Neuronal ageing is promoted by the decay of the microtubule cytoskeleton.

Natural ageing is accompanied by a decline in motor, sensory, and cognitive functions, all impacting quality of life. Ageing is also the predominant risk factor for many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. We need to therefore gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the large amount of time required to age mammalian or vertebrate animal models. Here, we introduce a new cellular model within the Drosophila brain, in which we report classical ageing hallmarks previously observed in the primate brain. These hallmarks include axonal swellings, cytoskeletal decay, a reduction in axonal calibre, and morphological changes arising at synaptic terminals. In the fly brain, these changes begin to occur within a few weeks, ideal to study the underlying mechanisms of ageing. We discovered that the decay of the neuronal microtubule (MT) cytoskeleton precedes the onset of other ageing hallmarks. We showed that the MT-binding factors Tau, EB1, and Shot/MACF1, are necessary for MT maintenance in axons and synapses, and that their functional loss during ageing triggers MT bundle decay, followed by a decline in axons and synaptic terminals. Furthermore, genetic manipulations that improve MT networks slowed down the onset of neuronal ageing hallmarks and confer aged specimens the ability to outperform age-matched controls. Our work suggests that MT networks are a key lesion site in ageing neurons and therefore the MT cytoskeleton offers a promising target to improve neuronal decay in advanced age.

Neuronal expression in Drosophila of an evolutionarily conserved metallophosphodiesterase reveals pleiotropic roles in longevity and odorant response.

Evolutionarily conserved genes often play critical roles in organismal physiology. Here, we describe multiple roles of a previously uncharacterized Class III metallophosphodiesterase in Drosophila, an ortholog of the MPPED1 and MPPED2 proteins expressed in the mammalian brain. dMpped, the product of CG16717, hydrolyzed phosphodiester substrates including cAMP and cGMP in a metal-dependent manner. dMpped is expressed during development and in the adult fly. RNA-seq analysis of dMppedKO flies revealed misregulation of innate immune pathways. dMppedKO flies showed a reduced lifespan, which could be restored in Dredd hypomorphs, indicating that excessive production of antimicrobial peptides contributed to reduced longevity. Elevated levels of cAMP and cGMP in the brain of dMppedKO flies was restored on neuronal expression of dMpped, with a concomitant reduction in levels of antimicrobial peptides and restoration of normal life span. We observed that dMpped is expressed in the antennal lobe in the fly brain. dMppedKO flies showed defective specific attractant perception and desiccation sensitivity, correlated with the overexpression of Obp28 and Obp59 in knock-out flies. Importantly, neuronal expression of mammalian MPPED2 restored lifespan in dMppedKO flies. This is the first description of the pleiotropic roles of an evolutionarily conserved metallophosphodiesterase that may moonlight in diverse signaling pathways in an organism.

First report of Planomicrobium okeanokoites associated with Himantothallus grandifolius (Desmarestiales, Phaeophyta) from Southern Hemisphere.

Gram-positive, aerobic, motile, rod-shaped, mesophilic epiphytic bacterium Planomicrobium okeanokoites was isolated from the surface of endemic species Himantothallus grandifolius in Larsemann Hills, Eastern Antarctica. The diversity of epiphytic bacterial communities living on marine algae remains primarily unexplored; virtually no reports from Antarctic seaweeds. The present study used morpho-molecular approaches for the macroalgae and epiphytic bacterium characterization. Phylogenetic analysis was performed using mitochondrial genome encoded COX1 gene; chloroplast genome encodes rbcL; nuclear genome encoded large subunit ribosomal RNA gene (LSU rRNA) for Himantothallus grandifolius and ribosomal encoded 16S rRNA for Planomicrobium okeanokoites. Morphological and molecular data revealed that the isolate is identified as Himantothallus grandifolius, which belongs to Family Desmarestiaceae of Order Desmarestiales in Class Phaeophyceae showing 99.8% similarity to the sequences of Himantothallus grandifolius, from King George Island, Antarctica (HE866853). The isolated bacterial strain was identified on the basis of chemotaxonomic, morpho-phylogenetic, and biochemical assays. A phylogenetic study based on 16S rRNA gene sequences revealed that the epiphytic bacterial strain SLA-357 was closest related to the Planomicrobium okeanokoites showing 98.7% sequence similarity. The study revealed the first report of this species from the Southern Hemisphere to date. Also, there has been no report regarding the association between the Planomicrobium okeanokoites and Himantothallus grandifolius; however, there are some reports on this bacterium isolated from sediments, soils, and lakes from Northern Hemisphere. This study may open a gateway for further research to know about the mode of interactions and how they affect the physiology and metabolism of each other.

