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Abstract Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1–34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11 + cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

Mnaza Noreen,1 Muhammad Bilal,1,2 Muhammad Usman Qamar,3,4 Nasir Rasool,1 Abid Mahmood,5 Sobia Umar Din,1 Tawaf Ali Shah,6 Yousef A Bin Jardan,7 Mohammed Bourhia,8 Lahcen Ouahmane9 1Department of Chemistry, Government College University Faisalabad, Faisalabad, 38000, Pakistan; 2School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, People’s Republic of China; 3Institute of Microbiology, Faculty of Life Sciences, Government College, University Faisalabad, Faisalabad, 38000, Pakistan; 4Division of Infectious Disease and Department of Medicine, University of Geneva, Geneva, Switzerland; 5Department of Pharmaceutical Chemistry, Government College University Faisalabad, Faisalabad, 38000, Pakistan; 6College of Agriculture Engineering and Food Science, Shandong University of Technology, Zibo, 25500, People’s Republic of China; 7Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 8Department of Chemistry and Biochemistry, Faculty of Medicine and Pharmacy, Ibn Zohr University, Laayoune, 70000, Morocco; 9Laboratory of Microbial Biotechnologies, Agrosciences and Environment (Biomage), Labeled Research Unit-CNRSTN° 4, Cadi Ayyad University, Marrakesh, 40000, MoroccoCorrespondence: Nasir Rasool; Mohammed Bourhia, Email nasirrasool@gcuf.edu.pk; m.bourhia@uiz.ac.maIntroduction: New Delhi Metallo-β-lactamase producing Klebsiella pneumoniae (NDM-1-KP) sequence type (ST) 147 poses a significant threat in clinical settings due to its evolution into two distinct directions: hypervirulence and carbapenem resistance. Hypervirulence results from a range of virulence factors, while carbapenem resistance stems from complex biological mechanisms. The NDM-1-KP ST147 clone has emerged as a recent addition to the family of successful clones within the species.Methods: In this study, we successfully synthesized 5-bromo-N-alkylthiophene-2-sulfonamides ( 3a-c) by reacting 5-bromothiophene-2-sulfonamide ( 1) with various alkyl bromides ( 2) using LiH. We also synthesized a series of compounds ( 4a-g) from compound ( 3b) using the Suzuki-Miyaura cross-coupling reaction with fair to good yields (56– 72%). Further, we screened the synthesized molecules against clinically isolated New Delhi Metallo-β-lactamase producing Klebsiella pneumoniae ST147. Subsequently, we conducted in-silico tests on compound 3b against a protein extracted from NDM-KP ST147 with PDB ID: 5N5I.Results: The compound ( 3b) with favourable drug candidate status, MIC of 0.39 μg/mL, and MBC of 0.78 μg/mL. This low molecular weight compound exhibited the highest potency against the resistant bacterial strains. The in-silico tests revealed that the compound 3b against a protein extracted from NDM-KP ST147 with PDB ID: 5N5I demonstrated H-bond and hydrophobic interactions.Conclusion: The 5-bromo-N-alkylthiophene-2-sulfonamides displayed antibacterial efficacy against New Delhi Metallo-β-lactamase producing Klebsiella pneumoniae ST147. After the in-vivo trial, this substance might offer an alternative therapeutic option. Keywords: NDM-1, antibacterial, drug resistance, Klebsiella pneumoniae, ST, sulfonamides

In the last decade, the detection and attribution science that links climate change to extreme weather and climate events has emerged as a growing field of research with an increasing body of literature. This paper overviews the methods for extreme event attribution (EEA) and discusses the new insights that EEA provides for infrastructure adaptation. We found that EEA can inform stakeholders about current climate risk, support vulnerability-based and hazard-based adaptations, assist in the development of cost-effective adaptation strategies, and enhance justice and equity in the allocation of adaptation resources. As engineering practice shifts from a retrospective approach to a proactive, forward-looking risk management strategy, EEA can be used together with climate projections to enhance the comprehensiveness of decision making, including planning and preparing for unprecedented extreme events. Additionally, attribution assessment can be more useful for adaptation planning when the exposure and vulnerability of communities to past events are analyzed, and future changes in the probability of extreme events are evaluated. Given large uncertainties inherent in event attribution and climate projections, future research should examine the sensitivity of engineering design to climate model uncertainties, and adapt engineering practice, including building codes, to uncertain future conditions. While this study focuses on adaptation planning, EEA can also be a useful tool for informing and enhancing decisions related to climate mitigation.

The aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevant in vitro studies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8–7.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.

The rising problem of plastic pollution is becoming one of the major environmental issues for the world. In the ocean, plastics undergo degradation into smaller microplastics (MPs) and nanoplastics (NPs). Wild fish and farmed salmon would likely be exposed to these NPs and MPs both through skin and through skin wounds. Keratocyte cells, located in the skin epithelial layer, are scavenger cells which may remove foreign materials and maintain the salmon’s health. They are therefore first in line to handle and to suffer from MP and NP exposure. While the impacts of MPs have been well studied in many different organisms, much less is known about the effects of NP exposure, particularly at the subcellular level. Here, we have used holotomographic and fluorescence microscopy to show that both skin and corneal salmon keratocyte cells fully internalize 500–1000 nm polystyrene particles, as well as inorganic 500 nm silica particles. The fact that corneal epithelial cells also take up particles is novel. Furthermore, some of these particles likely end up in lysosomal compartments within 2 hours of exposure. Here, we show that both conventional and new modalities of microscopy have a role to play to understand how micro- and nano particles affect epithelial cells.

Shazia Naheed,1 Irum Umar Din,1 Muhammad Usman Qamar,2 Nasir Rasool,1 Matloob Ahmad,1 Muhammad Bilal,1 Aqsa Khalid,3 Gulraiz Ahmad,1 Sami A Al-Hussain,4 Magdi EA Zaki4 1Department of Chemistry, Government College University Faisalabad, Faisalabad, 38000, Pakistan; 2Institute of Microbiology, Faculty of Life Sciences, Government College University, Faisalabad, 38000, Pakistan; 3School of Interdisciplinary Engineering & Science (SINES), National University of Sciences and Technology (NUST), Islamabad, 44000, Pakistan; 4Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyad, 11623, Saudi ArabiaCorrespondence: Nasir Rasool; Magdi E A Zaki, Email nasirrasool@gcuf.edu.pk; mezaki@imamu.edu.saIntroduction: Global public health concerns include the emergence and spread of methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase Escherichia coli (ESBL-E. coli). These pathogens cause infections that are difficult to treat, which can have fatal outcomes and require lengthy hospital stays. As a result, we created butyl 2-bromoisonicotinate and tested its antibacterial effectiveness against the ESBL-E. coli ST 405 and MRSA pathogens. Natural product discovery is complemented by synthetic compound synthesis because of the latter’s potential for superior characteristics, target specificity, scalability, intellectual advantages, and chemical diversity. Because of this, the potential for discovering new medicinal compounds is increased, and the constraints placed on natural sources are overcome. Natural items are tough to obtain since they are hard to isolate and synthesize. Therefore, modern science is actively searching for small molecules as therapeutic agents by applying sustainable techniques that can be commercialized.Methods: Two patients’ blood samples were taken, and the BACTEC/Alert system was used to process them. On blood and MacConkey agar, the positive samples were subcultured and incubated aerobically at 37 °C. Using the VITEK 2 compact system, the isolates were subjected to isolate identification and MIC. MLST of the ESBL-E. coli was performed by PCR. Additionally, Fischer esterification was used to create butyl 2-bromoisonicotinate in excellent yields. A commercially available palladium catalyst was then used to arylate the compound, resulting in medium to good yields of arylated butyl 2-bromoisonicotinates. Using the agar well diffusion assay and the micro-broth dilution method, we assessed the in-vitro activities of the synthesized molecules (3, 5a-h) against clinically isolated ESBL-E. coli ST405, and MRSA. A molecular operating environment was used to carry out in silico validation of the synthesized compounds’ binding to the active site and to evaluate the stability of their molecular interactions with the target E. coli 2Y2T protein.Results: MRSA and ESBL-producing E. coli were identified as the two clinical isolates. While MRSA was also resistant to beta-lactam drugs and least resistant to vancomycin, ESBL-producing E. coli belonged to ST405 and was resistant to cephalosporins and sensitive to carbapenems. Good yields of the desired compounds were produced by our effective and economical synthesis. By using a micro-broth dilution assay, the Molecules (3, 5a, and 5d) were most effective against both resistant strains. The Molecules (3, 5a, 5b, and 5d) also displayed good binding energies.Conclusion: The butyl 2-bromoisonicotinate displayed antibacterial efficacy against ESBL-producing E. coli ST405 and MRSA strains. After the in-vivo trial, this substance might offer an alternative therapeutic option.Keywords: ESBL, MRSA, MLST, Fischer esterification, Suzuki-Miyaura, docking studies

