-binding. Here, we report the creation of a novel site-specific endonuclease by linking the N-terminal 147 amino acids of Gal4 to the cleavage domain of FokI endonuclease. The fusion protein is active and under optimal conditions, binds to a 17 bp consensus DNA site and cleaves near this site. As expected, the cleavage occurs on either side of the consensus binding site(s).
Antibacterial, allelopathic and antioxidant activities of essential oil ofSalvia officinalisL. growing wild in the Atlas Mountains of Morocco (2012)

Salvia officinalis (Common sage, Culinary sage) is an aromatic plant that is frequently used as a spice in Mediterranean cookery and in the food industry and as a traditional medicine for the treatment of several infectious diseases. The essential oils were obtained by two different methods [hydrodistillation (HD) and microwave (Mw)] from the aerial part of S. officinalis L. growing wild in Ourika-Marrakech in Morocco. Ourika is a large zone of the Atlas Mountains which is considered as a large reserve of Flora, especially medicinal and aromatic plants. The obtained oils were analysed by gas chromatography and gas chromatography-mass spectrometry and compared with that of Tunisia. Thirty-six compounds were identified from the Mw-extracted oil which accounted for 97.32% of the total oil composition. However, 33 compounds obtained by HD representing 98.67%. The major components were trans-thujone (14.10% and 29.84%), 1,8-cineole (5.10% and 16.82%), camphor (4.99% and 9.14%), viridiflorol (16.42% and 9.92%), β-caryophyllene (19.83% and 5.20%) and α-humulene (13.54% and 4.02%). Antibacterial, allelopathic (% germination in lettuce seeds and inhibited root growth obtained after treatment with S. officinalis oils) and antioxidant (IC₅₀ values 22 mg/mL) activities were studied.
Pulse Transit Time as a Predictor of the Efficacy of a Celiac Plexus Block in Patients With Chronic Intractable Abdominal Pain (2015)

Prolongation of E-T PTT at 5 minutes after CPB correlates closely with a significant analgesic effect.
Synthesis of unlabelled and carboxyl-labelled 3-Amino-5-hydroxybenzoic acid (1981)

Efficient syntheses are reported of the natural amino acid 3-amino-5-hydroxybenzoic acid in unlabelled and carboxyl-labelled forms from 3,5-dinitrobenzoic acid and 3,5-dinitroanisole, respectively.
Validation of candidate gene markers for marker-assisted selection of potato cultivars with improved tuber quality (2013)

Tuber yield, starch content, starch yield and chip color are complex traits that are important for industrial uses and food processing of potato. Chip color depends on the quantity of reducing sugars glucose and fructose in the tubers, which are generated by starch degradation. Reducing sugars accumulate when tubers are stored at low temperatures. Early and efficient selection of cultivars with superior yield, starch yield and chip color is hampered by the fact that reliable phenotypic selection requires multiple year and location trials. Application of DNA-based markers early in the breeding cycle, which are diagnostic for superior alleles of genes that control natural variation of tuber quality, will reduce the number of clones to be evaluated in field trials. Association mapping using genes functional in carbohydrate metabolism as markers has discovered alleles of invertases and starch phosphorylases that are associated with tuber quality traits. Here, we report on new DNA variants at loci encoding ADP-glucose pyrophosphorylase and the invertase Pain-1, which are associated with positive or negative effect with chip color, tuber starch content and starch yield. Marker-assisted selection (MAS) and marker validation were performed in tetraploid breeding populations, using various combinations of 11 allele-specific markers associated with tuber quality traits. To facilitate MAS, user-friendly PCR assays were developed for specific candidate gene alleles. In a multi-parental population of advanced breeding clones, genotypes were selected for having different combinations of five positive and the corresponding negative marker alleles. Genotypes combining five positive marker alleles performed on average better than genotypes with four negative alleles and one positive allele. When tested individually, seven of eight markers showed an effect on at least one quality trait. The direction of effect was as expected. Combinations of two to three marker alleles were identified that significantly improved average chip quality after cold storage and tuber starch content. In F1 progeny of a single-cross combination, MAS with six markers did not give the expected result. Reasons and implications for MAS in potato are discussed.
The GI microbiome and its role in Chronic Fatigue Syndrome: A summary of bacteriotherapy (2012)

Introduction: Chronic Fatigue Syndrome (CFS) has a complex and multifactorial etiology making treatment and definitive diagnosis, currently made through exclusion, difficult. Current therapies, such as cognitive behaviour therapy and graded exercises, are inadequate and targeted to address symptoms, rather than the underlying disease pathology. Increasing evidence implicates the microbiota of the gut in a number of conditions previously thought distinct from the gastrointestinal system. Previous work with bacteriotherapy in CFS has suggested a link between the condition and the composition and health of the gut microbiota. Here, we review and further examine a larger cohort of CFS patients who had undergone bacteriotherapy for their CFS. Method: A total of 60 patients from the Centre for Digestive Diseases presented with CFS. Of these, 52 patients had concurrent IBS and 4 patients additionally had constipation. All underwent initial transcolonoscopic infusion of 13 non-pathogenic enteric bacteria. 52/60 patients undertook an additional rectal infusion a day later and 3/60 undertook an additional 2 rectal infusions. Results: 35/60 patients who underwent initial bacteriotherapy responded to treatment. 10/15 patients who failed this course were offered a secondary transcolonoscopic infusion followed by a rectal infusion or an oral course of cultured bacteria. Of these 7/10 responded, giving a total of 42/60 (70%) patients who responded to treatment. Contact was achieved with 12 patients after 15-20 year follow-up. Complete resolution of symptoms was maintained in seven of the twelve patients and 5/12 did not experience recurrence for approximately 1.5-3 years post bacteriotherapy. Conclusion: Bacteriotherapy achieves initial success rate of 70% in CFS and a 58% sustained response. Given that manipulation of the colonic microbiota improved CFS symptoms, bacteriotherapy for CFS warrants further investigation and may provide further insight into a possible etiology of CFS.
Oxcarbazepine extended-release formulation in epilepsy (2009)

