Miracle-dz/UniFAR-FTUs huggingface dataset:
Activity of Aromathecins against African Trypanosomes

African sleeping sickness is responsible for thousands of deaths annually, and new therapeutics are needed. This study evaluated aromathecins, experimental inhibitors of mammalian topoisomerase IB, against Trypanosoma brucei African trypanosomes. ABSTRACT African sleeping sickness is responsible for thousands of deaths annually, and new therapeutics are needed. This study evaluated aromathecins, experimental inhibitors of mammalian topoisomerase IB, against Trypanosoma brucei African trypanosomes. The compounds had selectively toxic antiparasitic potency, in situ poisoning activity against the phylogenetically unique topoisomerase in these parasites, and a representative compound intercalated into DNA with micromolar affinity. DNA intercalation and topoisomerase poisoning may contribute to the antitrypanosomal activity of aromathecins.
The measure tells the tale: Clinical outcome measures in multiple sclerosis

626 journals.sagepub. com/home/msj Clinical trials and research projects depend on valid and reliable outcome measures.1 Here, there are several important questions, such as: Is the measure validated for use in a multiple sclerosis (MS) population? Does the measure reflect the function that we are interested in? Is it reliable over time and between different raters? Moreover, researchers are increasingly interested in so-called clinically meaningful improvement on these measures, reflective of the (perceived) day-to-day functioning of patients. In other words, we are in great need for solid, robust, and clinically meaningful measures in order to “tell the tale” in clinical and therapeutic practice.
Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

ABSTRACT The echinocandins caspofungin, micafungin, and anidulafungin, inhibitors of cell wall β-1,3-glucan synthesis, were recently elevated to first-line agents for treating infections due to the azole-refractory yeast Candida glabrata. In Candida albicans, echinocandin resistance is strictly associated with mutations in Fks1, a large integral membrane protein and putative β-1,3-glucan synthase, while mutations in both Fks1 and its paralog Fks2 (but not Fks3) have been associated with resistance in C. glabrata. To further explore their function, regulation, and role in resistance, C. glabrata fks genes were disrupted and subjected to mutational analysis, and their differential regulation was explored. An fks1Δ fks2Δ double disruptant was not able to be generated; otherwise, all three single and remaining two double disruptants displayed normal growth and echinocandin susceptibility, indicating Fks1-Fks2 redundancy. Selection on echinocandin-containing medium for resistant mutants was dependent on strain background: only fks1Δ and fks1Δ fks3Δ strains consistently yielded mutants exhibiting high-level resistance, all with Fks2 hot spot 1 mutations. Thus, Fks1-Fks2 redundancy attenuates the rate of resistance; further analysis showed that it also attenuates the impact of resistance-conferring mutations. Growth of the fks1Δ and, especially, fks1Δ fks3Δ strains was specifically susceptible to the calcineurin inhibitor FK506. Relatedly, FK506 addition or calcineurin gene CMP2 disruption specifically reversed Fks2-mediated resistance of laboratory mutants and clinical isolates. RNA analysis suggests that transcriptional control is not the sole mechanism by which calcineurin modulates Fks2 activity.
Editorial - Body Mass Index, Waist-to-Height Ratio, Cardiometabolic Risk Factors and Diseasesin a New Obesity Classification Proposal

In this mini-hot topic issue, methods of body composition analysis are reviewed, a new shape chart based on waist-to-height ratio is presented and a new obesity classification system is proposed. Anthropometric indices are surrogate measures of body fat and are cost-free, practical and easy to interpret for health care providers and lay people. The answer to the question of "the best anthropometric index" varies according to study design, geographic area, characteristics of the study population and the outcome assessed. Recent studies suggest using measures of general obesity and abdominal obesity for assessment of excess body fat. The use of waist-to-height ratio as a global anthropometric index for children and adults is suggested in this mini-hot topic. Anthropometric indices have a good performance in predicting health risks in epidemiologic studies, but by themselves have limited use in treatment decisions of individual obese patients. Body mass index is strongly correlated with total body adipose tissue mass and is a measure of general obesity. Current classification of obesity is based on body mass index, an anthropometric index that does not inform about body fat distribution, is not a powerful discriminator of cardiometabolic risk factors and does not convey information about the presence of risk factors or co-morbidities. Therefore, a new obesity classification system is needed. I suggest this should be based on body mass index, waist-to-height ratio and obesity associated risk factors and diseases. Future studies should focus on seeing how the proposed obesity classification system works in different populations.
Mobile Digital Calendars: An Interview Study

