Dan Deming, KKM Financial

Todd Colvin, Ambrosino Brothers

Bob Iaccino, Path Trading Partners

Todd Colvin, Ambrosino Brothers

Bob Iaccino, Path Trading Partners

Todd Colvin, Ambrosino Brothers

Todd Colvin, Ambrosino Brothers

Bob Iaccino, Path Trading Partners

Larry Shover, Efficient Advisors

Todd Colvin, Ambrosino Brothers

Bob Iaccino, Path Trading Partners

Larry Shover, Efficient Advisors

Bob Iaccino, Path Trading Partners

Larry Shover, Efficient Advisors

Todd Colvin, Ambrosino Brothers

Bob Iaccino, Path Trading Partners

Dan Deming, KKM Financial

Bob Iaccino, Path Trading Partners

Larry Shover, Efficient Advisors

Todd Colvin, Ambrosino Brothers

The post Using SOLIDWORKS Sheet Metal for Cardboard Packaging Design appeared first on SOLIDWORKS Education Blog.

As per the normal review of market volatility to ensure adequate collateral coverage, the Chicago Mercantile Exchange Inc., Clearing House Risk Management staff approved the performance bond requirements for the following products listed in the advisory at the link below.

The rates will be effective after the close of business on 4/24/2020.

Click here for the full text of the advisory

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As per the normal review of market volatility to ensure adequate collateral coverage, the Chicago Mercantile Exchange Inc., Clearing House Risk Management staff approved the performance bond requirements for the following products listed in the advisory in the link below. Please email any questions to Clearing.RiskManagement@cmegroup.com

The rates will be effective after the close of business on Friday, April 24, 2020.

For the full text of this advisory, please click here.

As per the normal review of market volatility to ensure adequate collateral coverage, the Chicago Mercantile Exchange Inc., Clearing House Risk Management staff approved the performance bond requirements for the following products listed in the advisory at the link below.

The rates will be effective after the close of business on 05/01/2020.

Click here for the full text of the advisory

20-183

As per the normal review of market volatility to ensure adequate collateral coverage, the Chicago Mercantile Exchange Inc., Clearing House Risk Management staff approved the performance bond requirements for the following products listed in the advisory at the link below. Please email any questions to Clearing.RiskManagement@cmegroup.com

The rates will be effective after the close of business on Friday, May 1, 2020.

For the full text of this advisory, please click here.

As per the normal review of market volatility to ensure adequate collateral coverage, the Chicago Mercantile Exchange Inc., Clearing House Risk Management staff approved the performance bond requirements for the following products listed in the advisory at the link below. Please email any questions to Clearing.RiskManagement@cmegroup.com

The rates will be effective after the close of business on Friday, May 8, 2020.

For the full text of this advisory, please click here.

The post An Electrical Engineer Using Sheet Metal? appeared first on The SOLIDWORKS Blog.

By Father Dave Pivonka, TOR

“This is the time of fulfillment.”

Those are the first words Jesus speaks to us in the Gospel of Mark. For 14 verses, he says nothing. He meets John the Baptist, the Holy Spirit descends upon him, and he faces temptation in the wilderness. But through it all, he doesn’t say a word. Then, finally, Jesus speaks: “This is the time of fulfillment. The kingdom of God is at hand. Repent, and believe in the gospel” (Mark 1:15).

The temptation, for most of us, is to hear those words in the past tense. We hear them as something Jesus said long ago to Jewish people in Roman-occupied Galilee.

But that’s not how the Scriptures work. They’re not simply a record of things that were said 2,000 years ago. They’re not a collection of history books like we find at our local library. They are “living and active, sharper than any two-edged sword . . . and discerning the thoughts and intentions of the heart” (Heb. 4:12).

This means Scripture speaks to us today. Jesus speaks to us today. Right here. Right now. This is the time of fulfillment. This is the time Jesus invites us to know him and follow him and encounter the Kingdom of Heaven. But he doesn’t just invite us. In Mark 1:15, he also tells us how we answer that invitation: “Repent, and believe.”

The Greek word used there for “repent and believe” is metanoia. It implies a turning or a change of mind. So, what Jesus says is, “Turn away from sin, and turn toward me. Change your focus—from sin, from the world, from a culture of distraction—and focus on me instead.” Ultimately, he issues a call to conversion, a call to a new way of thinking and a new way of living. And he issues that call, not just to Peter, James, John, and the rest of the 12, but to you and me.

Which means the question for us is: how do we answer that call? How, here and now, do we repent and believe? How do we experience metanoia?

Last year, the team from 4PM Media and I attempted to answer that question, when we spent 17 days in the Holy Land, filming Metanoia, a new 10-part video series on conversion and discipleship.

But the trip turned out to be much more than that.

