Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site

Many pathogenic bacteria utilise sialic acids as an energy source or use them as an external coating to evade immune detection. As such, bacteria that colonise sialylated environments deploy specific transporters to mediate import of scavenged sialic acids. Here, we report a substrate-bound 1.95 Å resolution structure and subsequent characterisation of SiaT, a sialic acid transporter from Proteus mirabilis. SiaT is a secondary active transporter of the sodium solute symporter (SSS) family, which use Na+ gradients to drive the uptake of extracellular substrates. SiaT adopts the LeuT-fold and is in an outward-open conformation in complex with the sialic acid N-acetylneuraminic acid and two Na+ ions. One Na+ binds to the conserved Na2 site, while the second Na+ binds to a new position, termed Na3, which is conserved in many SSS family members. Functional and molecular dynamics studies validate the substrate-binding site and demonstrate that both Na+ sites regulate N-acetylneuraminic acid transport

A micromechanics-based recurrent neural networks model for path-dependent cyclic deformation of short fiber composites

The macroscopic response of short fiber reinforced composites (SFRCs) is dependent on an extensive range of microstructural parameters. Thus, micromechanical modeling of these materials is challenging and in some cases, computationally expensive. This is particularly important when path-dependent plastic behavior is needed to be predicted. A solution to this challenge is to enhance micromechanical solutions with machine learning techniques such as artificial neural networks. In this work, a recurrent deep neural network model is trained to predict the path-dependent elasto-plastic stress response of SFRCs, given the microstructural parameters and the strain path. Micromechanical mean-field simulations are conducted to create a database for training the validating the model. The model gives very accurate predictions in a computationally efficient manner when compared with independent micromechanical simulations

Teleparallel Lagrange Geometry and a Unified Field Theory

In this paper, we construct a field theory unifying gravity and electromagnetism in the context of Extended Absolute Parallelism (EAP-) geometry. This geometry combines, within its structure, the geometric richness of the tangent bundle and the mathematical simplicity of Absolute Parallelism (AP-) geometry. The constructed field theory is a generalization of the Generalized Field Theory (GFT) formulated by Mikhail and Wanas. The theory obtained is purely geometric. The horizontal (resp. vertical) field equations are derived by applying the Euler-Lagrange equations to an appropriate horizontal (resp. vertical) scalar Lagrangian. The symmetric part of the resulting horizontal (resp. vertical) field equations gives rise to a generalized form of Einstein's field equations in which the horizontal (resp. vertical) energy-momentum tensor is purely geometric. The skew-symmetric part of the resulting horizontal (resp. vertical) field equations gives rise to a generalized form of Maxwell equations in which the electromagnetic field is purely geometric. Some interesting special cases, which reveal the role of the nonlinear connection in the obtained field equations, are examined. Finally, the condition under which our constructed field equations reduce to the GFT is explicitly established.Comment: Latex file, 33 page

The Vehicle, Fall 1987

Table of Contents Sketches in the SunRodger L. Patiencepage 3 Reflecting PoolRob Montgomerypage 5 Grandpa\u27s Porcelain DollRichard E. Hallpage 6 Tintype 1837Catherine Friemannpage 6 PhotographSteven M. Beamerpage 7 Washerwoman\u27s SongBob Zordanipage 8 Scrambled Eggs for D.O.Lynne A. Rafoolpage 8 my mother would sayMonica Grothpage 9 Retired by His ChildrenDan Von Holtenpage 10 I am the oldestMonica Grothpage 11 Ice on WheatRob Montgomerypage 12 The Nature of the RoseTroy Mayfieldpage 12 Past NebraskaDan Hornbostelpage 13 Five Minute Jamaican VacationChristy Dunphypage 14 PhotographSteven M. Beamerpage 14 The Angry PoemChristy Dunphypage 15 Road UnfamiliarChristy Dunphypage 15 raised voicesMonica Grothpage 16 Old Ladies & MiniskirtsKara Shannonpage 17 FreakspeakBob Zordanipage 18 PortraitDan Von Holtenpage 18 Mobile VacuumKathleen L. Fairfieldpage 19 Rev. Fermus DickSteve Hagemannpage 20 PhotographSteven M. Beamerpage 21 What\u27s the Name of That Flower?Richard Jesse Davispage 22 RequestChristy Dunphypage 23 SketchPaul Seabaughpage 24 ExperiencedMarilyn Wilsonpage 26 Leaving: Two ViewsTina Phillipspage 27 AntaeusDan Von Holtenpage 28 Misogyny at 19J. D. Finfrockpage 29 A Mental CrippleSteve Hagemannpage 32 AssociationsRhonda Ealypage 33 Banana BreadGail Bowerpage 34 Bill and JackBradford B. Autenpage 35 After Image No. 2Rob Montgomerypage 35 VrrooomBeth Goodmanpage 36 Mr. Modern LoverMolly Maddenpage 36 TravelogueRodger L. Patiencepage 37 Down the HighwayJoan Sebastianpage 38 A Retread HeavenRob Montgomerypage 41 StuporDan Von Holtenpage 42 Love Poem After a Seizure in Your BedBob Zordanipage 43 PalsyChristy Dunphypage 44 Interview with Mr. MatthewsBob Zordanipage 45 Chasing Down Hot Air Balloons on a Sunday MorningRob Montgomerypage 48https://thekeep.eiu.edu/vehicle/1049/thumbnail.jp