A primary dataset capturing five distinct types of sheep activities in realistic settings was constructed at various resolutions and viewing angles, targeting the expansion of the domain knowledge for non-contact virtual fencing approaches. The present dataset can be used to develop non-invasive approaches for sheep activity detection, which can be proven useful for farming activities including, but not limited to, sheep counting, virtual fencing, behavior detection for health status, and effective sheep breeding. Sheep activity classes include grazing, running, sitting, standing, and walking. The activities of individuals, as well as herds of sheep, were recorded at different resolutions and angles to provide a dataset of diverse characteristics, as summarized in Table 1. Overall, a total of 149,327 frames from 417 videos (the equivalent of 59 minutes of footage) are presented with a balanced set for each activity class, which can be utilized for robust non-invasive detection models based on computer vision techniques. Despite a decent existence of noise within the original data (e.g., segments with no sheep present, multiple sheep in single frames, multiple activities by one or more sheep in single as well as multiple frames, segments with sheep alongside other non-sheep objects), we provide original videos and the original videos’ frames (with videos and frames containing humans omitted for privacy reasons). The present dataset includes diverse sheep activity characteristics and can be useful for robust detection and recognition models, as well as advanced activity detection models as a function of time for the applications.

Abstract Background Acute toxicity (LD50) test provides an indication on the range of doses of a substance that could be toxic to the body systems. This study was aimed at determining the LD50 of different extracts of Bombax costatum stem bark and its effects on the histology of liver and kidneys in rats. Results Phytochemical screening of n-hexane, ethanol and chloroform extracts of B. costatum stem bark has revealed the presence of alkaloids, flavonoid, saponins, steroid, terpenes, anthraquinones and cardiac glycosides. No mortality was recorded after testing all the different extracts on rats. However, mild body weaknesses and pilo erection were observed in the first hour of extracts’ administration. No statistically significant differences was observed in most of the serum levels of kidney function biomarkers, although a significant decrease (p 0.05) were observed in hematological parameters as well as in the liver functions biomarkers in all the 3 extract exposed groups when compared to the control, except significant decrease (p

Engineering structures are often subjected to the influences of performance deterioration and multiple hazards during their service lives, and consequently may suffer from damage/failure as a result of external loads. Structural reliability and resilience assessment is a powerful tool for quantifying the structural ability to withstand these environmental or operational attacks. This paper proposes new formulas for structural time-dependent reliability and resilience analyses in the presence of multiple hazards, which are functions of the duration of the reference period of interest. The joint impacts of nonstationarities in multiple hazards due to a changing environment, as well as the deterioration of structural performance, are explicitly incorporated. The correlation between the structural resistances/capacities associated with different hazard types is modeled by employing a copula function. It is observed that, under the context of multiple hazards and aging effects, the time-dependent resilience takes a generalized form of time-dependent reliability. The proposed formulas can be used to guide the adaptive design of structures, where adaptive strategies are identified across a range of possible future service conditions. An example is presented to demonstrate the applicability of the proposed method for structural reliability and resilience analyses.