This paper reports on a series of qualitative interviews conducted as an exploratory research effort to understand the motivations behind knowledge workers’ usage of mobile digital calendars. Other findings reported on are general complaints related to the design and usage of mobile digital calendars. Semi-structured interviews were conducted with fifteen professionals who are regular users of mobile digital calendars, and have been using their system of choice for more than one year. The respondents were categorized into three categories characterized by their motivations for use and usage styles. These categories serve to better explain the reasons to use mobile digital calendars.
Project Progress Tracking Template &#8212; Using a Repeatable GSS Process to Facilitate Project Process Management

This article presents the findings of an action research study in which a repeatable GSS (Group Support System) process was adopted by project teams to track their progress. The repeatable GSS process, implemented by means of a GSS template, was employed and evaluated in both face-to-face and distributed group interactions. The study results indicate that use of a GSS template can facilitate project progress tracking by providing structural support for team interaction and serving as an electronic repository or permanent memory of team interaction. The results also suggest that existing GSS software could be improved though various feature enhancements and additions.
Two Distinct Major Facilitator Superfamily Drug Efflux Pumps Mediate Chloramphenicol Resistance in Streptomyces coelicolor

ABSTRACT Chloramphenicol, florfenicol, and thiamphenicol are used as antibacterial drugs in clinical and veterinary medicine. Two efflux pumps of the major facilitator superfamily encoded by the cmlR1 and cmlR2 genes mediate resistance to these antibiotics in Streptomyces coelicolor, a close relative of Mycobacterium tuberculosis. The transcription of both genes was observed by reverse transcription-PCR. Disruption of cmlR1 decreased the chloramphenicol MIC 1.6-fold, while disruption of cmlR2 lowered the MIC 16-fold. The chloramphenicol MIC of wild-type S. coelicolor decreased fourfold and eightfold in the presence of reserpine and Phe-Arg-β-naphthylamide, respectively. These compounds are known to potentiate the activity of some antibacterial drugs via efflux pump inhibition. While reserpine is known to potentiate drug activity against gram-positive bacteria, this is the first time that Phe-Arg-β-naphthylamide has been shown to potentiate drug activity against a gram-positive bacterium.
Discovering Web Communities in the Blogspace

With the emergence of a range of second generation Internet based services such as Weblogs and their hosting services, many loosely organized communities of bloggers have started to form around common interests. Those communities have quickly evolved into a new information and knowledge dissemination channel. Most current search engines cannot discover Weblog communities through regular keyword search. In this paper we propose a new way of collecting and preparing information for Weblog community discovery. Weblog community is treated as a social network and the data collection stage focuses on gaining knowledge of the strength of social ties between Web logs. The strength of social ties and the clustering feature of social network are used to extract communities from a large blogspace. We also develop a few metrics to rank communities as well as individual members in the community. We report several experimental results on "Web services" communities
Prospective Randomized Trial of Six-Month versus Nine-Month Therapy for Intestinal Tuberculosis

ABSTRACT Intestinal tuberculosis (TB) continues to be a common disease worldwide. However, the optimal duration of anti-TB medication has not been well established. We therefore compared the efficacy of 6-month and 9-month therapy in the treatment of intestinal TB. Ninety patients definitely diagnosed with intestinal TB were randomized into 6-month (n = 45) or 9-month (n = 45) treatment groups, prospectively. The primary end point was complete response, defined as endoscopic healing of active lesions. Patients were followed up monthly for 3 months after therapy initiation, then every 3 months until the end of therapy, and finally 1 year later. Relapse was assessed 1 year after the end of therapy by patient interview and colonoscopy. Baseline characteristics were similar in the 6-month and 9-month groups. Intention-to-treat analysis revealed no significant differences between the two groups in complete response (6-month group, 93.3%; 9-month group, 91.1%; P = 1.00) or recurrence rate (6-month group, 2.4%; 9-month group, 0.0%; P = 1.00). Median follow-up duration was 39 months in the 6-month group and 32 months in the 9-month group. No surgery was performed on any patient in either group. In conclusion, the 6-month therapy was as effective as 9-month therapy in patients with intestinal TB and may have the additional benefits of reduced treatment cost and increased compliance.
Natalizumab during pregnancy and lactation

Background: Managing medication during pregnancy and lactation in multiple sclerosis (MS) patients needs to balance potential risks to the newborn with the substantial risks of ongoing disease activity. Objective: To evaluate the potential transfer of natalizumab (NAT) into breast milk and into the serum of newborn babies in women who continued NAT treatment during pregnancy and lactation. Methods: Serum samples of 11 mother–infant pairs and mother milk samples of a further 4 women were analyzed for free NAT using a HL60 cell-based fluorescence-activated cell sorting (FACS) assay. Two mother–baby pairs were analyzed for cell-bound NAT, very-late-antigen (VLA)-4 expression, and saturation with NAT on immune cells by FACS analysis. Results: In the majority of the mother–infant serum pairs (6/11) and in all breast milk samples, free NAT was detectable. Cell-bound NAT was measurable in both mother–baby pairs with significant higher levels in babies. VLA-4 expression seems to be higher in newborns. Saturation with NAT was comparable between newborns and mothers. Conclusion: NAT can pass placental barrier before delivery and into breast milk. Measurable NAT on neonatal lymphocytes may have functional impact. Further investigations are needed to clarify safety and risk of NAT exposure during pregnancy and lactation.
Taxonomy for multi-perspective assessment of the value of health information systems

