Numerical and Experimental Extraction of Dynamic Parameters for Pyramidal Truss Core Sandwich Beams with Laminated Face Sheets

Sandwich beams that are composed of laminated face sheets and aluminum pyramidal truss cores are considered to be essential elements of building and aerospace structures. In this paper, a methodology for the experimental and numerical analysis of such structures is presented in order to support their industrial application. The scope of the present research covers both the experimental and numerical extraction of the dynamic parameters of the sandwich beams. Vibration tests are performed while using an optical system for three-dimensional vibrations sensing. The in-plane and out-of-plane vibration modes can thus be examined. A detailed numerical model of the sandwich beam is developed, including an adhesive joint (an additional layer of material) between the parent components of the beam. The numerically predicted modal parameters (eigenfrequencies, mode shapes, modal loss factors) are comported with their corresponding experimentally-obtained values. The modal loss factors are predicted based on the strain energy method, for which a brief theoretical introduction is provided. The obtained experimental and numerical results coincide with good accuracy. The circumstances for possible model simplifications are provided depending on the solution objectives.     

A brief appraisal of computational modeling of antimicrobial peptides’ activity

We present a brief overview of computer simulations over the span of last two decades that have made some serious attempts in providing key insights toward the mechanistic aspects of antimicrobial peptides and biomimetic peptides. We review some of the success stories of computational modeling of antimicrobial activity and also point toward the present shortcomings of the current approaches. Finally, we shed light upon the future potential directions that computational approach can adopt toward direct and closer comparisons with experiments on antimicrobial activity.     

Brief Report: The effect of tethering on the clearance rate of suspension-feeding plankton

Many planktonic suspension feeders are attached to particles or tethered by gravity when feeding. It is commonly accepted that the feeding flows of tethered suspension feeders are stronger than those of their freely swimming counterparts. However, recent flow simulations indicate the opposite, and the cause of the opposing conclusions is not clear. To explore the effect of tethering on suspension feeding, we use a low-Reynolds-number flow model. We find that it is favorable to be freely swimming instead of tethered since the resulting feeding flow past the cell body is stronger, leading to a higher clearance rate. Our result underscores the significance of the near-field flow in shaping planktonic feeding modes, and it suggests that organisms tether for reasons that are not directly fluid dynamical (e.g., to stay near surfaces where the concentration of bacterial prey is high).     

COVID-19: From bench to bed side

Background and aimsThe last two decades have experienced the outbreaks of three different coronaviruses in the different parts of the world namely; Severe acute respiratory syndrome cornonavirus-1 (SARS-CoV-1), Middle East respiratory syndrome (MERS-CoV) and Severe acute respiratory syndrome cornonavirus-2 (SARS-CoV-2). We aimed to delineate the differences in viral dynamics and clinical features between them and tried to focus on every basic details of SARS-COV-2 (COVID-19) that every health care provider must know.MethodsWe systematically searched the PubMed database up till April 2, 2020 and retrieved all the articles published on SARS-CoV-2, SARS-CoV-1, MERS-CoV that dealt with viral dynamics.ResultsAmple data is available to suggest the differences in etiology, transmission cycle, diagnosis, genetics, hosts, reproductive rates, clinical features, laboratory diagnosis and radiological features between SARS-CoV-1, MERS-CoV and SARS-CoV-2.ConclusionAlthough SARS-CoV-2 (COVID-19) is more infectious than SARS-CoV-1 and MERS-CoV, most infections are generally mild and self-limiting. However, case-fatality rates are very high in patients with COVID-19 with comorbidities, compared to SARS-CoV-1 and MERS-CoV.     

Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses

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Fabrication of Microdots Using Piezoelectric Dispensing Technique for Viscous Fluids

A simple microfluidic control method that uses a piezoelectric dispenser head is developed to fabricate microdots. A glycerol mixture was used as the test fluid to simulate conductive metallic solutions. The orifice diameter of the dispenser was 50 μm. Investigations were conducted at room temperature (25 °C). For each bipolar waveform, fluid was extruded in the form of a stretching liquid column, which eventually retracted into the dispenser orifice. Microdots were obtained by governing the liquid transfer process between the dispenser orifice and the target surface, where the gap was smaller than the maximum extrusion length during liquid column formation. Three fluid behaviors were observed using high-speed imaging, namely extrusion, impact on the target surface, and pinch-off of liquid ligament. For gaps of below 70 μm, some of the fluid sticking on the target surface resulted in a microdot diameter of 26 μm (about half of the orifice diameter).     

