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Abstract: Insulin is an essential factor for mammalian organisms: a regulator of glucose metabolism and other key signaling pathways. Insulin is also a multifunctional hormone whose absence can cause many diseases. Recombinant insulin is widely used in the treatment of diabetes. Understanding insulin, biosimilars, and biobetters from a holistic perspective will help pharmacologically user-friendly molecules design and develop personalized medicine-oriented therapeutic strategies for diabetes. Additionally, it helps to understand the underlying mechanism of other insulindependent metabolic disorders. The purpose of this atlas is to review insulin from a biotechnological, basic science, and clinical perspective, explain nearly all insulin-related disorders and their underlying molecular mechanisms, explore exogenous/recombinant production strategies of patented and research-level insulin/analogs, and highlight their mechanism of action from a structural perspective. Combined with computational analysis, comparisons of insulin and analogs also provide novel information about the structural dynamics of insulin.

Aim: Impaired calcium homeostasis limits life expectancy and quality in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease is caused by loss-of-function mutations in CLDN16 or CLDN19 genes leading to impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). The ensuing late distal nephron and collecting duct system partially compensate for the defect in cTAL by increased transcellular Ca2+ reabsorption via the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium-potassium exchanger (NCX1). The loop diuretic furosemide induces compensatory activation in these distal segments due to blockade of NaCl and divalent cation reabsorption in the preceeding TAL. Although furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL in general population, this effect is not expected in FHHNC patients with already severely impaired Ca2+ transport in the cTAL. The present study follows the hypothesis that furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca2+ transport proteins. Methods: Cldn16-deficient mice (Cldn16-/- ) served as a FHHNC model. Wild-type (WT) and Cldn16-/- mice were treated with furosemide (7 days of 40 mg/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins. Results: Cldn16-/- mice show increased Ca2+ excretion than WT and compensatory stimulation of Cldn2 in the proximal tubule, as well as of TRPV5, and NCX1 in the distal nephron at baseline. Furosemide reduced hypercalciuria in Cldn16-/- mice and enhanced TRPV5 and PMCA levels in Cldn16-/- but not in WT mice. Conclusions: Furosemide alleviated hypercalciuria in a mouse FHHNC model, likely via stimulation of transcellular luminal and basolateral Ca2+ transport systems in the distal nephron and collecting duct. These results may have a clinical implication in FHHNC patients. No conflict of interests This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. Complex renal parenchymal damage occurs for cyclosporine A (CsA) as well as for the currently favoured tacrolimus (Tac). To test for distinct CsA and Tac damaging patterns, we combined multiomics analysis with histopathology from rat kidneys exposed to continuous CNI delivery. Damage forms varied strikingly. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. Should this translate to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share products identified from multiomics for differential pathognomonic biomarkers.Translational StatementCalcineurin inhibitors (CNI) are first-choice immunosuppressive agents. Their nephrotoxic side effects may often limit their use. Tacrolimus is currently preferred to cyclosporine although its superiority remains unclear. Within the nephron, damage to the filtration barrier is greater for tacrolimus, whereas cyclosporine side effects locate more to the proximal tubular epithelium when compared in our rodent model. We identify the distinctive location and nature of damage by both drugs and unravel involved mechanisms. By detecting differential protein signatures we make available pathognomonic biomarkers for renal allograft health under CNI treatment.

Frataxin is a 23 KDa mitochondrial iron-binding protein that is involved in biogenesis of iron sulfur clusters. A deficiency in frataxin leads to Friedreich’s ataxia, a progressive neurodegenerative disorder. The bacterial ortholog of eukaryotic mitochondrial frataxin, CyaY, is thought to play a role in iron sulfur cluster assembly as an iron supplier, making it an important target for study. Here, we present the first ambient temperature crystal structure of CyaY protein fromEscherichia coli, obtained using the Turkish Light Source “Turkish DeLight”. This study reveals the dynamic structural characteristics of CyaY at near-physiological temperature and displays an alternate conformation, highlighting the importance of temperature considerations in protein structure characterization and providing new insights into the protein’s flexibility.

Tumor Necrosis Factor Receptor Associated Factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system (CNS), and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. RING domain and zinc fingers mediate the activation of nuclear factor kappa B (NF-κB), which has essential roles in the regulation of inflammatory responses, proliferation, differentiation, migration, cell adhesion, and apoptosis. Therefore, it has been found that TRAF6 is overexpressed in various types of cancer including pancreatic, liver, lung, head and neck, breast, colorectal cancers, and melanoma along with inflammatory, autoimmune and neurodegenerative disorders. Furthermore, TRAF6 is an important therapeutic target for numerous disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we present a TRAF6 N-terminal structure determined at the Turkish Light Source “Turkish DeLight” to 2.6 Å resolution at cryogenic temperature. This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research.

