Karim Fifel
Jan 24, 2018; 38:784-786
Journal Club

"This could be the oldest and longest-lived team ball game in the world," says one archaeologist

Demand for bilingual, biliterate graduates is high. Experts in dual-language learning explain how schools can start programs and strengthen existing ones.

Szymon Talaga and Andrzej Nowak: Real-world social networks often exhibit high levels of clustering, positive degree assortativity, short average path lengths (small-world property) and right-skewed but rarely power law degree distributions. On the other hand homophily, defined as the propensity of similar agents to connect to each other, is one of the most fundamental social processes observed in many human and animal societies. In this paper we examine the extent to which homophily is sufficient to produce the typical structural properties of social networks. To do so, we conduct a simulation study based on the Social Distance Attachment (SDA) model, a particular kind of Random Geometric Graph (RGG), in which nodes are embedded in a social space and connection probabilities depend functionally on distances between nodes. We derive the form of the model from first principles based on existing analytical results and argue that the mathematical construction of RGGs corresponds directly to the homophily principle, so they provide a good model for it. We find that homophily, especially when combined with a random edge rewiring, is sufficient to reproduce many of the characteristic features of social networks. Additionally, we devise a hybrid model combining SDA with the configuration model that allows generating homophilic networks with arbitrary degree sequences and we use it to study interactions of homophily with processes imposing constraints on degree distributions. We show that the effects of homophily on clustering are robust with respect to distribution constraints, while degree assortativity can be highly dependent on the particular kind of enforced degree sequence.

Data-driven businesses use technology as an insight platform to empower nontechnical users.

The post Data-driven to business insights appeared first on The Data Roundtable.

If I talk about my life, it was much simpler when I used to live with my parents. They took good care of whatever I wanted - in fact, they still do. But now, I am living alone, and sometimes I buy...

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You must deal with many reports in your daily life – for your health, financial accounts, credit, your child’s academic records, and the count goes on. Ever noticed that these reports contain many details, most of which you don’t wa...(read more)

Imagine you are on a vacation with your family, and suddenly, your phone starts buzzing. You pick it up and what are you looking at is a bunch of pending, unanswered e-mails. You start recollecting the checklist you had made before taking off only to realize that you haven’t put on the automatic replies! (read more)

What is a Power Distribution Network (PDN) after all but resistance, inductance, and capacitance in the PCB and components? And, of course, it is there to deliver the right current and voltage to each component on your PCB. But is that all? Are there oth...(read more)

So, what if you can figure out all that can go wrong when your product is being assembled early on? Not guess but know and correct at an early stage – not wait for the fabricator or manufacturer to send you a long report of what needs to change. That’s why Design for Assembly (DFA) rules(read more)

Brexit; It’s been the buzz word dominating the media recently and it’s likely to continue for some time. The UK’s decision to leave the EU has left both supporting sides of the ‘leave’ and ‘remain’ campaign in a somewhat collective state of uncertainty as to how this decision will impact the country right now and in the future years.

Brexit; It’s been the buzz word dominating the media recently and it’s likely to continue for some time. The UK’s decision to leave the EU has left both supporting sides of the ‘leave’ and ‘remain’ campaign in a somewhat collective state of uncertainty as to how this decision will impact the country right now and in the future years.

On 20th March, we held the 'Coronavirus Insights and practical solutions for landlords' webinar. 

On 20th March, we held the 'Coronavirus Insights and practical solutions for landlords' webinar.  In this webinar, our speakers discussed how the outbreak of Covid-19 and the subsequent political and economic impact is having a signific...

In this session we answered some of the most common questions clients have asked us over recent weeks as well as digging into more detail around how your business should proceed with specific legal and technical challenges according to French, Germa...

The law on force majeure differs from country to country, not least between common law and civil law jurisdictions. We have produced a both a Global Guide to Force Majeure and an Asia-Pacific Guide to Force Majeure that provides some preliminary ad...

Listen as our panel answer some of the most common questions clients have asked us over recent weeks as well as digging into more detail around how your business should proceed with specific legal and technical challenges. A recording of the session...

ABSTRACT

Burkholderia pseudomallei, the founding member of the B. pseudomallei complex (Bpc), is a biothreat agent and causes melioidosis, a disease whose treatment mainly relies on ceftazidime and meropenem. The concern is that B. pseudomallei could enhance its drug resistance repertoire by the acquisition of DNA from resistant near-neighbor species. Burkholderia ubonensis, a member of the B. cepacia complex (Bcc), is commonly coisolated from environments where B. pseudomallei is present. Unlike B. pseudomallei, in which significant primary carbapenem resistance is rare, it is not uncommon in B. ubonensis, but the underlying mechanisms are unknown. We established that carbapenem resistance in B. ubonensis is due to an inducible class A PenB β-lactamase, as has been shown for other Bcc bacteria. Inducibility is not sufficient for high-level resistance but also requires other determinants, such as a PenB that is more robust than that present in susceptible isolates, as well as other resistance factors. Curiously and diagnostic for the two complexes, both Bpc and Bcc bacteria contain distinct annotated PenA class A β-lactamases. However, the protein from Bcc bacteria is missing its essential active-site serine and, therefore, is not a β-lactamase. Regulated expression of a transcriptional penB'-lacZ (β-galactosidase) fusion in the B. pseudomallei surrogate B. thailandensis confirms that although Bpc bacteria lack an inducible β-lactamase, they contain the components required for responding to aberrant peptidoglycan synthesis resulting from β-lactam challenge. Understanding the diversity of antimicrobial resistance in Burkholderia species is informative about how the challenges arising from potential resistance transfer between them can be met.

