Dr. Stan Wagon of Macalester College discusses the mathematics behind rolling a square smoothly. In 1997, inspired by a square wheel exhibit at The Exploratorium museum in San Francsico, Dr. Stan Wagon enlisted his neighbor Loren Kellen in building a square-wheeled tricycle and accompanying catenary track. For years, you could ride the tricycle at Macalester College in St. Paul, Minnesota. The National Museum of Mathematics in New York now also has square-wheeled tricycles that can be ridden around a circular track. And more recently, the impressive Cody Dock Rolling Bridge was built using rolling square mathematics by Thomas Randall-Page in London.

Ming-Lun Hsieh and Shunsuke Yamana
Trans. Amer. Math. Soc. 377 (), 5617-5672.
Abstract, references and article information

Jian Li
Proc. Amer. Math. Soc. 152 (), 5207-5217.
Abstract, references and article information

The bacterial enhancer-binding protein (bEBP) FlrC, controls motility and colonization of Vibrio cholerae by regulating the transcription of class-III flagellar genes in σ54-dependent manner. However, the mechanism by which FlrC regulates transcription is not fully elucidated. Although, most bEBPs require nucleotides to stimulate the oligomerization necessary for function, our previous study showed that the central domain of FlrC (FlrCC) forms heptamer in a nucleotide-independent manner. Furthermore, heptameric FlrCC binds ATP in “cis-mediated” style without any contribution from sensor I motif 285REDXXYR291 of the trans protomer. This atypical ATP binding raises the question of whether heptamerization of FlrC is solely required for transcription regulation, or if it is also critical for ATPase activity. ATPase assays and size exclusion chromatography of the trans-variants FlrCC-Y290A and FlrCC-R291A showed destabilization of heptameric assembly with concomitant abrogation of ATPase activity. Crystal structures showed that in the cis-variant FlrCC-R349A drastic shift of Walker A encroached ATP-binding site, whereas the site remained occupied by ADP in FlrCC-Y290A. We postulated that FlrCC heptamerizes through concentration-dependent cooperativity for maximal ATPase activity and upon heptamerization, packing of trans-acting Tyr290 against cis-acting Arg349 compels Arg349 to maintain proper conformation of Walker A. Finally, a Trp quenching study revealed binding of cyclic-di-GMP with FlrCC. Excess cyclic-di-GMP repressed ATPase activity of FlrCC through destabilization of heptameric assembly, especially at low concentration of protein. Systematic phylogenetic analysis allowed us to propose similar regulatory mechanisms for FlrCs of several Vibrio species and a set of monotrichous Gram-negative bacteria.

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ1-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by up-regulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: l-tetrahydro-2-furoic acid, cyclopentanecarboxylate, l-thiazolidine-4-carboxylate, l-thiazolidine-2-carboxylate, and N-formyl l-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 μm. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an α-helix by 1 Å. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1 knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.

The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein–coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule–binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.

Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone–rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB.

The kinesin-3 family contains the fastest and most processive motors of the three neuronal transport kinesin families, yet the sequence of states and rates of kinetic transitions that comprise the chemomechanical cycle and give rise to their unique properties are poorly understood. We used stopped-flow fluorescence spectroscopy and single-molecule motility assays to delineate the chemomechanical cycle of the kinesin-3, KIF1A. Our bacterially expressed KIF1A construct, dimerized via a kinesin-1 coiled-coil, exhibits fast velocity and superprocessivity behavior similar to WT KIF1A. We established that the KIF1A forward step is triggered by hydrolysis of ATP and not by ATP binding, meaning that KIF1A follows the same chemomechanical cycle as established for kinesin-1 and -2. The ATP-triggered half-site release rate of KIF1A was similar to the stepping rate, indicating that during stepping, rear-head detachment is an order of magnitude faster than in kinesin-1 and kinesin-2. Thus, KIF1A spends the majority of its hydrolysis cycle in a one-head-bound state. Both the ADP off-rate and the ATP on-rate at physiological ATP concentration were fast, eliminating these steps as possible rate-limiting transitions. Based on the measured run length and the relatively slow off-rate in ADP, we conclude that attachment of the tethered head is the rate-limiting transition in the KIF1A stepping cycle. Thus, KIF1A's activity can be explained by a fast rear-head detachment rate, a rate-limiting step of tethered-head attachment that follows ATP hydrolysis, and a relatively strong electrostatic interaction with the microtubule in the weakly bound post-hydrolysis state.

