bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic engineering with ATP-citrate lyase and nitrogen source supplementation improves itaconic acid production in Aspergillus niger
Authors: Hossain Abeer H. , van Gerven Roy , Overkamp Karin M. , Lübeck Peter S. , Taşpınar Hatice , Türker Mustafa , Punt Peter J.
Published: October 2019

Background

Bio-based production of organic acids promises to be an attractive alternative for the chemicals industry to substitute petrochemicals as building-block chemicals. In recent years, itaconic acid (IA, methylenesuccinic acid) has been established as a sustainable building-block chemical for the manufacture of various products such as synthetic resins, coatings, and biofuels. The natural IA producer Aspergillus terreus is currently used for industrial IA production; however, the filamentous fungus Aspergillus niger has been suggested to be a more suitable host for this purpose. In our previous report, we communicated the overexpression of a putative cytosolic citrate synthase citB in an A. niger strain carrying the full IA biosynthesis gene cluster from A. terreus, which resulted in the highest final titer reported for A. niger (26.2 g/L IA). In this research, we have attempted to improve this pathway by increasing the cytosolic acetyl-CoA pool. Additionally, we have also performed fermentation optimization by varying the nitrogen source and concentration.

Results

To increase the cytosolic acetyl-CoA pool, we have overexpressed genes acl1 and acl2 that together encode for ATP-citrate lyase (ACL). Metabolic engineering of ACL resulted in improved IA production through an apparent increase in glycolytic flux. Strains that overexpress acl12 show an increased yield, titer and productivity in comparison with parental strain CitB#99. Furthermore, IA fermentation conditions were improved by nitrogen supplementation, which resulted in alkalization of the medium and thereby reducing IA-induced weak-acid stress. In turn, the alkalizing effect of nitrogen supplementation enabled an elongated idiophase and allowed final titers up to 42.7 g/L to be reached at a productivity of 0.18 g/L/h and yield of 0.26 g/g in 10-L bioreactors.

Conclusion

Ultimately, this study shows that metabolic engineering of ACL in our rewired IA biosynthesis pathway leads to improved IA production in A. niger due to an increase in glycolytic flux. Furthermore, IA fermentation conditions were improved by nitrogen supplementation that alleviates IA induced weak-acid stress and extends the idiophase.
CSACI position statement: Newer generation H1-antihistamines are safer than first-generation H1-antihistamines and should be the first-line antihistamines for the treatment of allergic rhinitis and urticaria
Authors: Fein Michael N. , Fischer David A. , O’Keefe Andrew W. , Sussman Gord L.
Published: October 2019

Oral H1-antihistamines (AHs) are the most commonly used therapy to treat allergic rhinitis and chronic urticaria. Older, first-generation AHs (e.g. diphenhydramine, hydroxyzine) have significant and common side effects including sedation, impairment with decreased cognitive function, poor sleep quality, dry mouth, dizziness, and orthostatic hypotension. These drugs have also been found to result in death from accidents, intentional or unintentional overdoses, and sudden cardiac death. The unfavourable risk–benefit profile of first-generation AHs led to the development of newer, less-sedating second- and third-generation AHs, which first became available in Canada in the 1980s. High-quality trials have proven that newer generation AHs are superior in safety compared to older first-generation AHs. On average, they have improved potency and efficacy. Second- and third-generation AHs are the recommended first-line treatment for mild allergic rhinitis and acute and chronic urticaria. Despite this evidence, older first-generation AHs continue to be over-utilized because of their over-the-counter (OTC) status and long history of use. The Canadian Society of Allergy Clinical Immunology (CSACI) recommends that newer generation AHs should be preferred over first-generation AHs for the treatment of allergic rhino-conjunctivitis and urticaria. To promote this recommendation, education of health professionals and the public is necessary. Further, given the dangers of older first-generation AHs, we believe they should be used only as a last resort with eventual consideration given to having them only available behind the counter in pharmacies.
Lactoferrin translocates to the nucleus of bovine rectal epithelial cells in the presence of Escherichia coli O157:H7
Authors: Rybarczyk Joanna , Khalenkow Dmitry , Kieckens Evelien , Skirtach Andre G. , Cox Eric , Vanrompay Daisy
Published: October 2019