The Sodium Sialic Acid Symporter From Staphylococcus aureus Has Altered Substrate Specificity

Mammalian cell surfaces are decorated with complex glycoconjugates that terminate with negatively charged sialic acids. Commensal and pathogenic bacteria can use host-derived sialic acids for a competitive advantage, but require a functional sialic acid transporter to import the sugar into the cell. This work investigates the sodium sialic acid symporter (SiaT) from Staphylococcus aureus (SaSiaT). We demonstrate that SaSiaT rescues an Escherichia coli strain lacking its endogenous sialic acid transporter when grown on the sialic acids N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). We then develop an expression, purification and detergent solubilization system for SaSiaT and demonstrate that the protein is largely monodisperse in solution with a stable monomeric oligomeric state. Binding studies reveal that SaSiaT has a higher affinity for Neu5Gc over Neu5Ac, which was unexpected and is not seen in another SiaT homolog. We develop a homology model and use comparative sequence analyses to identify substitutions in the substrate-binding site of SaSiaT that may explain the altered specificity. SaSiaT is shown to be electrogenic, and transport is dependent upon more than one Na+ ion for every sialic acid molecule. A functional sialic acid transporter is essential for the uptake and utilization of sialic acid in a range of pathogenic bacteria, and developing new inhibitors that target these transporters is a valid mechanism for inhibiting bacterial growth. By demonstrating a route to functional recombinant SaSiaT, and developing the in vivo and in vitro assay systems, our work underpins the design of inhibitors to this transporter

The basis for non-canonical ROK family function in the N-acetylmannosamine kinase from the pathogen Staphylococcus aureus

In environments where glucose is limited, some pathogenic bacteria metabolize host-derived sialic acid as a nutrient source. N-Acetylmannosamine kinase (NanK) is the second enzyme of the bacterial sialic acid import and degradation pathway and adds phosphate to N-acetylmannosamine using ATP to prime the molecule for future pathway reactions. Sequence alignments reveal that Gram-positive NanK enzymes belong to the Repressor, ORF, Kinase (ROK) family, but many lack the canonical Zn-binding motif expected for this function, and the sugar-binding EXGH motif is altered to EXGY. As a result, it is unclear how they perform this important reaction. Here, we study the Staphylococcus aureus NanK (SaNanK), which is the first characterization of a Gram-positive NanK. We report the kinetic activity of SaNanK along with the ligand-free, N-acetylmannosamine-bound and substrate analog GlcNAc-bound crystal structures (2.33, 2.20, and 2.20 Å resolution, respectively). These demonstrate, in combination with small-angle X-ray scattering, that SaNanK is a dimer that adopts a closed conformation upon substrate binding. Analysis of the EXGY motif reveals that the tyrosine binds to the N-acetyl group to select for the "boat" conformation of N-acetylmannosamine. Moreover, SaNanK has a stacked arginine pair coordinated by negative residues critical for thermal stability and catalysis. These combined elements serve to constrain the active site and orient the substrate in lieu of Zn binding, representing a significant departure from canonical NanK binding. This characterization provides insight into differences in the ROK family and highlights a novel area for antimicrobial discovery to fight Gram-positive and S. aureus infections

Development and deployment of COVID-19 vaccines forthose most vulnerable

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable

Adverse effects of extra-articular corticosteroid injections: a systematic review

<p>Abstract</p> <p>Background</p> <p>To estimate the occurrence and type of adverse effects after application of an extra-articular (soft tissue) corticosteroid injection.</p> <p>Methods</p> <p>A systematic review of the literature was made based on a PubMed and Embase search covering the period 1956 to January 2010. Case reports were included, as were prospective and retrospective studies that reported adverse events of corticosteroid injection. All clinical trials which used extra-articular corticosteroid injections were examined. We divided the reported adverse events into major (defined as those needing intervention or not disappearing) and minor ones (transient, not requiring intervention).</p> <p>Results</p> <p>The search yielded 87 relevant studies:44 case reports, 37 prospective studies and 6 retrospective studies. The major adverse events included osteomyelitis and protothecosis; one fatal necrotizing fasciitis; cellulitis and ecchymosis; tendon ruptures; atrophy of the plantar fat was described after injecting a neuroma; and local skin effects appeared as atrophy, hypopigmentation or as skin defect. The minor adverse events effects ranged from skin rash to flushing and disturbed menstrual pattern. Increased pain or steroid flare after injection was reported in 19 studies. After extra-articular injection, the incidence of major adverse events ranged from 0-5.8% and that of minor adverse events from 0-81%. It was not feasible to pool the risk for adverse effects due to heterogeneity of study populations and difference in interventions and variance in reporting.</p> <p>Conclusion</p> <p>In this literature review it was difficult to accurately quantify the incidence of adverse effects after extra-articular corticosteroid injection. The reported adverse events were relatively mild, although one fatal reaction was reported.</p