Oxcarbazepine (OXC) is a 10-keto-analogue of carbamazepine, which was developed and labeled as a follow-up antiepileptic drug, that was intended to overcome some of the pharmacological drawbacks of carbamazepine with similar efficacy. The main advantage is the nonoxidative metabolic pathway that allows a lower enzyme-induction profile and fewer drug interactions. OXC is rapidly and extensively reduced by cytosolic hepatic enzymes to its monohydroxylated derivative (MHD), thus OXC may be regarded as a prodrug with MHD representing the active antiepileptic agent. The immediate-release (IR) formulation of OXC (Trileptal(®), Timox(®)) has an almost complete bioavailibilty. It is rapidly absorbed and reaches peak concentrations after 1-3 h. MHD peak concentrations are measured within 4-12 h. Elimination half-life in healthy subjects is 1-5 h for OXC and 7-20 h for MHD. The OXC plasma concentration peak may have been responsible for side effects, such as dizziness, vertigo, coordination problems or blurred vision, which appeared more often with this formulation in individual cases than with the formulation available prior to 2000, or with another formulation that has been distributed in Scandinavian countries. Both possibilities offer a profile approaching the characteristics of an extended-release (ER) formulation. ER OXC was labeled in Germany in 2008 (Apydan(®) extent, Desitin Arzneimittel GmbH, Hamburg, Germany). Under steady-state conditions, Phase I studies show bioequivalence between IR and ER OXC. With ER OXC, OXC plasma peak concentrations and both OXC and MHD peak-trough fluctuations are markedly reduced. In clinical trials, comparisons between IR OXC twice daily versus ER OXC once daily failed to show significant differences; efficacy tended to be better with IR OXC, whereas OXC ER showed insignificant tolerability advantages. Another study is currently ongoing to compare the tolerability of both formulations under twice-daily administration conditions in patients with difficult-to-treat epilepsies who require a dosage increase of OXC and who are randomized to IR or ER OXC.
Engineering of genetically detoxified pertussis toxin analogs for development of a recombinant whooping cough vaccine (1990)

Pertussis toxin (PT) is an important protective antigen in vaccines against whooping cough, and a genetically detoxified PT analog is the preferred form of the immunogen. Several amino acids of the S1 subunit were identified as functionally critical residues by site-directed mutagenesis, specifically, those at positions 9, 13, 26, 35, 41, 58, and 129. Eighty-three mutated PT operons were introduced into Bordetella parapertussis, and the resultant toxin analogs were screened for expression levels, enzymatic activity, residual toxicity, and antigenicity. While more than half of the mutants were found to be poorly secreted or assembled, the rest were fully assembled and most were highly detoxified. Single mutations resulted in up to a 1,000-fold reduction in both toxic and enzymatic activities, while PT analogs with multiple mutations (Lys-9 Gly-129, Glu-58 Gly-129, and Lys-9 Glu-58 Gly-129) were 10(6)-fold detoxified. Operons coding for stable and nontoxic mutants shown to express a critical immunodominant protective epitope were returned to the chromosome of Bordetella pertussis by allelic exchange. In vivo analysis of the toxin analogs showed a dramatic reduction in histamine sensitization and lymphocytosis-promoting activities, paralleling the reduction in toxic activities. All mutants were protective in an intracerebral challenge test, and the Lys-9 Gly-129 analog was found to be significantly more immunogenic than the toxoid. PT analogs such as those described represent suitable components for the design of a recombinant whooping cough vaccine.
A randomised controlled trial of the effect of continuous electronic physiological monitoring on the adverse event rate in high risk medical and surgical patients (2006)

We conducted a randomised controlled trial of mandated five-channel physiological monitoring vs standard care, in acute medical and surgical wards in a single UK teaching hospital. In all, 402 high-risk medical and surgical patients were studied. The primary outcome was the proportion of patients experiencing one or more major adverse events, including urgent staff calls, changes to higher care levels, cardiac arrests or death, in 96 h following randomisation. Secondary outcomes were the proportion of patients requiring acute treatment changes, and the 30-day and hospital mortality. In the 96 h following randomisation, 113 (56%) patients in the monitored arm and 116 (58%) in the control arm (OR 0.94, 95% CI 0.63-1.40, p = 0.76) had a major event. An acute change in treatment was necessary in 107 (53%) monitored patients and 101 (50%) control patients (OR 0.55, 95% CI 0.87-1.29). Thirty-four (17%) monitored patients and 35 (17%) control patients died within 30 days. Thirteen patients in the control group received full five-channel monitoring at the request of the ward staff. We conclude that mandated electronic vital signs monitoring in high risk medical and surgical patients has no effect on adverse events or mortality.