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a foodborne pathogen which causes illness in humans. Ruminants are the main reservoirs and EHEC predominantly colonizes the epithelium of the recto-anal junction of cattle. Immunosuppression by EHEC promotes re-infection of cattle. However, bovine lactoferrin (bLF) apparently can overrule the immunosuppression by inducing EHEC-specific IgA responses at the mucosal site. The IgA responses are significantly correlated with reduced EHEC shedding and the absence of colonization at the rectal mucosa following re-infection. Therefore, to examine the interaction between bLF and bovine rectal epithelial cells, we first developed a method to establish a primary cell culture of epithelial cells of the rectum of cattle. Furthermore, we used LC–MS/MS to demonstrate the presence of secreted lactoferrin in bovine milk and the absence of a “delta” isoform which is known to translocate to the nucleus of cells. Nevertheless, lactoferrin derived from bovine milk was internalized by rectal epithelial cells and translocated to the nuclei. Moreover, nuclear translocation of bLF was significantly enhanced when the epithelial cells were inoculated with EHEC, as demonstrated by confocal fluorescence microscopy and confirmed by Raman microscopy and 3D imaging.
Precise large deviations for the aggregate claims in a dependent compound renewal risk model
Authors: Wang Kaiyong , Chen Lamei
Published: October 2019

We consider a dependent compound renewal risk model, where the interarrival times of accidents and the claim numbers follow a dependence structure characterized by a conditional tail probability and the claim sizes have a pairwise negatively quadrant dependence structure or a related dependence structure with the upper tail asymptotical dependence structure. When the distributions of the claim sizes belong to the dominated variation distribution class, we give the asymptotic lower and upper bounds for the precise large deviations of the aggregate claims.
Counting the non-existing: causes of death of undocumented migrants in Brussels-Capital Region (Belgium), 2005–2010
Authors: Lafaut Dirk , Vandenheede Hadewijch , Surkyn Johan , Coene Gily
Published: October 2019

Background

So far knowledge about undocumented migrant health status is poor. The objective of this study is to compare patterns in causes of death between undocumented migrants and legal residents, of both migrant and non-migrant origin.

Method

Using cause-of-death data, we compared undocumented migrants with Belgian residents and documented migrants through logistic regression analyses..

Results

This study shows that male undocumented migrants have a significantly higher risk of death from cardiovascular diseases compared to male Belgian residents (OR: 1.37) and documented migrants (OR: 2.17). Male undocumented migrants also have an increased risk of dying from external causes of death compared to documented migrants (OR: 1.93). Furthermore, we found a lower risk of suicidal death in undocumented migrants compared to Belgian residents (OR men: 0.29, OR women: 0.15).

Conclusions

We found important differences in underlying causes of death between undocumented migrants and residents in Belgium. These findings urge us to claim improved healthcare provision for undocumented migrants in Belgium.

Trial registration

Medical ethics committee UZ Jette, Brussels, Belgium – Registration date: 18/05/2016 – Registration number: B.U.N. 143201628279.
Perceptions of extended-release naltrexone, methadone, and buprenorphine treatments following release from jail
Authors: Velasquez Melissa , Flannery Mara , Badolato Ryan , Vittitow Alexandria , McDonald Ryan D. , Tofighi Babak , Garment Ann R. , Giftos Jonathan , Lee Joshua D.
Published: October 2019

Background

Few studies have documented patient attitudes and experiences with extended-release naltrexone (XR-NTX) opioid relapse prevention in criminal justice settings. This study assessed barriers and facilitators of jail-to-community reentry among adults with opioid use disorder (OUD) treated with XR-NTX, buprenorphine, methadone, and no medications.

Methods

This qualitative study conducted individual interviews with a purposeful and convenience sample of adults with OUD who were recently released from NYC jails. XR-NTX, no medication, and methadone participants were concurrently enrolled in a large randomized controlled trial evaluating XR-NTX vs. a no medication Enhanced Treatment As Usual (ETAU) condition, or enrolled in a non-randomized quasi-experimental methadone maintenance cohort. Buprenorphine participants were referred from NYC jails to a public hospital office-based buprenorphine program and not enrolled in the parent trial. Interviews were audio recorded, transcribed, independently coded by two researchers, and analyzed per a grounded theory approach adapted to the Social Cognitive Theory framework. The research team reviewed transcripts and coding to reach consensus on emergent themes.

Results

N = 33 adults with OUD (28 male, 5 female) completed a single individual interview. Purposeful sampling recruited persons leaving jail on XR-NTX (n = 11), no active medication treatment (n = 9), methadone (n = 9), and buprenorphine (n = 4). Emergent themes were: (1) general satisfaction with XR-NTX’s long-acting antagonist effects and control of cravings; (2) “testing” XR-NTX’s blockade with heroin upon reentry was common; (3) early discontinuation of XR-NTX treatment was most common among persons with high self-efficacy and/or heavy exposure to drug use environments and peers; (4) similar satisfaction regarding effects of methadone and buprenorphine maintenance among retained-in-treatment individuals, alongside general dissatisfaction with daily observed dosing requirements and misinformation and stigmas regarding methadone adverse effects; (5) unstable housing, economic insecurity, and exposure to actively using peers were attributed to early termination of treatment and relapse; (6) individual motivation and willpower as central to long-term opioid abstinence and reentry success.