Mechanistic Understanding of KOt Bu-Mediated Direct Amidation of Esters with Anilines: An Experimental Study and Computational Approach.

A sustainable and cost-effective protocol has been reported for the synthesis of amide bonds from unactivated esters and non-nucleophilic amines promoted by potassium tert-butoxide under aerobic conditions. The reaction proceeds under relatively mild conditions, encompassing wide substrate scope. A combined experimental and quantum chemical study has been performed to shed light on the mechanism, which implied that a radical pathway is operating for the present protocol.

Simulation-based clinical assessment identifies threshold competence to practise physiotherapy in Australia: a crossover trial.

BACKGROUND: Although evidence exists for the efficacy of high-fidelity simulation as an educational tool, there is limited evidence for its application in high-stakes professional threshold competency assessment. An alternative model of simulation-based assessment was developed by the Australian Physiotherapy Council (APC), using purpose-written standardised patients, mapped to the appropriate threshold level. The aim of this two-phase study was to investigate whether simulation-based clinical assessments resulted in equivalent outcomes to standard, real-life assessments for overseas-trained physiotherapists seeking registration to practice in Australia. METHODS: A randomised crossover trial comparing simulation-based assessment to real-life assessment was completed. Participants were internationally trained physiotherapists applying for registration to practice in Australia, voluntarily recruited from the Australian Physiotherapy Council (APC) assessment waiting list: study 1 n = 25, study 2 n = 144. Study 1 participants completed usual APC real-life assessments in 3 practice areas, completed on different days at APC partner healthcare facilities. Participants also underwent 3 practice area-matched simulation-based assessments, completed on the same day at purpose-designed simulation facilities. Study 2 participants completed 3 simulation-based assessments and 1 real-life assessment that was randomly allocated for order and practice area. Assessment of competency followed the standard APC procedure of 90-minute examinations using The Moderated Assessment Form (MAF). RESULTS: The overall pass rate was higher for real-life assessments in both studies: study 1, 50% versus 42.7%; study 2, 55.6% versus 44.4%. Chi-square analysis showed a high to moderate level of exact matching of pass/fail grades across all assessments: study 1, 73.4% (p < 0.001); study 2, 58.3% (p = 0.027). Binary logistic regression showed that the best predictors of real-life pass/fail grade were simulation-based MAF pass/fail grade (study 1, OR 7.86 p < 0.001; study 2, OR 2.037, p = 0.038) and simulation-based total MAF score (study 1, OR 1.464 p < 0.001; study 2, OR 1.234, p = 0.001). CONCLUSION: Simulation-based assessment is a significant predictor of clinical performance and can be used to successfully identify high stakes threshold competence to practice physiotherapy in Australia.

Re-evaluating the actin-dependence of spectraplakin functions during axon growth and maintenance.

Axons are the long and slender processes of neurons constituting the biological cables that wire the nervous system. The growth and maintenance of axons require loose microtubule bundles that extend through their entire length. Understanding microtubule regulation is therefore an essential aspect of axon biology. Key regulators of neuronal microtubules are the spectraplakins, a well-conserved family of cytoskeletal cross-linkers that underlie neuropathies in mouse and humans. Spectraplakin deficiency in mouse or Drosophila causes severe decay of microtubule bundles and reduced axon growth. The underlying mechanisms are best understood for Drosophila's spectraplakin Short stop (Shot) and believed to involve cytoskeletal cross-linkage: Shot's binding to microtubules and Eb1 via its C-terminus has been thoroughly investigated, whereas its F-actin interaction via N-terminal calponin homology (CH) domains is little understood. Here, we have gained new understanding by showing that the F-actin interaction must be finely balanced: altering the properties of F-actin networks or deleting/exchanging Shot's CH domains induces changes in Shot function-with a Lifeact-containing Shot variant causing remarkable remodeling of neuronal microtubules. In addition to actin-microtubule (MT) cross-linkage, we find strong indications that Shot executes redundant MT bundle-promoting roles that are F-actin-independent. We argue that these likely involve the neuronal Shot-PH isoform, which is characterized by a large, unexplored central plakin repeat region (PRR) similarly existing also in mammalian spectraplakins.