Climate change can accelerate infrastructure deterioration in coastal areas because increased temperature and humidity can promote steel corrosion. This study (1) projects corrosion rate changes for reinforced concrete and steel structures in 223 coastal counties, (2) assesses the impact of corrosion rate changes on the useful life of structures, and (3) evaluates direct economic losses due to shortened useful life of highway bridges over the period 2000-2100. The results show that the useful life of concrete structures may decrease by 1.7-2.7% under the representative concentration pathway (RCP) 8.5 and decrease by 0.7-1.1% under RCP 4.5 by the end of the 21st century. The useful life of steel structures may decrease by 7.9-15.9% under RCP 8.5 and 3.3-6.7% under RCP 4.5. Concrete bridges may suffer an average loss of $6.5-11.7/m2 under RCP 8.5 and $3.3-16.5/m2 under RCP 4.5 due to shortened useful life. Steel bridges may suffer an average loss of $73.4-111.3/m2 under RCP 8.5 and $46.9-81.2/m2 under RCP 4.5. In both climate scenarios, 10% of counties may have negative losses and 10% of counties may have losses greater than $20 million due to corrosion rate changes for concrete and steel bridges. The results reveal the spatial difference of climate change impacts on infrastructural deterioration and suggest the importance of developing regional specific adaptation strategies.

Many cryogenic electron microscopy (cryo-EM) single particle analyses are constrained by the sample preparation step upon which aggregation, dissociation, and/or preferential orientation of particles can be introduced. Here, we report how we solved these problems in the case of CDC48A, a hexameric AAA ATPase from Arabidopsis thaliana. CDC48A hexamers are well preserved under negative staining conditions but disassemble during grid freezing using the classical blotting method. Vitrification of grids using the blot-free Chameleon method preserved the integrity of particles but resulted in their strong preferential orientation. We then used a strategy where we improved in parallel the purification of CDC48A and the conditions for cryo-EM data acquisition. Indeed, we noted that images taken from thicker ice presented an even distribution of intact particles with random orientations, but resulted in a lower image resolution. Consequently, in our case, distribution, orientation, image resolution, and the integrity of particles were tightly correlated with ice thickness. By combining the more homogeneous and stable CDC48A hexamers resulting from our improved purification protocol with an iterative search across different ice thicknesses, we identified an intermediate thickness that retained sufficiently high-resolution structural information while maintaining a complete distribution of particle orientations. Our approach may provide a simple, fast, and generally applicable strategy to record data of sufficient quality under standard laboratory and microscope settings. This method may be of particular value when time and resources are limited.

Human brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1, which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a ‘disease-in-a-dish’ model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development. This article has an associated First Person interview with the first author of the paper.

Pretreatment of reverse osmosis (RO) feed water of high mineral scaling propensity was evaluated with respect to downstream RO membrane scaling, for two different feed pretreatment configurations. The pretreatment schemes included (i) media sand filtration, followed by a hydrocyclone (HC) and (ii) a hydrocyclone, microfilter, and a UF module, where both configurations included mesh screens for added protection. The first pretreatment configuration reduced the source water turbidity to ~0.5 NTU, while treatment that included UF feed yielded turbidity of <˜0.1 NTU; both pretreatment strategies provided feed water turbidity within the range recommended for RO desalination. Membrane scaling tests, with the pretreated water without antiscalant dosing, using a plate-and-frame RO unit and a membrane monitoring system, provided real-time membrane surface images that were quantified with respect to the progression of mineral scaling. RO desalting of source water pretreated with the first configuration revealed flux decline that was 75% greater and scale coverage (primarily gypsum) a factor of approximately eight higher relative to desalting of UF-treated source water. The results suggest that RO desalting of high mineral scaling propensity water can significantly benefit from added UF treatment to achieve feedwater turbidity to well below the typically recommended 0.5 NTU upper limit.