Conclusions

In the context of more familiar agonist maintenance treatments, XR-NTX relapse prevention during jail-to-community reentry was viewed as a helpful and unique intervention though with important limitations. Commonly described barriers to treatment retention and heroin abstinence included homelessness, economic insecurity, and drug-using peers.

Trial registration ClinicalTrials.gov, NCT01999946 (XOR), Registered 03 December 2013, https://clinicaltrials.gov/ct2/show/NCT01999946.
The impact of the Green Revolution on indigenous crops of India
Authors: Eliazer Nelson Ann Raeboline Lincy , Ravichandran Kavitha , Antony Usha
Published: October 2019

The Green Revolution in India was initiated in the 1960s by introducing high-yielding varieties of rice and wheat to increase food production in order to alleviate hunger and poverty. Post-Green Revolution, the production of wheat and rice doubled due to initiatives of the government, but the production of other food crops such as indigenous rice varieties and millets declined. This led to the loss of distinct indigenous crops from cultivation and also caused extinction. This review deals with the impacts the Green Revolution had on the production of indigenous crops, its effects on society, environment, nutrition intake, and per capita availability of foods, and also the methods that can be implemented to revive the indigenous crops back into cultivation and carry the knowledge to the future generation forward.
Do we really need a surgery for hip fractures in elderly patients? Mortality rate and influencing factors
Authors: Hwang Kyu-Tae , Moon Jun-Ki , Kim Young-Ho
Published: October 2019

Background

Hip fractures are associated with notable mortality rates in elderly patients. The purpose of the study was to evaluate the mortality rate and influencing factors associated with mortality in the elderly patients with hip fractures.

Methods

Between October 2000 and December 2009, 807 elderly patients with hip fractures were enrolled in this study. There were 197 men and 610 women. The mean age at injuries were 78 years (range, 65–99 years). The fractures consisted of 390 femoral neck fractures and 417 intertrochanteric fractures. The mortality rate was evaluated between patients who underwent surgical and nonsurgical treatments. The influencing factors associated with mortality rate were evaluated statistically.

Results

Overall, 691 (85.6%) patients treated surgically and 116 (14.4%) patients treated nonsurgically were included. The overall mortality rates one and two years after injuries were 16.6 and 39.4%, respectively. In surgical treatment group, the mortality rate one and two years after injuries were 12.0 and 35.7%, respectively. In nonsurgical treatment group, the mortality rates were 44.0 and 61.2%, respectively (p < 0.05). No significant difference was noted between the types of fractures and the time from injury to surgery. Regardless of surgical methods, a significantly higher mortality rate was observed in patients with heart disease, chronic renal disease, dementia, and cancer, or in patients with 3 or more comorbidities.

Conclusions

In elderly patients with hip fractures, surgical treatments can decrease the mortality rate as compared with nonsurgical treatments. In addition, patients who had three or more comorbidities (heart disease, chronic renal failure, dementia, and history of cancer) are associated with a higher risk of mortality.

Trial registration

Retrospectively registered.
Just say N2O – nitrous oxide misuse: essential information for psychiatrists
Authors: Sheldon Rollo J. G. , Reid Michael , Schon Frederick , Poole Norman A.
Published: October 2019

Nitrous oxide (N2O) misuse is widespread in the UK. Although it is well-known that it can cause devastating myeloneuropathy, psychiatric presentations are poorly described. There is little understanding of who it affects, how it presents, its mechanism of action and principles of treatment. We begin this article with a case study. We then review the literature to help psychiatrists understand this area and deal with this increasing problem, and make diagnosis and treatment recommendations. We describe a diagnostic pentad of weakness, numbness, paraesthesia, psychosis and cognitive impairment to alert clinicians to the need to urgently treat these patients. Nitrous oxide misuse is a pending neuropsychiatric emergency requiring urgent treatment with vitamin B12 to prevent potentially irreversible neurological and psychiatric symptoms.
Effectiveness of cognitive–behavioural therapy for depression in advanced cancer: CanTalk randomised controlled trial
Authors: Serfaty Marc , King Michael , Nazareth Irwin , Moorey Stirling , Aspden Trefor , Mannix Kathryn , Davis Sarah , Wood John , Jones Louise
Published: October 2019

Background

Depression is one of the most common mental disorders in people with advanced cancer. Although cognitive–behavioural therapy (CBT) has been shown to be effective for depression in people with cancer, it is unclear whether this is the case for people with advanced cancer and depression.

Aims

We sought to determine whether CBT is more clinically effective than treatment as usual (TAU) for treating depression in people with advanced cancer (trial registration number ISRCTN07622709).

Method

A multi-centre, parallel-group single-blind randomised controlled trial comparing TAU with CBT (plus TAU). Participants (n = 230) with advanced cancer and depression were randomly allocated to (a) up to 12 sessions of individual CBT or (b) TAU. The primary outcome measure was the Beck Depression Inventory-II (BDI-II). Secondary outcome measures included the Patient Health Questionnaire-9, the Eastern Cooperative Oncology Group Performance Status, and Satisfaction with Care.