IMPORTANCE Burkholderia pseudomallei causes melioidosis, a tropical disease that is highly fatal if not properly treated. Our data show that, in contrast to B. pseudomallei, B. ubonensis β-lactam resistance is fundamentally different because intrinsic resistance is mediated by an inducible class A β-lactamase. This includes resistance to carbapenems. Our work demonstrates that studies with near-neighbor species are informative about the diversity of antimicrobial resistance in Burkholderia and can also provide clues about the potential of resistance transfer between bacteria inhabiting the same environment. Knowledge about potential adverse challenges resulting from the horizontal transfer of resistance genes between members of the two complexes enables the design of effective countermeasures.

Objective

To specifically report on ataxic-hypotonic cerebral palsy (CP) using registry data and to directly compare its features with other CP subtypes.

The Bcl-2 (B cell lymphoma 2)-related protein Nr-13 plays a major role in the regulation of cell death in developing avian B cells. With over 65% sequence similarity to the chicken Nr-13, herpesvirus of turkeys (HVT) vNr-13, encoded by the HVT079 and HVT096 genes, is the first known alphaherpesvirus-encoded Bcl-2 homolog. HVT-infected cells were reported to be relatively more resistant to serum starvation, suggested that vNr-13 could be involved in protecting the cells. Here, we describe CRISPR/Cas9-based editing of exon 1 of the HVT079 and HVT096 genes from the HVT genome to generate the mutant HVT-vNr-13 to gain insights into its functional roles. Overall, wild-type HVT and HVT-vNr-13 showed similar growth kinetics; however, at early time points, HVT-vNr-13 showed 1.3- to 1.7-fold-lower growth of cell-associated virus and 3- to 6.2-fold-lower growth of cell-free virus. In transfected cells, HVT vNr-13 showed a mainly diffuse cytoplasmic distribution with faint nuclear staining. Further, vNr-13 localized to the mitochondria and endoplasmic reticulum (ER) and disrupted mitochondrial network morphology in the transfected cells. In the wild-type HVT-infected cells, vNr-13 expression appeared to be directly involved in the disruption of the mitochondrial network, as the mitochondrial network morphology was substantially restored in the HVT-vNr-13-infected cells. IncuCyte S3 real-time apoptosis monitoring demonstrated that vNr-13 is unequivocally involved in the apoptosis inhibition, and it is associated with an increase of PFU, especially under serum-free conditions in the later stages of the viral replication cycle. Furthermore, HVT blocks apoptosis in infected cells but activates apoptosis in noninfected bystander cells.

IMPORTANCE B cell lymphoma 2 (Bcl-2) family proteins play important roles in regulating apoptosis during homeostasis, tissue development, and infectious diseases. Several viruses encode homologs of cellular Bcl-2-proteins (vBcl-2) to inhibit apoptosis, which enable them to replicate and persist in the infected cells and to evade/modulate the immune response of the host. Herpesvirus of turkeys (HVT) is a nonpathogenic alphaherpesvirus of turkeys and chickens that is widely used as a live vaccine against Marek’s disease and as recombinant vaccine viral vectors for protecting against multiple avian diseases. Identical copies of the HVT genes HVT079 and HVT096 encode the Bcl-2 homolog vNr-13. While previous studies have identified the potential ability of vNr-13 in inhibiting apoptosis induced by serum deprivation, there have been no detailed investigations on the functions of vNr-13. Using CRISPR/Cas9-based ablation of the vNr-13 gene, we demonstrated the roles of HVT vNr-13 in early stages of the viral replication cycle, mitochondrial morphology disruption, and apoptosis inhibition in later stages of viral replication.

Manoella Gemaque Cavalcante, Cleusa Yoshiko Nagamachi, Julio Cesar Pieczarka, and Renata Coelho Rodrigues Noronha

Eukaryotic genomes exhibit substantial accumulation of repetitive DNA sequences. These sequences can participate in chromosomal reorganization events and undergo molecular cooption to interfere with the function and evolution of genomes. In turtles, repetitive DNA sequences appear to be accumulated at probable break points and may participate in events such as non-homologous recombination and chromosomal rearrangements. In this study, repeated sequences of 5S rDNA, U2 snRNA and Tc1/Mariner transposons were amplified from the genomes of the turtles, Podocnemis expansa and Podocnemis unifilis, and mapped by fluorescence in situ hybridization. Our data confirm the 2n=28 chromosomes for these species (the second lowest 2n in the order Testudines). We observe high conservation of the co-located 5S rDNA and U2 snRNA genes on a small chromosome pair (pair 13), and surmise that this represents the ancestral condition. Our analysis reveals a wide distribution of the Tc1/Mariner transposons and we discuss how the mobility of these transposons can act on karyotypic reorganization events (contributing to the 2n decrease of those species). Our data add new information for the order Testudines and provide important insights into the dynamics and organization of these sequences in the chelonian genomes.