Projecting future supply and demand for physical therapists in Japan using system dynamics

ObjectivesJapan is the oldest country in the world, and its demand for medical care is expected to increase. Although a clear vision regarding the supply and demand for physical therapy services is necessary, there has been no research that forecasts the supply and demand for physical therapists in Japan. Consensus has not been reached on whether the supply of physical therapists is sufficient. This study projects this supply and demand to provide medical policymakers with basic data.MethodsA system dynamics model was created to predict the number of physical therapists working in hospitals and clinics in Japan from 2014 to 2040. The future demand for physical therapy was estimated using the rehabilitation service utilization data from Open National Database, a publicly available nationwide health claims database. Sufficiency rates (supply/demand) were calculated, and sensitivity analysis was conducted on supply-related parameters.ResultsThe number of physical therapists was projected to be 1.74 and 2.54 times greater in 2025 and 2040, respectively, than in 2014. The sufficiency rates were 1.72, 2.39, and 3.30 in 2015, 2025, and 2040, respectively. The sensitivity analysis revealed that attrition rates had the greatest effects on sufficiency.ConclusionsAlthough the current supply appears to be needed, considering the expected increase and uncertainty in medical needs. However, there is a possibility of a future oversupply, especially after 2025, when the rate of increase in demand will lessen. Further studies are required to evaluate the distribution of physical therapists among regions and specialties.     

Structure-Based Identification of Natural Products as SARS-CoV-2 Mpro Antagonist from Echinacea angustifolia Using Computational Approaches

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (M^pro) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from Echinacea-angustifolia, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 M^pro. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>−10 kcal/mol) in the SARS-CoV-2 M^pro catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<−4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 M^pro with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from Echinacea angustifolia for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 M^pro antagonist with higher affinity and drug-likeness.     

The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation

The Src-homology-2 domain–containing phosphatase SHP2 is a critical regulator of signal transduction, being implicated in cell growth and differentiation. Activating mutations cause developmental disorders and act as oncogenic drivers in hematologic cancers. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as the key “allosteric switch” driving SHP2 activation. To test the putative coupling between binding cleft opening and SHP2 activation as assumed by the allosteric switch model, we critically reviewed structural data of SHP2, and we used extensive molecular dynamics (MD) simulation and free energy calculations of isolated N-SH2 in solution, SHP2 in solution, and SHP2 in a crystal environment. Our results demonstrate that the binding cleft in N-SH2 is constitutively flexible and open in solution and that a closed cleft found in certain structures is a consequence of crystal contacts. The degree of opening of the binding cleft has only a negligible effect on the free energy of SHP2 activation. Instead, SHP2 activation is greatly favored by the opening of the central β-sheet of N-SH2. We conclude that opening of the N-SH2 binding cleft is not the key allosteric switch triggering SHP2 activation.