Results

Multilevel modelling, including complier-average intention-to-treat analysis, found no benefit of CBT. CBT delivery was proficient, but there was no treatment effect (−0.84, 95% CI −2.76 to 1.08) or effects for secondary measures. Exploratory subgroup analysis suggested an effect of CBT on the BDI-II in those widowed, divorced or separated (−7.21, 95% CI −11.15 to −3.28).

Conclusions

UK National Institute for Health and Care Excellence (NICE) guidelines recommend CBT for treating depression. Delivery of CBT through the Improving Access to Psychological Therapies (IAPT) programme has been advocated for long-term conditions such as cancer. Although it is feasible to deliver CBT through IAPT proficiently to people with advanced cancer, this is not clinically effective. CBT for people widowed, divorced or separated needs further exploration. Alternate models of CBT delivery may yield different results.
Variation Between and Within Hospitals in Single Injection Caudal Local Anesthetic Dose: A Report From the Pediatric Regional Anesthesia Network
Authors: Taenzer Andreas H. , Hoyt Matthew , Krane Elliot J. , Walker Benjamin J. , Flack Sean , Bosenberg Adrian , Sethna Navil F. , Franklin Andrew D. , Polaner David M. ,   for the PRAN investigators
Published: October 2019

BACKGROUND:

Given that variation exists in health care utilization, expenditure, and medical practice, there is a paucity of data on variation within the practice of anesthesia. The Pediatric Regional Anesthesia Network (PRAN) data lend itself to explore whether different medical practice patterns exist and if there are nerve blocks with more local anesthetic dosing variation than others. The primary aim of this study was to quantify variation in single injection caudal block dosing, and the secondary aim was to explore possible causes for variation (eg, number of blocks performed versus geographic location).

METHODS:

We queried the PRAN database for single injection caudal blocks in children <1 year of age. Data were analyzed for local anesthetic dose, variation within and across institutions, and possible causes.

RESULTS:

Mean dose of bupivacaine equivalents per kilogram (BE·kg−1) among sites ranged from 1.39 to 2.22 with an interdecile range (IDR) containing the mid 80% of all doses ranging from 0.21 to 1.48. Mean dose (BE·kg−1) was associated with site, age, weight, and local anesthetic used (all P < .0001). Cohen’s F effect size estimate was 10 times higher for site (0.65) than for age (0.05) or weight (0.02). Variation (IDR) was not related to number of blocks done at each site (P = .23). Mean volume per kilogram was 0.9± ± 0.2 (mean ± ±standard deviation) and was more strongly associated with site (Cohen’s F 0.3) than age (0.04) or weight (0.07).

CONCLUSIONS:

Wide variation in caudal local anesthetic dosing and administered volume exists. This variation is independent of the number of cases performed at each center but rather is determined by study site (ie, variation between centers) with considerable additional variation within study centers, suggesting additional variability dependent on individual practitioners. While there are legitimate reasons to vary dosing, the current approach is inconsistent and not supported by strong evidence over giving a standardized dose.
Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish
Authors: Kalasekar Sharanya M. , Kotiyal Srishti , Conley Christopher , Phan Cindy , Young Annika , Evason Kimberley J.
Published: October 2019

Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.
Cellular senescence in development, regeneration and disease
Authors: Rhinn Muriel , Ritschka Birgit , Keyes William M.
Published: October 2019

Cellular senescence is a state comprising an essentially irreversible proliferative arrest combined with phenotypic changes and pronounced secretory activity. Although senescence has long been linked with aging, recent studies have uncovered functional roles for senescence in embryonic development, regeneration and reprogramming, and have helped to advance our understanding of this process as a highly coordinated and programmed cellular state. In this Primer article, we summarize some of the key findings in the field and attempt to explain them in a simple model that reconciles the normal and pathological roles for senescence. We discuss how a primary role of cellular senescence is to contribute to normal development, cell plasticity and tissue repair, as a dynamic and tightly regulated cellular program. However, when this process is perturbed, the beneficial effects turn detrimental and can contribute to disease and aging.
Development of human limb muscles based on whole-mount immunostaining and the links between ontogeny and evolution
Authors: Diogo Rui , Siomava Natalia , Gitton Yorick
Published: October 2019

We provide the first detailed ontogenetic analysis of human limb muscles using whole-mount immunostaining. We compare our observations with the few earlier studies that have focused on the development of these muscles, and with data available on limb evolution, variations and pathologies. Our study confirms the transient presence of several atavistic muscles – present in our ancestors but normally absent from the adult human – during normal embryonic human development, and reveals the existence of others not previously described in human embryos. These atavistic muscles are found both as rare variations in the adult population and as anomalies in human congenital malformations, reinforcing the idea that such variations/anomalies can be related to delayed or arrested development. We further show that there is a striking difference in the developmental order of muscle appearance in the upper versus lower limbs, reinforcing the idea that the similarity between various distal upper versus lower limb muscles of tetrapod adults may be derived.
The use of genetically humanized animal models for personalized medicine approaches
Authors: Aartsma-Rus Annemieke , van Putten Maaike
Published: October 2019