Chemically Integrating a 2D Metal-Organic Framework with 2D Functionalized Graphene.

Two-dimensional metal-organic frameworks (2D MOFs) are the next-generation 2D crystalline solids. Integrating 2D MOFs with conventional 2D materials like graphene is promising for a variety of applications, including energy or gas storage, catalysis, and sensing. However, unraveling the importance of chemical interaction over an additive effect is essential. Here, we present an unconventional chemistry to integrate a Cu-based 2D MOF, Cu-HHTP (HHTP = 2,3,6,7,10,11-hexahydroxytriphenylene), with 2D functionalized graphene, reduced graphene oxide (rGO), by an in situ oxidation-reduction reaction. Combined Raman spectroscopy, electron spin resonance (ESR) spectroscopy, and X-ray photoelectron spectroscopy (XPS) measurements along with structural analysis evidenced the chemical interaction between Cu-HHTP and rGO, which was subsequently assigned to be the key for the manifestation of significantly modified physical properties. Of particular mention is the conversion of an n-type crystalline solid to a p-type crystalline solid upon the chemical integration of Cu-HHTP with rGO, as revealed by Seebeck coefficient. More importantly, the thermoelectric power factor exhibited an increasing trend with increasing temperature, unlike an opposite trend observed due to an additive effect. The results anticipate the ability of a redox reaction to chemically integrate other 2D MOFs with rGO and show how an in situ synthesis can trigger chemical interaction between two distinctive 2D materials.

Spin-Flip Diffusion Length in 5d Transition Metal Elements: A First-Principles Benchmark.

Little is known about the spin-flip diffusion length l_{sf}, one of the most important material parameters in the field of spintronics. We use a density-functional-theory based scattering approach to determine values of l_{sf} that result from electron-phonon scattering as a function of temperature for all 5d transition metal elements. l_{sf} does not decrease monotonically with the atomic number Z but is found to be inversely proportional to the density of states at the Fermi level. By using the same local current methodology to calculate the spin Hall angle Θ_{sH} that characterizes the efficiency of the spin Hall effect, we show that the products ρ(T)l_{sf}(T) and Θ_{sH}(T)l_{sf}(T) are constant.

Development of an Electroactive Hydrogel as a Scaffold for Excitable Tissues.

For many cells used in tissue engineering applications, the scaffolds upon which they are seeded do not entirely mimic their native environment, particularly in the case of excitable tissues. For instance, muscle cells experience contraction and relaxation driven by the electrical input of an action potential. Electroactive materials can also deform in response to electrical input; however, few such materials are currently suitable as cell scaffolds. We previously described the development of poly(ethyelene glycol) diacrylate-poly(acrylic acid) as an electroactive scaffold. Although the scaffold itself supported cell growth and attachment, the voltage (20 V) required to actuate these scaffolds was cytotoxic. Here, we describe the further development of our hydrogels into scaffolds capable of actuation at voltages (5 V) that were not cytotoxic to seeded cells. This study describes the critical next steps towards the first functional electroactive tissue engineering scaffold.

A mechanistic insight of phytoestrogens used for Rheumatoid arthritis: An evidence-based review.

Assessment of the potential therapeutic benefits offered by naturally occurring phytoestrogens necessitate inspection of their potency and sites of action in impeding the chronic, systemic, autoimmune, joint destructing disorder Rheumatoid arthritis (RA). Possessing structural and functional similarity with human estrogen, phytoestrogen promisingly replaces the use of hormone therapy in eradicating RA symptoms with their anti-inflammatory, anti-oxidative, anti-proliferative, anti-angiogenesis, immunomodulatory, joint protection properties abolishing the harmful side effects of synthetic drugs. Scientific evidences revealed that use of phytoestrogens from different chemical categories including flavonoids, alkaloids, stilbenoids derived from different plant species manifest beneficial effects on RA through various cellular mechanisms including suppression of pro-inflammatory cytokines in particular tumor necrosis factor (TNF-α), interleukin(IL-6) and nuclear factor kappa B (NF-κB) and destructive metalloproteinases, inhibition of oxidative stress, suppressing inflammatory signalling pathways, attenuating osteoclastogenesis ameliorating cartilage degradation and bone erosion. This review summarizes the evidences of different phytoestrogen treatment and their pharmacological mechanisms in both in vitro and in vivo studies along with discussing clinical evaluations in RA patients showing phytoestrogen as a promising agent for RA therapy. Further investigations and more clinical trials are mandatory to clarify the utility of these plant derived compounds in RA prevention and in managing oestrogen deficient diseases in patients.