Purpose:

Preclinical data demonstrating androgen receptor (AR)–positive (AR⁺) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR⁺ (≥10%) breast cancer.

Cefazolin has become a prominent therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, an important concern is the cefazolin inoculum effect (CzIE), a phenomenon mediated by staphylococcal β-lactamases. Four variants of staphylococcal β-lactamases have been described based on serological methodologies and limited sequence information. Here, we sought to reassess the classification of staphylococcal β-lactamases and their correlation with the CzIE. We included a large collection of 690 contemporary bloodstream MSSA isolates recovered from Latin America, a region with a high prevalence of the CzIE. We determined cefazolin MICs at standard and high inoculums by broth microdilution. Whole-genome sequencing was performed to classify the β-lactamase in each isolate based on the predicted full sequence of BlaZ. We used the classical schemes for β-lactamase classification and compared it to BlaZ allotypes found in unique sequences using the genomic information. Phylogenetic analyses were performed based on the BlaZ and core-genome sequences. The overall prevalence of the CzIE was 40%. Among 641 genomes, type C was the most predominant β-lactamase (37%), followed by type A (33%). We found 29 allotypes and 43 different substitutions in BlaZ. A single allotype, designated BlaZ-2, showed a robust and statistically significant association with the CzIE. Two other allotypes (BlaZ-3 and BlaZ-5) were associated with a lack of the CzIE. Three amino acid substitutions (A9V, E112A, and G145E) showed statistically significant association with the CzIE (P = <0.01). CC30 was the predominant clone among isolates displaying the CzIE. Thus, we provide a novel approach to the classification of the staphylococcal β-lactamases with the potential to more accurately identify MSSA strains exhibiting the CzIE.

Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98; P < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward P. vivax malaria elimination.

Ceftobiprole is an advanced-generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, as well as susceptible Gram-negative pathogens, including Pseudomonas sp. pathogens. In the case of Pseudomonas aeruginosa, ceftobiprole acts by inhibiting P. aeruginosa penicillin-binding protein 3 (PBP3). Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3-ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528 to L536 region adopts a conformation previously not observed in PBP3, including partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of β-lactam-PBP interactions that result in major changes in protein structure, as well as suggesting how to fine-tune current inhibitors and to develop novel inhibitors of this PBP.

Inflammasomes assemble in the cytosol of myeloid and epithelial cells on sensing of cellular stress and pathogen-associated molecular patterns and serve as scaffolds for recruitment and activation of inflammatory caspases. Inflammasomes play beneficial roles in host and immune responses against diverse pathogens but may also promote inflammatory tissue damage if uncontrolled. Gasdermin D (GSDMD) is a recently identified substrate of murine caspase-1 and caspase-11, and human caspases-1, -4, and -5 that mediates a regulated lytic cell death mode termed pyroptosis. Recent studies have identified pyroptosis as a critical inflammasome effector mechanism that controls inflammasome-dependent cytokine secretion and contributes to antimicrobial defense and inflammasome-mediated autoinflammatory diseases. Here, we review recent developments on inflammasome-associated effector functions with an emphasis on the emerging roles of gasdermin pores and pyroptosis.

BACKGROUND AND PURPOSE:

Brain metastases are a common finding on brain MRI. However, the factors that dictate their size and distribution are incompletely understood. Our aim was to discover a statistical model that can account for the size distribution of parenchymal metastases in the brain as measured on contrast-enhanced MR imaging.

Signing off after 30 years at the ABC, award-winning reporter Margot O'Neill writes about the thrill of the big scoop and gives an insight into the grinding slog of investigative journalism.

Following meetings with then-Commissioner Scott Gottlieb and senior leadership from the Center for Drug Evaluation and Research on the role of CROs and technology companies in designing and implementing risk-based monitoring (RBM) of clinical trials, ACRO this week submitted extensive comments on recent FDA Guidance.Increasing the use of innovative RBM technologies helps make clinical trials safer, more efficient and higher quality. ACRO’s comments offer unique insights into the recent expansion of RBM implementation and call for further increasing the use of these oversight technologies.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Nov 8, 2019

An exclusive interview with Lord Nicholas Stern, one of the world’s foremost experts on climate change.

Apr 8, 2020

Rebecca Henderson, the John and Natty McArthur University Professor at Harvard University, shared her perspectives on how large organizations are changing in response to the coronavirus pandemic and climate change in the newest episode of "Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program," a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here. Listen to the interview here.

Mar 27, 2020

Columbia University Professor Scott Barrett assessed the massive global efforts underway to address COVID-19 and the potential impacts of the pandemic on our lives in the future in a special episode of “Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program,” a podcast produced by the Harvard Environmental Economics Program. Listen to the interview here.