For many genetic diseases, researchers are developing personalized medicine approaches. These sometimes employ custom genetic interventions such as antisense-mediated exon skipping or genome editing, aiming to restore protein function in a mutation-specific manner. Animal models can facilitate the development of personalized medicine approaches; however, given that they target human mutations and therefore human genetic sequences, scientists rely on the availability of humanized animal models. Here, we outline the usefulness, caveats and potential of such models, using the example of the hDMDdel52/mdx model, a humanized model recently generated for Duchenne muscular dystrophy (DMD).
Optimal Forward Guidance
Authors: Bilbiie Florin O.
Published: October 2019

Optimal forward guidance is the simple policy of keeping interest rates low for some optimally determined number of periods after the liquidity trap ends and moving to normal-times optimal policy thereafter. I solve for the optimal duration in closed form in a new Keynesian model and show that it is close to fully optimal Ramsey policy. The simple rule “announce a duration of half of the trap’s duration times the disruption” is a good approximation, including in a medium-scale dynamic stochastic general equilibrium (DSGE) model. By anchoring expectations of Delphic agents (who mistake commitment for bad news), the simple rule is also often welfare-preferable to Odyssean commitment. (JEL D84, E12, E43, E52, E56)
Pregnancy success and outcomes after uterine fibroid embolization: updated review of published literature
Authors: Ludwig Parker E , Huff Trevor J , Shanahan Meaghan M , Stavas Joseph M
Published: October 2019

Females with symptomatic leiomyomas (fibroids) wishing to maintain fertility are faced with difficult treatment choices. These include uterine fibroid embolization (UFE), myomectomy, hormonal therapy, MRI high intensity focused ultrasound, and myolysis. This review focuses on UFE, one of the most commonly accepted minimally invasive procedural choices among patients with symptomatic fibroids wishing to retain the option of becoming pregnant in the future, and makes comparisons to myomectomy which has historically been the surgical choice for fertility-preserving fibroid treatment. Pubmed and Google Scholar searches using keywords such as: uterine artery embolization, uterine fibroid embolization, pregnancy, complications, infertility were performed between Jan 1, 2019 and May 10, 2019. Publications were chosen based on their inclusion of information pertaining to fertility or pregnancy after UFE without being limited to single case reports.

Randomized controlled trials comparing myomectomy and UFE are limited due to study size and confounding variables, but through registry data and familiarity with referring clinicians, UFE has gained wide acceptance. Healthy pregnancies following UFE have been sporadically reported but the actual fertility rate after UFE remains uncertain. Conversely, low birth weight, miscarriage and prematurity have been associated with UFE. Despite inherent risks of possible fertility issues after UFE, the procedure remains an option for females with clinically symptomatic fibroids who desire pregnancy. However, additional research regarding rates of conception and obstetrical risks of infertility following UFE is necessary.
Brazilian REIT: Alternative Investment to Real Estate, Stock and Bonds
Authors: Yokoyama Karen Yukari , Sarlo Neto Alfredo , Cunha Cláudio Márcio Pereira da
Published: October 2019

Given the recent expansion of real estate securities in the Brazilian market, the present study examines Brazilian REITs (FIIs) returns’ exposure to underlying market returns (real estate, stock and bond) in order to assess evidence of diversification power provided by this investment type in light of Modern Portfolio Theory. The research considers a sample of FIIs listed on the São Paulo Stock Exchange, during the period of 2008-2014, applying Clayton and Mackinnon´s (2003) methodology, where the econometric model explaining REIT returns is decomposed into three market factors. Results indicate that although FII returns reflect their hybrid nature, the proposed model is not sufficient to explain their total returns, suggesting that FII performance is not primarily driven by any of these underlying markets. In fact, FII would consist of a unique asset class and as such may provide diversification benefits in a mixed portfolio, depending on the selected FII type.
Large scale enterohemorrhagic E coli population genomic analysis using whole genome typing reveals recombination clusters and potential drug target
Authors: Bandoy DJ Darwin
Published: October 2019