Healthcare-providing organisations realise astonishing advances in treatment procedures and medical technology that strongly impact health outcome. Despite recognition of potential contributions of Health Information Systems (HIS), their adoption is comparatively low. Based on the unified theory of acceptance and use of technology, six key variables are applied for a concept-driven literature research of criteria determining value of HIS. The resulting taxonomy contributes to the knowledge base a more detailed understanding of domain-specific HIS value indicators, which is tested for validity through a factor analysis.
Giardia, Entamoeba, and Trichomonas Enzymes Activate Metronidazole (Nitroreductases) and Inactivate Metronidazole (Nitroimidazole Reductases)

ABSTRACT Infections with Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis, which cause diarrhea, dysentery, and vaginitis, respectively, are each treated with metronidazole. Here we show that Giardia, Entamoeba, and Trichomonas have oxygen-insensitive nitroreductase (ntr) genes which are homologous to those genes that have nonsense mutations in metronidazole-resistant Helicobacter pylori isolates. Entamoeba and Trichomonas also have nim genes which are homologous to those genes expressed in metronidazole-resistant Bacteroides fragilis isolates. Recombinant Giardia, Entamoeba, and Trichomonas nitroreductases used NADH rather than the NADPH used by Helicobacter, and two recombinant Entamoeba nitroreductases increased the metronidazole sensitivity of transformed Escherichia coli strains. Conversely, the recombinant nitroimidazole reductases (NIMs) of Entamoeba and Trichmonas conferred very strong metronidazole resistance to transformed bacteria. The Ehntr1 gene of the genome project HM-1:IMSS strain of Entamoeba histolytica had a nonsense mutation, and the same nonsense mutation was present in 3 of 22 clinical isolates of Entamoeba. While ntr and nim mRNAs were variably expressed by cultured Entamoeba and Trichomonas isolates, there was no relationship to metronidazole sensitivity. We conclude that microaerophilic protists have bacterium-like enzymes capable of activating metronidazole (nitroreductases) and inactivating metronidazole (NIMs). While Entamoeba and Trichomonas displayed some of the changes (nonsense mutations and gene overexpression) associated with metronidazole resistance in bacteria, these changes did not confer metronidazole resistance to the microaerophilic protists examined here.
Inverse Transmission Model and Compensation Control of a Single-Tendon–Sheath Actuator

Tendon-sheath actuation mechanism is popular in many applications such as surgical robots, robotic hands, and exoskeleton devices due to its simplicity, dexterity, and remote transmission. There exist, however, undesirable nonlinear dynamic properties like backlash, hysteresis, and friction in tendon-sheath transmission. Controlling the distal-end position and force accurately is a very challenging task, since the needed sensors can hardly be placed at the distal end of the system. This paper develops a displacement transmission model of a single-tendon-sheath transmission system based on the force transmission model and proposes a new approach to control the distal-end force and position by inverse transmission without any feedback from the output side. The inverse model is calibrated by offline measurements using the sensors mounted at the proximal end. An experimental setup of single-tendon-sheath actuation is presented, and the improved control performance, with respect to distal-end position and force tracking, is validated by experiments.
Regional ventilation in infancy. Reversal of adult pattern.

Abstract There is evidence that in infants with unilateral lung disease, oxygenation improves when the good lung is uppermost — the reverse of the situation in adults. We performed krypton-81m ventilation scanning in 18 infants and very young children (11 days to 27 months old) with and without abnormal chest radiographs. Scanning was performed with the subject supine, in the left decubitus posture (right lung uppermost), and in the right decubitus posture (right lung dependent). Fractional ventilation to the right lung fell when that lung was dependent and rose when it was uppermost (P<0.001). This pattern was seen regardless of the appearance of the chest radiograph. The distribution of ventilation away from dependent lung regions represents a reversal of the adult pattern, which may be due to differences between infants and adults in lung mechanics and diaphragmatic function. This study adds further weight to the argument that infants and very young children with unilateral lung disease should be posit.
Identification of Five Structurally Unrelated Quorum-Sensing Inhibitors of Pseudomonas aeruginosa from a Natural-Derivative Database