Shot on location in some of our faith’s most sacred places, including the Sea of Galilee, the River Jordan, and the desert of temptations, Metanoia invites viewers to an encounter with Christ in both Scripture and history. It also invites each of us to look deep into our hearts, so we can hear how Christ is calling us to conversion.

For many Catholics, it’s tempting to think of conversion as a once and done event. It’s equally tempting to think of it as something other people need: that Jesus is calling other people to repent and believe—“those bishops and priests” or “those people who are in serious sin”—but not us. No, we think, it’s those people who need conversion. Never us. But in reality, it is always us.

Every one of us struggles in some way to live the Gospel. Every one of us has some area of our life that we have not handed over to Jesus. Every one of us, to some extent, bears some responsibility for the problems in the Church and world today.

That’s why conversion is a process each and every one of us must continually enter into. It’s a lifelong journey of being transformed by Christ and conformed to Christ. It’s never done. At least, not until we see Jesus face to face and hear the words, “Well done, good and faithful servant.”

And so, over the course of 10 weeks, Metanoia will invite Catholics to become the witness the world needs us to be and the disciples Jesus calls us to be. It does that by asking us to look at different areas of our life and faith—from our understanding of who Christ is and what it means to pray, to how we approach the Church’s more challenging teachings. It then invites us to think and pray about how Jesus calls us to conversion in those areas.

The whole series is really one big invitation to let God into every aspect of our life and transform it all.

Metanoia launches on Monday, February 3. Episodes will be available to watch at wildgoose.tv. I hope you join us. Because this is the time of fulfillment. Jesus is here. He has something for us right now. But we will never experience it if we don’t repent and believe. We will never experience it without metanoia.

Nicola Sturgeon won plaudits from some unlikely quarters this week for her “grown-up conversation” on lifting the lockdown.

Theatre

Associations between short sleep duration, obesity, and metabolic dysfunction have been proposed for children but have not been explored appropriately.

The main findings included a nonlinear trend between sleep duration and body weight and the finding that children's sleep averaged 8 hours per night regardless of body weight. Lower sleep duration values were strongly associated with increased metabolic risk. (Read the full article)

Changes in BMI category appear to be common in young children and are associated with cardiometabolic risk in cross-sectional studies. However, there are few longitudinal studies and little information from multiethnic samples of US middle school children.

Findings demonstrate that shifts in BMI category are common in middle-school-aged children and associated with clinically meaningful changes in cardiometabolic risk factors. Programs to promote decreases in BMI, prevent increases, and moderate risk are indicated. (Read the full article)

Diabetes during pregnancy has been associated with general development impairments in offspring; however, associations between autism and maternal diabetes have been inconsistent. Few studies have examined related conditions accompanied by underlying increased insulin resistance and their association with developmental outcomes.

This population-based study in young children provides evidence that maternal metabolic conditions are a risk factor for autism, developmental delay without autistic symptoms, and impairments in several domains of development, particularly expressive language, after adjusting for sociodemographic and other characteristics. (Read the full article)

In utero exposure to glucocorticoids in animal models influences vascular development. Studies in young adults have shown that exposure to antenatal glucocorticoids alters glucose metabolism, but it is not known whether there are any cardiovascular effects.

Glucocorticoid exposure is associated with a localized increase in aortic arch stiffness, similar in magnitude to term-born individuals a decade older. The change in stiffness does not relate to changes in glucose metabolism that were also evident in this cohort. (Read the full article)

Despite the dramatic rise in prevalence of metabolic syndrome (MetS) among children and adolescents, and that MetS is associated with cognitive and brain impairments among adults, no data on the impact of MetS on the brain exist in children.

It provides the first data on the impact of MetS on brain in adolescence. We show reductions in cognitive function and brain structural integrity in nondiabetic adolescents with MetS, thus suggesting that even pre-clinical metabolic illness may give rise to brain complications. (Read the full article)

In the United States, adolescent obesity rates have tripled in the last 3 decades, with concomitant increases in other metabolic risk factors, including the metabolic syndrome (MetSyn). However, in Asian countries, these same risks have only recently begun increasing.

Representative data for the United States and Korea reveal trends in adolescent obesity and MetSyn moving in opposite directions. This study provides a benchmark for Korea and other Asian countries toward mitigating the upward trends in obesity and MetSyn. (Read the full article)

The presence of elevated cardiometabolic risk factors, such as obesity, high glucose or lipid levels, and smoking, in adolescents has been shown to be associated with earlier onset of chronic conditions, such as diabetes and heart disease.

Obesity, smoking, and elevated glucose increases the risk of dying before the age of 55 years. This is the first study to focus on risk factors and mortality among adolescents and young adults in a nationally representative US sample. (Read the full article)

Obesity is associated with cardiometabolic risk factors and chronic conditions, such as type 2 diabetes. However, a proportion of overweight and obese youth remain free from cardiometabolic risk factors and are considered metabolically healthy.