Enterohemorrhagic Escherichia coli continues to be a significant public health risk. With the onset of next generation sequencing, whole genome sequences require a new paradigm of analysis relevant for epidemiology and drug discovery. A large-scale bacterial population genomic analysis was applied to 702 isolates of serotypes associated with EHEC resulting in five pangenome clusters. Serotype incongruence with pangenome types suggests recombination clusters. Core genome analysis was performed to determine the population wide distribution of sdiA as potential drug target. Protein modelling revealed nonsynonymous variants are notably absent in the ligand binding site for quorum sensing, indicating that population wide conservation of the sdiA ligand site can be targeted for potential prophylactic purposes. Applying pathotype-wide pangenomics as a guide for determining evolution of pharmacophore sites is a potential approach in drug discovery.
A unique insert in the genomes of high-risk human papillomaviruses with a predicted dual role in conferring oncogenic risk
Authors: Auslander Noam , Wolf Yuri I. , Shabalina Svetlana A. , Koonin Eugene V.
Published: October 2019

The differences between high risk and low risk human papillomaviruses (HR-HPV and LR-HPV, respectively) that contribute to the tumorigenic potential of HR-HPV are not well understood but can be expected to involve the HPV oncoproteins, E6 and E7. We combine genome comparison and machine learning techniques to identify a previously unnoticed insert near the 3’-end of the E6 oncoprotein gene that is unique to HR-HPV. Analysis of the insert sequence suggests that it exerts a dual effect, by creating a PDZ domain-binding motif at the C-terminus of E6, as well as eliminating the overlap between the E6 and E7 coding regions in HR-HPV. We show that, as a result, the insert might enable coupled termination-reinitiation of the E6 and E7 genes, supported by motifs complementary to the human 18S rRNA. We hypothesize that the added functionality of E6 and positive regulation of E7 expression jointly account for the tumorigenic potential of HR-HPV.
Recent advances in nontuberculous mycobacterial lung infections
Authors: Horne David , Skerrett Shawn
Published: October 2019

Nontuberculous mycobacteria (NTM) are members of the Mycobacterium genus other than Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM are widely distributed in the environment and are increasingly recognized as causes of chronic lung disease that can be challenging to treat. In this brief review, we consider recent developments in the ecology, epidemiology, natural history, and treatment of NTM lung disease with a focus on Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex.
In silico analysis of a major allergen from Rattus norvegicus, Rat n 1, and cross-reactivity with domestic pets
Authors: Munera Marlon , Contreras Neyder , Sánchez Andres , Sánchez Jorge , Emiliani Yuliana
Published: October 2019

Background: Lipocalins play a role in the cellular trafficking of pheromones and are involved in allergic responses to domestic pets. However, the cross-reactivity among allergens of this group has been poorly explored, and the pheromone linking capacity is not well characterized. The aim of this study was to explore cross-reactive epitopes and pheromone linking capacity among Rat n 1 and homologues in domestic pets through an in silico approach.

Methods: ElliPro and BepiPred in silico tools were used to predict B cell linear and cross-reactive epitopes. The pheromone linking capacity was explored by docking virtual screening with 2-ethylhexanol, 2,5-dimethylpyrazine, 2-sec-butyl-4,5-dihydrothiazole, and 2-heptanone ligands.

Results: According to the analysis, Rat n 1 shares 52% identity with Equ c 1, Can f 6, Fel d 4, and Mus m 1 allergens. The overlapping structures assay revealed high structural homology (root mean square deviation < 1). Four lineal and three discontinuous epitopes were predicted on Ra t n 1. A lineal epitope located between amino acids residues 24 and 36 was highly conserved on all allergens explored. A cross-reactive discontinuous epitope (T142, K143, D144, L145, S146, S147, D148, K152, L170, T171, T173, D174) was also found. Docking molecular simulations revealed the active site, and we identified the properties of the binding of four pheromones and the binding potential of Rat n 1. Critical residues for interactions are reported in this study.

Conclusions: We identified some possible allergens from Rattus norvegicus, and those allergens could have cross-reactivity with allergens from some animals. The results need to be confirmed with in vitro studies and could be utilized to contribute to immunotherapy and reduce allergic diseases related to lipocalins.
Women Don’t Mean Business? Gender Penalty in Board Composition
Authors: Solal Isabelle , Snellman Kaisa
Published: October 2019

We examine investor responses to board diversity and highlight a previously unexplored mechanism to explain negative market reactions to senior female appointments. Drawing on signaling theory, we propose that an increase in board diversity leads investors to update their beliefs about firm preferences. Specifically, we argue that a gender-diverse board is interpreted as revealing a preference for diversity and a weaker commitment to shareholder value. Consequently, firms with more female directors will be penalized. We test our argument using 14 years of panel data on U.S. public firms. We find that firms that increase board diversity suffer a decrease in market value and that this effect is amplified for firms that have received higher ratings for their diversity practices across the organization. These results suggest that observers respond to the presence of female leaders not simply on their own merit but as broader cues of firm preferences and that firms may counteract any potential signaling effect through careful framing.
Deep-NFVOrch: leveraging deep reinforcement learning to achieve adaptive vNF service chaining in DCI-EONs
Authors: Li Baojia , Lu Wei , Zhu Zuqing
Published: October 2019