In SAS Life Science Analytics Framework 4.6, group membership removal fails with an exception if a user is set as assignee, a candidate, or a notification recipient in a user task for a Process Flow . The Process

Driven by the energy of a photon, the visual pigments in rod and cone photoreceptor cells isomerize 11-cis-retinal to the all-trans configuration. This photochemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a visual signal to the brain and leaves the opsins insensitive to further light stimulation. For the eye to restore light sensitivity, opsins require recharging with 11-cis-retinal. This trans–cis back conversion is achieved through a series of enzymatic reactions composing the retinoid (visual) cycle. Although it is evident that the classical retinoid cycle is critical for vision, the existence of an adjunct pathway for 11-cis-retinal regeneration has been debated for many years. Retinal pigment epithelium (RPE)–retinal G protein-coupled receptor (RGR) has been identified previously as a mammalian retinaldehyde photoisomerase homologous to retinochrome found in invertebrates. Using pharmacological, genetic, and biochemical approaches, researchers have now established the physiological relevance of the RGR in 11-cis-retinal regeneration. The photoisomerase activity of RGR in the RPE and Müller glia explains how the eye can remain responsive in daylight. In this review, we will focus on retinoid metabolism in the eye and visual chromophore regeneration mediated by RGR.  

Insulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G₁. Consistent with the APC/C's role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.

A British daredevil was intentionally dragged behind his motorcycle at a speed of 159.52 mph to break a Guinness World Record.

Google is educating users about the lunar cycle with its latest interactive Doodle released Thursday.

Theater students in Scunthorpe, England, rehearse for their performance celebrating the life of homegrown cyclist Lal White

Dave Campbell of Thunder Bay, Ont., is resting his legs after taking the ride of his life through the Western Cape of South Africa in the 800-kilometre bikepacking 'Rhino Run.' Here are some of the photos he shared from his six-day expedition at the end of October.

Ontario Provincial Police (OPP) say one person is dead after a Saturday afternoon single-vehicle collision in Essex County involving a motorcycle.

One person is dead after a motorcycle and an SUV collided in Mount Albert, Ont., on Monday, Ontario Provincial Police say.

367.382 mph in a Two-Wheeled Missile

SOLIDWORKS and COSMOS analysis software help legendary Italian manufacturer speed innovations to market

New 'everybike' reclaims the joy of your first two-wheeler

Eighty riders pedaling hundreds of miles in Pan-Massachusetts Challenge

3D CAD models are faster to create and easier to comprehend

Designed in SOLIDWORKS software, this lowriding sport machine becomes nimble highrider on demand

Cyclone Clean Air Engine burns cleaner, more efficiently to power cars, ships, etc.

Gavin Thomson Design developed Bicygnals front and rear bicycle lights with integrated turn signals

Designed and Tested in SOLIDWORKS and SOLIDWORKS Simulation, Each Reee Chair Made of Plastic From Nine Recycled Game Consoles

Company Renowned for ‘Headset’ Innovation Cuts Time and Cost with SolidWorks Design and Simulation Software

Luxury Bike Shop Eliminates Prototypes Using SOLIDWORKS Simulation Software

FISHER/UNITECH Provides Tools to Create a Collapsible, Detachable Roof That Can Be Pulled Over a Motorcycle in a Few Seconds

Over an eight-day period, 18 Ride2Transform cyclists travelled 690 kilometers, participating in a personal journey with the Lord and praying for the country of Malawi.

Ride 2 Transform takes its third tour of southern Malawi for ministry and support.