Shabir Ahmad,1 Sidra Munir,1 Nadia Zeb1,2 Asad Ullah,1 Behramand Khan,1 Javed Ali,3 Muhammad Bilal,3 Muhammad Omer,4 Muhammad Alamzeb,5 Syed Muhammad Salman,1 Saqib Ali51Department of Chemistry, Islamia College University, Peshawar 25120, Pakistan; 2Department of Chemistry, Government Girls Degree College, Peshawar, Pakistan; 3Department of Chemistry, Kohat University of Science and Technology, Kohat, Pakistan; 4Institute of Chemical Sciences, University of Swat, Swat, 19201, Pakistan; 5Department of Chemistry, University of Kotli 11100, Azad Jammu and Kashmir, PakistanBackground: Nanotechnology explores a variety of promising approaches in the area of material sciences on a molecular level, and silver nanoparticles (AgNPs) are of leading interest in the present scenario. This review is a comprehensive contribution in the field of green synthesis, characterization, and biological activities of AgNPs using different biological sources.Methods: Biosynthesis of AgNPs can be accomplished by physical, chemical, and green synthesis; however, synthesis via biological precursors has shown remarkable outcomes. In available reported data, these entities are used as reducing agents where the synthesized NPs are characterized by ultraviolet-visible and Fourier-transform infrared spectra and X-ray diffraction, scanning electron microscopy, and transmission electron microscopy.Results: Modulation of metals to a nanoscale drastically changes their chemical, physical, and optical properties, and is exploited further via antibacterial, antifungal, anticancer, antioxidant, and cardioprotective activities. Results showed excellent growth inhibition of the microorganism.Conclusion: Novel outcomes of green synthesis in the field of nanotechnology are appreciable where the synthesis and design of NPs have proven potential outcomes in diverse fields. The study of green synthesis can be extended to conduct the in silco and in vitro research to confirm these findings.Keywords: green synthesis, plant mediated synthesis, silver bioactivity, microorganism

ABSTRACT To test how osteoporosis drugs affect bone matrix maturation during cortical bone remodeling, 72 pregnant rats were switched from a 0.4% to a 0.01% calcium diet at parturition for a 23‐day lactation period. At weaning, eight dams were sacrificed to establish baseline values, while the remaining dams were returned to 0.4% calcium and treated with vehicle (saline), sodium fluoride (NaF), zoledronic acid (ZA), or sclerostin antibody (Scl‐Ab) for either 7 or 28 days (eight animals per group per time point). Femora were examined by μCT, dynamic histomorphometry, Fourier transform infrared imaging, and three‐point bending of notched specimens. Cortical porosity decreased in all groups from baseline to day 28. Intracortical mineralizing surface (MS/BS) and mineral apposition rate (MAR), as well as the mineral‐to‐matrix ratio were unaffected by treatment, but intracortical crystallinity was increased in the ZA group at day 10 compared with vehicle. Cortical area increased in all groups over 28 days mainly because of an addition of bone at the endocortical surface. Endocortical MS/BS did not vary among the groups, but endocortical MAR was suppressed in the NaF group at day 2 and elevated in the Scl‐Ab group at day 4 compared with vehicle. Endocortical mineral‐to‐matrix ratio was increased at days 5 and 10 following NaF treatment and endocortical crystallinity was increased at day 5 following ZA treatment compared with vehicle. Fracture toughness did not differ among the groups. Thus, the treatments affected matrix maturation more strongly at the endocortical then intracortical envelope. In this model of induced remodeling, the bone formation phase is synchronized at multiple sites, facilitating study of the effects of drugs or other bone‐targeting agents on matrix maturation independent of their effects on the initiation of remodeling. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Phytochromes are photoreceptors that are present in plants, bacteria and fungi. Here the authors present crystal structures of the phytochrome Agp2 from Agrobacterium fabrum in the parent Pfr state as well as a functional Meta-F intermediate and discuss mechanistic implications for photoconversion.

The prenyl-binding protein PrBP/δ is a solubilization factor involved in trafficking of prenylated proteins. Here the authors present the ligand-free apo-PrBP/δ structure and propose a "solubilization by depletion" mechanism, where PrBP/δ sequesters only soluble rod photoreceptor phosphodiesterase (PDE6), leading to a dissociation of membrane-bound PDE6.

Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein α-subunits (Gα*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction–diffusion simulations. Gα* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of Gα* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 Gα* · PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that Gα* · PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of Gα* which binds with lower affinity, forming Gα* · PDE6 · Gα*. Reaction–diffusion simulations show that the functional asymmetry of membrane-bound PDE6 constitutes a coincidence switch and explains the lack of G protein-related noise in visual signal transduction. The high local concentration of Gα* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated Gα* fails to activate the effector enzyme.

In recent years, reproduction of human mechanical hand with upgraded abilities is one of the major concerns. This paper addresses the problems of underactuated robotic hand with low cost design as it avoids electromyogram (EMG) sensors. The main goal is to balance the hand in the way, like grabbing, speed, and power, and provide a more robust and cost effective solution. All fingers have some mechanical consistency for picking up objects in a better way. A Flex sensor is attached to all fingers and it is interfaced with a computer using Arduino UNO microcontroller. The sensor aids the arm in three different directions: at first it senses whether an object is grasped or not. In the second step, it determines the coefficient of friction between the objects. Finally it grasps the object and stops. One of the primary issues of prosthetic hand is to have the capacity to satisfy every detail of torque, speed, and latency. In this research, we have developed a model of robotic hand with some modifications. The adaptability of grasping is compared with the degree of freedom (DOF) along with the quantity of fingers. We are controlling our hands via sensors based signal controlling system. The idea is to design a robotic hand, which has low cost, is easy to use, and is light in weight, which helps the amputees to use it with ease in their daily lives. The efficacy of the proposed control is verified and validated using simulations.

Musthika Wida Mashitah,1 Nurona Azizah,1 Nur Samsu,2 Muhammad Rasjad Indra,1 Muhammad Bilal,3 Meti Verdian Yunisa,4 Amildya Dwi Arisanti41Department of Biomedicine, Faculty of Medicine, Brawijaya University, Malang, 2Department of Internal Medicine, Division of Nephrology and Hypertension, Saiful Anwar General Hospital, Malang, 3Department of Medicine, Faculty of Medicine, Brawijaya University, Malang, 4Department of Nursing, Faculty of Medicine, Brawijaya University, Malang, IndonesiaBackground: Diabetic nephropathy (DN) is a serious vascular complication of diabetes and an important cause of end-stage renal disease. One mechanism by which hyperglycemia causes nephropathy is through the formation of advanced glycation end products (AGE). Development of vaccination would be a promising therapy for the future, while to date, anti-AGE therapy is based on medicines that are needed to be consumed lifelong. This study aimed to find out the effect of immunization of AGE-modified albumin against DN pathogenesis in streptozotocin-induced diabetic in mice.Methods: We used 24 BALB/c male mice as experimental animals, which were divided into six groups, two nondiabetic groups (negative control and AGE-modified bovine serum albumin [BSA] preimmunized groups) and four streptozotocin-induced diabetic groups (diabetic control group and diabetic preimmunized groups for AGE-BSA, Keyhole limpet hemocyanin (KLH), and AGE-BSA-KLH, respectively).Results: Diabetic preimmunized groups for AGE-BSA, KLH, and AGE-BSA-KLH showed amelioration in renal function and histopathology compared with the diabetic control group. Preimmunization also maintained nephrin intensity and decreased serum AGE level, kidney AGE deposition, and kidney cells apoptosis.Conclusion: AGE-BSA and AGE-BSA-KLH immunizations inhibit the progression of DN. Our results strengthen the evidence that the anti-AGE antibodies have a protective role against diabetic vascular complication, especially DN. This study provides a basis for the development of DN-based immunotherapy with AGE immunization as a potential candidate.Keywords: immunization, advanced glycation end products (AGE), AGE-modified albumin, anti-AGE antibody, diabetic nephropathy

Climate change is one of the prominent factors that causes an increased severity of extreme precipitation which, in turn, has a huge impact on drainage systems by means of flooding. Intensity−duration−frequency (IDF) curves play an essential role in designing robust drainage systems against extreme precipitation. It is important to incorporate the potential threat from climate change into the computation of IDF curves. Most existing works that have achieved this goal were based on Generalized Extreme Value (GEV) analysis combined with various circulation model simulations. Inspired by recent works that used machine learning algorithms for spatial downscaling, this paper proposes an alternative method to perform projections of precipitation intensity over short durations using machine learning. The method is based on temporal downscaling, a downscaling procedure performed over the time scale instead of the spatial scale. The method is trained and validated using data from around two thousand stations in the US. Future projection of IDF curves is calculated and discussed.