Src-homology-2–containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a classical nonreceptor protein tyrosine phosphatase (PTP). It has emerged as a key downstream regulator of several receptor tyrosine kinases (RTKs) and cytokine receptors, functioning as a positive or negative modulator in multiple signaling pathways (1–4). Germline mutations in the human PTPN11 gene have been associated with Noonan syndrome and with Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome), two multisystem developmental diseases (5–16). Somatic PTPN11 mutations were also linked with several types of human malignancies (17–25), such as myeloid leukemia (7, 26–30).The structure of SHP2 includes two tandemly arranged Src homology 2 domains (SH2), called N-SH2 and C-SH2, followed by the catalytic PTP domain, and a C-terminal tail with a poorly characterized function (Fig. 1) (31). The SH2 domains are structurally conserved recognition elements (32) that allow SHP2 to bind signaling peptides containing a phosphorylated tyrosine (pY) (33). The N-SH2 domain consists of a central antiparallel β-sheet, composed of three β-strands, denoted βB, βC, and βD, flanked by two α-helices, denoted αA and αB (Fig. 1A). The peptide binds in an extended conformation to the cleft that is perpendicular to the plane of the β-sheet (34). N-SH2 contains a conserved affinity pocket covered by the BC loop (also called phosphate-binding loop or pY loop), whose interaction with pY increases the binding of the peptide by 1,000-fold relative to unphosphorylated counterparts (35). Residues downstream of the pY bind to a more variable, less conserved site, which confers binding specificity and which is flanked by the EF and BG loops (36).Open in a separate windowFig. 1.(A) Cartoon representation of the N-SH2 domain in complex with the IRS-1 pY895 peptide (34). The peptide, shown in cyan, comprises the phosphotyrosine and residues from position +1 to +5 relative to the phosphotyrosine (see labels). Functionally important loops are highlighted in color: BC “pY” loop (green), DE “blocking loop” (light blue), EF loop (magenta), and BG loop (deep pink). The phosphotyrosine binds the site delimited by the pY loop and the central β-sheet (βB, βC, βD strands). EF and BG loops delimit the binding cleft (+5 site), where the peptide residue in position +5 is settled. (B) Crystal structure of autoinhibited SHP2 (37). The N-SH2 domain (cyan cartoon) blocks the catalytic site (red) of the PTP domain (pink) with the blocking loop (blue). The N-SH2 domain is connected to PTP in tandem with the homologous C-SH2 domain (orange). Closure of the N-SH2 binding cleft (green region), delimited by the EF and BG loops (magenta and deep pink), precludes high-affinity phosphopeptide binding. According to the “allosteric switch” model, the change in shape of the N-SH2 domain, which accompanies binding of phosphopeptide (yellow), perturbs surface complementarity for the PTP active site, thus promoting N-SH2 dissociation from the PTP domain. (C) Crystal structure of SHP2^E76K (38). The open conformation reveals a 120° rotation of the C-SH2 domain, relocation of the N-SH2 domain to a PTP surface opposite the active site, and a solvent-exposed catalytic pocket.In 1998, the first crystallographic structure of SHP2 at 2 Å resolution (Protein Data Bank [PDB] ID 2SHP) revealed that the N-SH2 domain tightly interacts with the PTP domain (Fig. 1B), so that the DE loop of N-SH2, thereafter indicated as “blocking loop,” occludes the active site of PTP, forcing SHP2 into an autoinhibited “closed” state (37). SHP2 structures of the active “open” state, obtained for the basally active, leukemia-associated E76K mutant, showed an alternative relative arrangement of N-SH2 and PTP that exposed the active site of the PTP domain to the solvent (Fig. 1C) (38). Unexpectedly, in both the autoinhibited and the active state of SHP2, the N-SH2 ligand binding site is exposed to solvent and does not directly interact with PTP or other domains (37–39). Hence, the need for an allosteric mechanism was proposed, according to which the binding of a phosphopeptide triggers a series of structural rearrangements in the N-SH2 domain to drive its release from PTP and the consequent activation of SHP2 (37, 39).The comparison of the autoinhibited structure of SHP2 (PDB ID 2SHP) (37) with the existing structures of the isolated N-SH2 domain, either in the absence of (PDB ID 1AYD) (34) or in complex with a phosphopeptide (PDB ID 1AYA, 1AYB, 4QSY) (34), showed that the EF and BG loops of the N-SH2 domain may undergo large conformational changes (Fig. 1B). In the autoinhibited structure of SHP2, the N-SH2 domain shares surface complementarity with the PTP catalytic site, but, as a result of the displacement of the EF loop toward the BG loop, it also contains a closed binding cleft that renders the N-SH2 domain unable to accommodate the C-terminal part of the phosphopeptide, in contrast to the isolated N-SH2 domain that exhibits an open binding cleft. Therefore, peptide binding seems only compatible with the conformation of isolated N-SH2, but not with the conformation of N-SH2 in autoinhibited SHP2 (37, 39).Because 1) the closure of the binding cleft in N-SH2 has been ascribed to its interaction with PTP and 2) the conformation adopted by the EF loop correlates with the activation of SHP2 in available structural data, the EF loop has been suggested as the key allosteric switch that drives the release of N-SH2 from PTP (37, 39). In light of that, conformation selection (9, 21, 40) and induced fit (41) models were put forward for the molecular events leading to functional activation of SHP2; however, both models consider the conformational change involving the EF loop as the key mechanism that drives SHP2 opening (9, 21, 40, 41). In conclusion, it has been widely accepted that the N-SH2 binding cleft, delimited by the EF and the BG loop, plays the role of an allosteric switch for the activation of SHP2 (39, 42). Accordingly, the binding of a ligand at the binding cleft of the N-SH2 domain would induce a transmitted conformational change that prevents PTP domain binding on the other side of N-SH2, and vice versa (37, 39).However, the allosteric switch model does not explain how the signal, coming from the displacement of the EF loop, is propagated to the rest of the protein (39). In addition, considering that the EF loop might be flexible, the comparison of crystallographic structures does not provide the energetic penalties involved in the motion of the EF loop and, consequently, the degree of destabilization of the N-SH2/PTP complex upon the binding cleft opening (39). Hence, the role of the EF loop as the key allosteric switch has not been rationalized in energetic terms.Recently, an allosteric interaction in N-SH2 has been proposed as an alternative mechanism of SHP2 activation (43). Molecular dynamics (MD) simulations have shown that the N-SH2 domain may adopt two distinct conformations, denoted as α- and β-states, which differ primarily in the conformation of the central β-sheet. In the α-state, the central β-sheet is open, adopting a Y-shaped structure; in the β-state, the central β-sheet is closed, adopting a parallel structure. The MD simulations suggested that the β-state of N-SH2 stabilizes the N-SH2/PTP contacts and, hence, the autoinhibited SHP2 conformation. In contrast, the α-state drives the N-SH2 dissociation and SHP2 activation. Notably, the α–β model of activation rationalized modified basal activity and responsiveness to ligand stimulation of certain mutations at codon 42 (15). However, the α–β model seems to contrast with the previously suggested allosteric switch model.To resolve this discrepancy, we revisited the allosteric switch model. We critically reviewed available crystallographic data of SHP2 in the autoinhibited state. In addition, we used MD simulations, free energy calculations, and enhanced sampling techniques to reveal the conformational dynamics of the binding cleft delimited by the BG and the EF loop in the isolated N-SH2 domain in water, in SHP2 in water, and in SHP2 in a crystal environment. Our results suggest that the binding cleft of N-SH2 is constitutively flexible and the effect of its degree of opening on the activation of SHP2 is negligible. In addition, free energy calculations revealed that, in the crystal environment, the closure of the binding cleft is not due to the allosteric interaction with the PTP domain, but instead a result of the crystal contacts affecting the binding cleft conformation.