This study provides insight into the determinants of cardiometabolic risk factors and the concept in health promotion of "fitness versus fatness." Hepatic lipid accumulation and not fitness level appears to drive cardiometabolic risk factor clustering among overweight and obese youth. (Read the full article)

The intestinal microbiome may play a role in immune system maturation, and it has been postulated that early-life probiotic administration may reduce the risk of allergies and asthma in childhood. To date, however, results from clinical trials have been inconsistent.

In this meta-analysis, administration of probiotics in early life may reduce total immunoglobulin E level and protect against atopic sensitization but do not seem to protect against asthma/wheezing. Future trials should carefully select probiotic strains and include longer follow-up. (Read the full article)

Early adiposity rebound is associated with future obesity and an increased risk of development of type 2 diabetes and coronary heart disease in adult life.

This study shows that early adiposity rebound is associated with future obesity and metabolic consequences of higher triglycerides, atherogenic index, apolipoprotein B, and blood pressure and lower high-density lipoprotein cholesterol at 12 years of age. (Read the full article)

The Centers for Disease Control and FITNESSGRAM BMI percentile thresholds are commonly used for obesity screening in youth. It is assumed that these thresholds are predictive of metabolic health risk, but little diagnostic data are available.

Both thresholds are predictive of metabolic syndrome, more so for boys than for girls, although with differing sensitivity and specificity. The diagnostic details of the thresholds can inform clinicians and practitioners about how these standards perform in practice. (Read the full article)

Resistance exercise is known to have a robust effect on glycemic control and cardiometabolic health among children and adolescents, even in the absence of weight loss.

Normalized strength capacity is associated with lower cardiometabolic risk clustering in boys and girls, even after adjustment for cardiorespiratory fitness, level of physical activity, and BMI. (Read the full article)

Prematurely born infants commonly have abnormal metabolic screens.

Both gestational and chronological age influence metabolic profiles used to screen for inborn errors of metabolism. (Read the full article)

Evidence on the cardiometabolic consequences of sedentary behavior in youth is inconsistent and mostly relies on cross-sectional studies. Studies with objective measures of sedentary time have found limited evidence of cross-sectional associations with adiposity markers but no other outcomes.

Objectively assessed daily sedentary time was not prospectively associated with cardiometabolic outcomes. Moderate to vigorous physical activity was beneficially associated with body fat mass, insulin, high-density lipoprotein cholesterol, and clustered cardiometabolic score. (Read the full article)

Childhood inflammatory mediators are associated with adult obesity, but the stimuli that initiate and perpetuate chronic inflammation start in early life are largely unknown.

Childhood infection-related hospitalization was independently associated with adverse adult metabolic variables, which suggests that infections and/or their treatment in childhood may contribute to causal pathways leading to adult cardiometabolic diseases. (Read the full article)

QPX7728 is a new ultra-broad-spectrum inhibitor of serine and metallo beta-lactamases from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A ESBLs (IC₅₀ range 1-3 nM) and carbapenemases such as KPC (IC₅₀ 2.9±0.4 nM) as well as class C P99 (IC₅₀ of 22±8 nM) with a potency that is comparable or higher than recently FDA approved BLIs avibactam, relebactam and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from A. baumannii (OXA-23/24/58, IC₅₀ range 1-2 nM) as well as MBLs such as NDM-1 (IC₅₀ 55±25 nM), VIM-1 (IC₅₀ 14±4 nM) and IMP-1 (IC₅₀ 610±70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high efficiency k₂/K ranging from of 6.3 x 10⁴ (for P99) to 9.9 x 10⁵ M^-1 s^-1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5-20 minutes for OXA carbapenemases from A. baumanii, ~50 minutes for OXA-48 and 2-3 hours for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on-fast-off kinetics, with K_is of 7.5±2.1 nM, 32±14 nM and 240±30 nM for VIM-1, NDM-1 and IMP-1, respectively. QPX7728 ultra-broad-spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound.

Multi-drug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely-used antibiotic class, the β-lactams, including the most recent-generation carbapenems. Interspecies spread renders these enzymes a serious clinical threat and there are no clinically-available inhibitors. We present crystal structures of IMP-13, a structurally-uncharacterized MBL from Gram-negative Pseudomonas aerugionasa found in clinical outbreaks globally, and characterize the binding using solution NMR-spectroscopy and molecular-dynamics simulations. Crystal structures of apo IMP-13 and bound to four clinically-relevant carbapenem antibiotics (doripenem, ertapenem, imipenem and meropenem) are presented. Active site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.