Due to the rise of cloud computing, how to realize adaptive and cost-effective virtual network function service chaining (vNF-SC) in a datacenter interconnection based on an elastic optical network (DCI-EON) has become an interesting but challenging problem. In this work, we tackle this problem by optimizing the design of a deep reinforcement learning (DRL)-based adaptive service framework, namely, Deep-NFVOrch. Specifically, Deep-NFVOrch works in service cycles and tries to reduce the setup latency of vNF-SC by invoking request prediction and pre-deployment at the beginning of each service cycle. We introduce a DRL-based observer (DRL-Observer) to select the duration of each service cycle adaptively according to the network status. The DRL-Observer is designed based on the advantage actor critic, which can interact with the network environment constantly through its deep neural network and learn how to make wise decisions based on the environment’s feedback. Our simulation results demonstrate that the DRL-Observer converges fast in online training with the help of a few asynchronous training threads, and the Deep-NFVOrch with it achieves better performance than several benchmarks, in terms of balancing the tradeoffs among overall resource utilization, vNF-SC request-blocking probability, and the number of network reconfigurations in a DCI-EON.
5-Hydroxymethylcytosines in Circulating Cell-Free DNA Reveal Vascular Complications of Type 2 Diabetes
Authors: Yang Ying , Zeng Chang , Lu Xingyu , Song Yanqun , Nie Ji , Ran Ruoxi , Zhang Zhou , He Chuan , Zhang Wei , Liu Song-Mei
Published: October 2019

BACKGROUND

Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, noninvasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions.

METHODS

A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case–control design.

RESULTS

Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without [testing set: area under the curve (AUC) = 0.85; 95% CI, 0.73–0.96], outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84; 95% CI, 0.68–0.99), showing superiority over conventional clinical variables.

CONCLUSIONS

The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, noninvasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.
The look: A look at non-Cartesian re-presentation
Authors: Gaietto Dawn
Published: October 2019

This is an attempt to elucidate non-Cartesian re-presentation (NCR) as a creative methodology allowing for the revealing of nonhuman agencies. Cartesian representation has presented a world of nonhumans ready for consumption, even exploitation. NCR works to reveal what-is and a sense of relational being through the arts encounter, negating a sense of human exceptionalism through movement, reciprocity and slippage. In this proposition I draw from the writing of Barbara Bolt to re-engage with the male philosophies of the past, to re-signify the lines of thinking, to imagine the potentialities of re-presentation outside of the predominate fictive imaginary.
Facile Synthesis and Biological Evaluation of Cyclopropyl-Pyrazole Hybrids in [bmim][PF6]- Water Biphasic System as Antifungal Agents
Authors: Burde P.C. , Rahatgaonkar A.M.
Published: October 2019

3-Cyclopropyl-5-(4-substituted)-1-phenyl-4,5-dihydro-1H-pyrazoles derived from corresponding chalcones were synthesized and evaluated for their biological activities. A convenient synthesis of a library of these compounds in 1-butyl-3-methylimidazolium hexafluorophosphatewater biphasic system at ambient temperature has been accomplished. The ionic liquid, [bmim][PF6] and water which are immiscible, has been easily recycled and reused after separation of the products without any noticeable diminution in its activity.
Structural changes of the thyroid gland. Causes of occurrence, diagnosis, treatment methods
Authors: Starkova N. T.
Published: October 2019

The article is devoted to structural changes of the thyroid gland, causes of occurrence, diagnosis, treatment methods.
Genetic factors in the pathogenesis of iodine deficiency goiter
Authors: Fadeev V. V. , Abramova N. A.
Published: October 2019

Iodine deficiency diseases (IDD) are the most common non-infectious human pathology. In general, 1.5 billion people live on the Earth in regions of iodine deficiency in the environment, 600 million of them have an increase in the thyroid gland, and 40 million have severe mental retardation as a result of iodine deficiency
Synthesis of Silver Nanoparticles (NPAg) using Andaliman (Zanthoxylum acanthopodium DC.) Fruit Water Extract and Its Application in Indigosol Blue Photodegradation
Authors: Lestari Gusti Ayu Dewi , Suprihatin Iryanti Eka , Sibarani James
Published: October 2019

Silver nanoparticles (NPAg) are silver metal particles that are less than 100 nm in size. NPAg has several advantages, one of which is as a catalyst in the process of photodegradation. NPAg was obtained by reducing AgNO3 using andaliman fruit water extract (Zanthoxylum acanthopodium DC.). This synthesis method is very effective because it is fast, non-toxic and environmentally friendly technology. This research aims to synthesize optimum NPAg and its application in the photodegradation process of Indigosol Blue in the form of volume, irradiation time, and optimum pH. NPAg synthesis was observed using a UV-VIS spectrophotometer while its size was observed using PSA (Particle Size Analyzer). The results showed the best NPAg synthesized using 1x10-3 M AgNO3 at 60°C with average NPAg size of 9.04 nm. NPAg which is formed is stable for ± 35 days. The optimum condition for the photodegradation process was achieved by using 2 mL NPAg 4 hour irradiation at pH 3. From the results of this study it can be concluded that NPAg can to reduce the concentration of Indigosol Blue dye by up to 94.75%.
Project portfolio prioritization strategy to extend the service life of offshore platforms – a Prométhée V approach
Authors: De Melo Rodrigo Toneto , Monteiro Gomes Luiz Flavio Autran , Filardi Fernando
Published: October 2019