Incidental Intramyocardial Bridging in a Myocarditis Patient Presenting With Focal ST Segment Depressions.

Myopericarditis is an entity known to present with typical symptoms of viral prodrome and diffuse ST elevation (STE) and/or PR depressions on electrocardiogram (EKG). Atypical presentations of myocarditis such as focal STE have been cited in the literature, reflecting true coronary ischemia. However, myocarditis or pericarditis presenting with focal ST depressions is rarely seen. Myocarditis is usually overlooked as a differential for ST depressions seen on EKGs; hence, the case we present in this report highlights the importance of nonischemic causes presenting as ischemic changes on EKG. This case is unique as we have postulated a possible explanation for this finding. This report discusses the case of a young patient with myopericarditis presenting with focal ST depressions. This patient was also incidentally found to have intramyocardial bridging, usually a benign finding, on cardiac catheterization (which is shown in the case report). Our hypothesis is that the inflammation due to myocarditis in this patient led to inflammation of intramyocardial vessels, presenting as ST depressions. Since intramyocardial bridging is a common anomaly, we propose the question as to whether this could be a risk factor for sudden cardiac death and if it depends on the characteristic of the intramyocardial vessel. We would like to emphasize on the atypical presentations of this usual condition, a possible explanation for this finding, and the need for further testing for risk stratification in patients with this anomaly.

Measles: taking steps forward to prevent going backwards.

PURPOSE OF REVIEW: The measles vaccine, first introduced in 1963, directly led to a dramatic decrease in the incidence of the disease. Measles transitioned from being a common childhood disease, affecting approximately three to four million children annually, to being eradicated in the United States in 2000. What was once an astounding victory for modern medicine, however, has recently seen a dramatic reversal in fortune, with a resurgence of measles cases in the United States. Hence, it merits careful discussion. RECENT FINDINGS: The United States has seen more measles cases in 2019 than in any prior year in the past 30 years. These outbreaks are because of many factors but a significant cause is the increase in vaccine refusal within sub-populations in America. This finding indicates that the current approach that healthcare workers take with families towards MMR vaccination could be more effective. SUMMARY: This article aims to educate the reader about the measles virus and its clinical presentation, the MMR vaccine and its overwhelming success, and the concerning current national and international trends in measles outbreaks. Importantly, we focus on positions proposed by hesitant vaccinators and determine how medical providers can participate in productive conversation about vaccination to better gain trust and guide improved shared clinical decision-making.

Exploring Magnetic XY Behavior in a Quasi-2D Anisotropic Triangular Lattice of Cu(II) by Functionalized Graphene.

Study on magnetism in two-dimensional (2D) spin-lattices is advancing rapidly. In this work, phase-pure botallackite (Bo) (Cu2(OH)3Br), a quasi-2D S = 1/2 anisotropic triangular spin-lattice is stabilized over 2D reduced graphene oxide (rGO) nanosheets via simple oxidation-reduction reaction chemistry. In comparison to polycrystalline Bo, such an anchoring resulted in the oriented growth of Bo crystallites in the Bo-rGO system. The Bo-rGO nanocomposite was found to be magnetically active with a Néel transition at ∼8.9 K, crossing over to possible XY anisotropy at ∼5 K-as revealed by complementary dc and ac susceptibility measurements-an unprecedented observation in the field assigned to an interfacial effect. This work demonstrates the potential usage of nonmagnetic 2D functionalized graphene to significantly modulate the magnetic properties of 2D spin-lattices.

Disorder Dependence of Interface Spin Memory Loss.