ABSTRACT Bacteria communicate by means of small signal molecules in a process termed quorum sensing (QS). QS enables bacteria to organize their activities at the population level, including the coordinated secretion of virulence factors. Certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), have been shown to effectively block QS and subsequently attenuate the virulence of Pseudomonas aeruginosa, as well as increasing its susceptibility to both antibiotics and the immune system. In this study, a structure-based virtual screening (SB-VS) approach was used for the discovery of novel QSI candidates. Three-dimensional structures of 3,040 natural compounds and their derivatives were obtained, after which molecular docking was performed using the QS receptor LasR as a target. Based on docking scores and molecular masses, 22 compounds were purchased to determine their efficacies as quorum-sensing inhibitors. Using a live reporter assay for quorum sensing, 5 compounds were found to be able to inhibit QS-regulated gene expression in P. aeruginosa in a dose-dependent manner. The most promising compound, G1, was evaluated by isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis, and it was found to significantly affect the abundance of 46 proteins (19 were upregulated; 27 were downregulated) in P. aeruginosa PAO1. It specifically reduced the expression of several quorum-sensing-regulated virulence factors, such as protease IV, chitinase, and pyoverdine synthetases. G1 was also able to reduce extracellular DNA release and inhibited the secretion of the virulence factor, elastase, whose expression is regulated by LasR. These results demonstrate the utility of SB-VS for the discovery of target-specific QSIs.
Sialidase Fusion Protein as Inhibitor of Infection by Influenza Virus

Malakhov et al. reported that sialidase fusion protein could be used as a novel broad-spectrum inhibitor of influenza virus infection (2). They showed a 90% effective concentration (nM) of 6.5 ± 86.8 in Table 1 as the concentration of DAS181 that gave rise to 90% cell protection from influenza virus A/Victoria/504/2000 infection (2). However, it is extremely unusual for three positive numbers with an average of 6.5 to have a standard deviation of 86.8, suggesting that the standard deviation may be a typographical error. The authors should explain this oddity. Malakhov et al. mentioned in the abstract of their paper that “mouse and ferret studies confirmed significant in vivo efficacy of the sialidase fusion in both prophylactic and treatment modes. ” In my opinion, the ferret studies presented in Table 6 of the paper do not really support that statement. Comparing the mean values of virus titers (log10 50% tissue culture infective dose/ml) between vehicle-treated ferrets and sialidase fusion protein-treated ferrets on day 1 (4.4 versus 2.4), day 2 (4.7 versus 4.6), day 3 (2.7 versus 3.9), day 4 (3.7 versus 3.4), and day 5 (negative value versus 2.6) postinfection, it is hard for readers to understand how Malakhov et al. could make the conclusion that differences between these two groups are significant. Furthermore, Malakhov et al. ignored the fact that in the group treated with the sialidase fusion protein, 7 of 12 ferrets shed virus on days 2 and 3 postchallenge, and 6 of 12 ferrets shed virus on day 4 postchallenge. More importantly, 2 of 12 ferrets in the group treated with the sialidase fusion protein still shed virus on day 5 postchallenge, while none of the 8 ferrets in the vehicle-treated group shed virus. Malakhov et al. also didn't mention that nasal virus titers in the sialidase fusion protein-treated ferrets were about 15 times higher on day 3 and at least 200 times higher on day 5 postchallenge than those in the vehicle-treated ferrets. Malakhov et al. should explain why 2 of 12 sialidase fusion protein-treated ferrets shed virus on day 5 postchallenge while none of the 8 vehicle-treated ferrets did and repeat the ferret studies before making conclusive statements. Nevertheless, Malakhov et al. did realize and describe the limitations of the ferret study in the Discussion section. Additionally, Malakhov et al. omitted the chapter title, page numbers, and names of the editors for their reference 12, which makes it difficult for readers to find the cited reference. Therefore, I list here the complete information for that reference (1).
Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

ABSTRACT New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for in vitro activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens.
Multimorbidity and delivery of care for long-term conditions in the English National Health Service: baseline data from a cohort study

Objectives Many patients with long-term conditions have multiple conditions. Current delivery of care is not designed around their needs and they may face barriers to effective self-management. This study assessed the relationships between multimorbidity, the delivery of care, and self-management. Methods We surveyed 2439 patients with long-term conditions concerning their experience of the delivery of care and self-management in England in 2011. We assessed multimorbidity in terms of a count of long-term conditions and the presence of ‘probable depression’. We explored the relationships between multimorbidity, patient experience of the delivery of care, and self-management Results Neither measure of multimorbidity was a significant predictor of patients’ experience of the delivery of care. Patients with multimorbidity reported higher levels of self-management behaviour, while the presence of depression was associated with less positive attitudes towards self-management. Conclusions The current data do not demonstrate a consistent impact of multimorbidity on patients’ experience of care or on self-management. Further research is required to assess those types of multimorbidity that are associated with significant deficits, or to identify other aspects of care that might be problematic in the context of multiple conditions.