This study puts forward the implementation of Multi-Criteria Decision Aid, through the PROMÉTHÉE V method, to support a decision on prioritizing a modification project portfolio on offshore oil and gas platforms. The chosen method supports, in a structured manner, the prioritization of a project portfolio which is necessary to leverage the oil production in offshore facilities, especially when they have already surpassed the plateau phase and presents production decline. Although the most relevant issues for investors are related to return on investments and the risks involved, the study suggests that other criteria are considered in specific settings. The research used data from 12 main projects of an oil and gas company and the criteria evaluations were made based on documents retrieved from the organization's database. This implementation represents a very important improvement for a well-known problem, in which the result is found based on criteria and their respective weights selected through a consensus. The results reinforce that any organization, with a constraint similar to the one presented in this study, may obtain relevant gains with the use of methods that clearly reflect the decision process and its criteria, assisting the decision maker's job significantly.
Systems success measurement: instrument & framework a new perspective
Authors: Fadhel Ibrahim Eskandar Ibrahim , Idrus Syed Zulkarnain Bin Syed , Abdullah Mohd Syukri Yeoh , Ibrahim Amani Ali Elmetwaly Ali , Omar Mazni Binti
Published: October 2019

There are major concerns regarding the previous research that can be said as having poor measurements, lack of theoretical grounding, and concern heavily on investment justifies. Some are also considered as having weak survey instruments, inappropriate data collection approaches, and lack of agreement on the dependent variables measurement that resulted in its incompatibility. Several related issues pertaining to high rates of systems’ failure that justify the heavy investment costs and affect the systems’ success of measurement. This matter had raised a high concern, especially for the researchers, practitioners, organization managers and systems administrators. Thus, the successful measurement of any systems is vital. The purpose of this study is to provide a framework and a high-quality validated instrument based on the literature review and experts’ validation. Subsequently, it can be used in the future studies to efficiently assist in the systems’ success measurement. The statistical test of 344 users with the smart PLS for the instrument shows an excellent result.
A Fuzzy EPQ Model for Non-Instantaneous Deteriorating Items where Production Depends on Demand which is Proportional to Population, Selling Price as well as Advertisement
Authors: Biswas Abhishek Kanti , Islam Sahidul
Published: October 2019

The inventory system has been drawing more intrigue because this system deals with the decision that minimizes the total average cost or maximizes the total average profit. For any farm, the demand for any items depends upon population, selling price and frequency of advertisement etc. Most of the model, it is assumed that deterioration of any item in inventory starts from the beginning of their production. But in reality, many goods are maintaining their good quality or original condition for some time. So, price discount is availed for defective items. Our target is to calculate the total optimal cost and the optimal inventory level for this inventory model in a crisp and fuzzy environment. Here Holding cost taken as constant and no-shortages are allowed. The cost parameters are considered as Triangular Fuzzy Numbers and to defuzzify the model Signed Distance Method is applied. A numerical example of the optimal solution is given to clarify the model. The changes of different parameters effect on the optimal total cost are presented and sensitivity analysis is given.JEL Classification: C44, Y80, C61Mathematics Subject Classification: 90B05
Present and perspectives of the intellectual capital management in Romanian university environment
Authors: Tonis Radu Bucea Manea , Braicu Cezar
Published: October 2019

The theory of organizational learning seems to be practical when researchers can find connections between two or more variables that can be justified and implemented. The term “intellectual capital” has appreciated over time acquiring a growing value. Work based on sustained learning contributes to the development of the intellectual capital not only of the employers, but also of the universities. In the current period of “knowledge economy” and “corporate university” development, the creation and evaluation of knowledge are recognized as important and necessary to be included in the educational programs. Knowledge management regards tacit and explicit knowledge. During the theoretical training, students mainly access information in written or verbal format, transmitted mainly on the teacher-student communication channel. During practical activities and mutual interactions, students agree to the informal knowledge, highly sought after by employers. In this paper, we will deal mainly with the ways of coding the information of statistical interest, which will be subject to a meta-level coding at the programming languages level, applicable to the analysis of the central trend and the shape of the data series distribution by estimating the parameters of the regression equation. According to the analysis, it results that in the absence of some measures to stimulate birth rate or attract foreign students, the Romanian higher education will register a considerable decline compared to the reference period in terms of the number of enrolled students.