The discontinuity of a spin-current through an interface caused by spin-orbit coupling is characterized by the spin memory loss (SML) parameter δ. We use first-principles scattering theory and a recently developed local current scheme to study the SML for Au|Pt, Au|Pd, Py|Pt, and Co|Pt interfaces. We find a minimal temperature dependence for nonmagnetic interfaces and a strong dependence for interfaces involving ferromagnets that we attribute to the spin disorder. The SML is larger for Co|Pt than for Py|Pt because the interface is more abrupt. Lattice mismatch and interface alloying strongly enhance the SML that is larger for a Au|Pt than for a Au|Pd interface. The effect of the proximity-induced magnetization of Pt is negligible.

Imparting Multifunctionality by Utilizing Biporosity in a Zirconium-Based Metal-Organic Framework.

In this work, we have synthesized nanocomposites made up of a metal-organic framework (MOF) and conducting polymers by polymerization of specialty monomers such as pyrrole (Py) and 3,4-ethylenedioxythiophene (EDOT) in the voids of a stable and biporous Zr-based MOF (UiO-66). FTIR and Raman data confirmed the presence of polypyrrole (PPy) and poly3,4-ethylenedioxythiophene (PEDOT) in UiO-66-PPy and UiO-66-PEDOT nanocomposites, respectively, and PXRD data revealed successful retention of the structure of the MOF. HRTEM images showed successful incorporation of polymer fibers inside the voids of the framework. Owing to the intrinsic biporosity of UiO-66, polymer chains were observed to selectively occupy only one of the voids. This resulted in a remarkable enhancement (million-fold) of the electrical conductivity while the nanocomposites retain 60-70 % of the porosity of the original MOF. These semiconducting yet significantly porous MOF nanocomposite systems exhibited ultralow thermal conductivity. Enhanced electrical conductivity with lowered thermal conductivity could qualify such MOF nanocomposites for thermoelectric applications.

Sphingolipids in COPD.

Sphingolipids are a distinct class of lipid molecules widely found in nature, principally as cell membrane constituents. After initial uncertainty about their function, sphingolipids have been increasingly recognised to be metabolically active entities involved in many biological processes, including the control of inflammation. Their role as mediators of inflammation may have significant implications for a range of lung diseases in which inflammation is a central element of pathogenesis. Chronic obstructive pulmonary disease (COPD), a highly prevalent and morbid condition predominantly affecting cigarette smokers, is a prime example of a respiratory illness with an inflammatory component. Understandably, sphingolipids have received growing attention for their increasingly demonstrated role in the pathophysiology of COPD. The present review aims to be among the first to focus exclusively on the connection between sphingolipids and lung inflammation in COPD, providing the reader with a clinically oriented synopsis of this intriguing association.

Embedding S = 1/2 Kagome-like Lattice in Reduced Graphene Oxide.

An elegant platform to explore frustrated magnetism is the kagome spin lattice. In this work, clinoatacamite, a naturally occurring S = 1/2 kagome-like antiferromagnetic insulator, is synthesized in water at ambient pressure for the first time from a cuprous chloride (CuCl) precursor whereby Cu(I) was spontaneously oxidized to Cu(II) in the form of clinoatacamite [Cu2(OH)3Cl] with a simultaneous reduction of graphene oxide (GO) to reduced graphene oxide (rGO) in one pot. A stable nanocomposite of phase-pure clinoatacamite nanocrystals embedded in the rGO matrix was isolated. The clinoatacamite-rGO nanocomposite was determined to be magnetically active with a markedly enhanced coercive field of ∼2500 Oe at 5 K as well as electronically active with a conductivity value of ∼200 S·m-1 at 300 K. Our results illustrate an avenue of combining exotic magnetic and electronic lattices without impeding their individual characteristics and synergistically generating a new class of magnetic semiconductors.

Metamagnetism in Nanosheets of CoII-MOF with TN at 26 K and a Giant Hysteretic Effect at 5 K.

Herein, we have synthesized at room-temperature two-dimensional nanosheets of a MOF comprised of cobalt(II) ion with benzenedicarboxylic acid  ligand, which exhibited unusual magnetic properties. Direct-current magnetic susceptibility revealed an antiferromagnetic (AFM) transition at 26 K (Néel temperature,  TN) followed by a canting of the spin moments along with the concomitant appearance of a sigmoidal-shaped magnetization versus field ( M- H) curve at 15 K. Such a canted AFM ordering led to nonzero remnant magnetization with a remarkably high coercive field of ∼10 kOe at 5 K. Metamagnetism was further substantiated by the alternating-current magnetic susceptibility measurements.