Penn State Great Valley has unveiled a mural depicting the Penn State Nittany Lion, created from upcycled plastic bottle caps by mosaic studio artist Judith Hokky.  

One girl’s dream comes true, as she is now able to go to a village primary school, started by OM.

Massive distribution efforts by OM teams in Bangladesh over more than 10 years sowed gospel seeds and made the Bengali New Testament a #1 best seller.

Today, OM Germany Field Leader Tobias Schultz sets off on a 14-day bicycle tour through Germany, visiting OM teams in Hamburg, Halle/Saale and Heilbronn.

The event was part of a trend of young Chinese travelling on the cheap and spending as little as possible at a time of scarce job prospects, when wages are under pressure.

Donated plastic will be used to offset the purchase price of a recycled-plastic bench.

The Delaware Division of the Arts’ Mezzanine Gallery presents artist Colleen Zufelt’s exhibition, Recycle, Repurpose…RE-IMAGINE, showing March 4 through 25, 2022. Her exhibit will also be part of Art Loop Wilmington — the monthly self-guided tour of art in and around the city.

The Delaware Department of Agriculture (DDA) announced that beginning on April 19, 2023, the Delaware Council on Farm & Food Policy (Council) will accept grant applications for the second cycle of the First State Food System Program. Through this program, funding is available to Delaware farmers and a diverse range of food supply chain entities. Awarded funds will aid local entities to expand capacity, coordinate with partners in their communities, and do their part to build resilience in Delaware’s food system.

The Delaware Council on Farm & Food Policy (Council) is accepting grant applications for Cycle 3 of the First State Food System Program. Through this program, funding is available to Delaware farmers and a diverse range of food supply chain entities. Awarded funds will aid local entities in expanding capacity, coordinating with partners in their communities, and doing their part to build resilience in Delaware’s food system.

Governor John Carney has proclaimed May as Motorcycle Awareness Month and the Delaware Division of Motor Vehicles (DMV), in support of the Delaware Office of Highway Safety’s (OHS) Motorcycle Safety campaign, urges both motorists and motorcyclists to create a safer ride through education and awareness. Motorcyclists of all skill levels, both novice and advanced can […]

Governor John Carney has proclaimed May is Motorcycle Awareness Month and the Delaware Division of Motor Vehicles (DMV) along with the Delaware Office of Highway Safety (OHS) encourages motorcyclists to ride smart and ride safely through education and awareness. Every year from April through November, DMV offers six motorcycle safety courses for various skill levels, […]

SB 86 will require anyone obtaining a new motorcycle endorsement starting September 1, 2023, to wear a helmet and eye protection during the first two years of their endorsement. A civil penalty will be assessed to those found to be in violation.

Drivers, do your part and give motorcyclists extra room to stop and maneuver. Always look out for motorcyclists when turning, changing lanes, and at intersections. Motorcyclists, make yourselves visible by always using your headlights. Wear protective clothing and dress for a crash, not just the ride, and never travel in a vehicle’s blindsight.

Notice of Funding Opportunity About Delaware 250 The year 2026 will see the United States Semiquincentennial, the commemoration of the 250th anniversary of America’s (and Delaware’s) independence. This anniversary provides an opportunity to reflect on Delaware’s unique history and its contributions over the course of the nation’s history. This is a story that begins millennia […]

Artificial intelligence (AI) is everywhere. Machine learning (ML) and its associated inference abilities promise to revolutionize everything from driving your car to making your breakfast. Verification is never truly complete; it is over when you run...(read more)

Parliamentary representation by women in Pacific Island countries remains stubbornly low at 8.4 percent. Yet women leaders across the region have been meeting every year for the past four decades to discuss goals and drive action to address gender inequality and the most pressing development challenges in the Pacific. One of the critical issues discussed […]

Rejoice Muzamani is studying in preparation for her next paper during the end-of-term examinations at Mwenje Primary School in Chiredzi, southeast Zimbabwe. The 13-year-old girl, who is in Grade 7 or final year of primary school, is not worried about leaving school early to make the 7-kilometer journey back home before dusk, risking attacks from […]