PURPOSE:A high percentage (50%-60%) of trauma patients die due to their injuries prior to arrival at the hospital. Studies on preclinical mortality including post-mortem examinations are rare. In this review, we summarized the literature focusing on clinical and preclinical mortality and studies included post-mortem examinations. METHODS:A literature search was conducted using PubMed/Medline database for relevant medical literature in English or German language published within the last four decades (1980-2015). The following MeSH search terms were used in different combinations: "multiple trauma", "epidemiology", "mortality ", "cause of death", and "autopsy". References from available studies were searched as well. RESULTS:Marked differences in demographic parameters and injury severity between studies were identified. Moreover, the incidence of penetrating injuries has shown a wide range (between 4% and 38%). Both unimodal and bimodal concepts of trauma mortality have been favored. Studies have shown a wide variation in time intervals used to analyze the distribution of death. Thus, it is difficult to say which distribution is correct. CONCLUSIONS:We have identified variable results indicating bimodal or unimodal death distribution. Further more stundardized studies in this field are needed. We would like to encourage investigators to choose the inclusion criteria more critically and to consider factors affecting the pattern of mortality.

Peristaltic pumping induced by a sinusoidal traveling wave in the walls of a two-dimensional channel filled with a viscous incompressible fluid mixed with rigid spherical particles is investigated theoretically taking the slip effect on the wall into account. A perturbation solution is obtained which satisfies the momentum equations for the case in which amplitude ratio (wave amplitude/channel half width) is small. The analysis has been carried out by duly accounting for the nonlinear convective acceleration terms and the slip condition for the fluid part on the wavy wall. The governing equations are developed up to the second order of the amplitude ratio. The zeroth-order terms yield the Poiseuille flow and the first-order terms give the Orr-Sommerfeld equation. The results show that the slip conditions have significant effect within certain range of concentration. The phenomenon of reflux (the mean flow reversal) is discussed under slip conditions. It is found that the critical reflux pressure is lower for the particle-fluid suspension than for the particle-free fluid and is affected by slip condition. A motivation of the present analysis has been the hope that such theory of two-phase flow process under slip condition is very useful in understanding the role of peristaltic muscular contraction in transporting biofluid behaving like a particle-fluid mixture. Also the theory is important to the engineering applications of pumping solid-fluid mixture by peristalsis.

Purpose. To report a case of acute hydrops in a 10-year-old child with advanced keratoconus. Case Presentation. A ten-year-old boy diagnosed as having right eye (RE) infectious keratitis, not responding to antimicrobial therapy, was referred to our hospital. The diagnosis of infectious keratitis was established one month prior to his presentation following an episode of acute corneal whitening, pain, and drop in visual acuity. Topical fortified antibiotics followed by topical antiviral therapy were used with no improvement. Slit lamp examination showed significant corneal protrusion with edema surrounding a rupture in Descemet’s membrane in the RE. The diagnosis of acute corneal hydrops from advanced keratoconus was highly suspected and confirmed with corneal topography. Conclusion. Although a relatively rare disease at the age of 10 years, keratoconus can be rapidly progressive in the pediatric group. Keratoconus should always be considered in the differential diagnosis of progressive vision loss in this age group.

Risks from future sea level rise entail significant uncertainties concerning overall potential impacts, the specific threats faced by particular areas and what benefit or costs are associated with strategies for addressing such risks. The proposed risk quantification and management framework is consistent with quantitative risk analysis practices in order to enable decision making. Quantifying risk enables the examination of adaptation measures requiring basic physical inputs that can underpin for engineering viable solutions for sustaining coastal infrastructure.