Scientific data 3, 160064 -(2016). doi:10.1038/sdata.2016.64, Single particle diffractive imaging data from Rice Dwarf Virus (RDV) were recorded using the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). RDV was chosen as it is a well-characterized model system, useful for proof-of-principle experiments, system optimization and algorithm development. RDV, an icosahedral virus of about 70 nm in diameter, was aerosolized and injected into the approximately 0.1 μm diameter focused hard X-ray beam at the CXI instrument of LCLS. Diffraction patterns from RDV with signal to 5.9 Ångström were recorded. The diffraction data are available through the Coherent X-ray Imaging Data Bank (CXIDB) as a resource for algorithm development, the contents of which are described here., Published by Nature Publ. Group, London

Candida boidinii NAD+-dependent formate dehydrogenase (CbFDH) has gained significant attention for its potential applications in the production of biofuels and various industrial chemicals from inorganic carbon dioxide. In this study, we present an atomic X-ray crystal structure of the apo CbFDH to 1.4 Å resolution determined at cryogenic temperature at the Turkish Light Source, “Turkish DeLight”. This structure offers a comprehensive view of the apo enzyme's dynamics, filling the gaps in our understanding from previous studies. Also, comparison of our high-resolution apo and previously available holo enzyme structures reveals major conformational changes of this dynamic enzyme in the absence and presence of the coenzyme and substrate/inhibitor complexes. Collectively all these information may provide invaluable insights into future protein engineering efforts that could enhance enzymatic activity and stability, potentially increasing its efficiency and effectiveness of CbFDH in industrial processes.

Candida boidiniiNAD+-dependent formate dehydrogenase (CbFDH) has gained significant attention for its potential applications in the production of biofuels and various industrial chemicals from inorganic carbon dioxide. In this study, we present an atomic X-ray crystal structure of the apoCbFDH to 1.4 Å resolution determined at cryogenic temperature at the Turkish Light Source,“Turkish DeLight”. This structure offers a comprehensive view of the apo enzyme’s dynamics, filling the gaps in our understanding from previous studies. Also, comparison of our high-resolution apo and previously available holo enzyme structures reveals major conformational changes of this dynamic enzyme in the absence and presence of the coenzyme and substrate/inhibitor complexes. Collectively all these information may provide invaluable insights into future protein engineering efforts that could enhance enzymatic activity and stability, potentially increasing its efficiency and effectiveness ofCbFDH in industrial processes.

An earthquake of magnitude 6.9 hit the city of Izmir (Turkey) on 30 October 2020, resulting in 117 deaths (in Turkey) and considerable economic losses. The earthquake also triggered a tsunami. Following the earthquake, field surveys are being conducted in a Covid-secure way to study and document the damages caused. The earthquake caused significant damages to residential buildings mainly located in the district of Bayrakli and Bornova. However, no damages were observed in railway and roadway bridges or tunnels and that helped the rescue operations. The damages were mainly structural which included the so-called pancake collapse (where the entire building collapsed) and soft storey type collapse (weak storey characterised with weak columns collapsed), and in some cases, only the ground floor completely collapsed. Due to the proximity of the epicentre and the geology of the area, it seemed that the ground motions were amplified. This technical note provides a summary of the seismological and recorded ground characteristics of the earthquake together with the lessons learnt.

Photolyases (PLs) reverse UV-induced DNA damage using blue light as an energy source. Of these photolyases, (6-4) PLs repair (6-4)-lesioned photoproducts. We recently identified a gene fromVibrio cholerae (Vc) encoding a (6-4) PL, but structural characterization is needed to elucidate specific interactions with the chromophore cofactors. Here, we determined the crystal structure ofVc(6-4) PL at 2.5 Å resolution. Our high-resolution structure revealed that the two well-known cofactors, flavin adenine dinucleotide (FAD) and the photoantenna 6,7-dimethyl 8-ribityl-lumazin (DMRL), stably interact with an α-helical and an α/β domain, respectively. Additionally, the structure has a third cofactor with distinct electron clouds corresponding to a [4Fe-4S] cluster. Moreover, we identified that Asp106 makes a hydrogen bond with the water and DMRL, which indicates further stabilization of the photoantenna DMRL withinVc(6-4) PL. Further analysis of theVc(6-4) PL structure revealed a possible region responsible for DNA binding. The region located between residues 478-484 may bind the lesioned DNA, with Arg483 potentially forming a salt bridge with DNA to stabilize further the interaction ofVc(6-4) PL with its substrate. Our comparative analysis revealed that the DNA lesion could not bind to theVc(6-4) PL in a similar fashion to theDrosophila melanogaster Dm(6-4) PL without a significant conformational change of the protein. The 23rdhelix of the bacterial (6-4) PLs seems to have remarkable plasticity, and conformational changes facilitate DNA binding. In conclusion, our structure provides further insight into DNA repair by a (6-4) PL containing three cofactors.

Objectives Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is an autosomal dominant disorder caused by mutations of the transthyretin (TTR) gene. The mutant ATTRv protein causes a systemic accumulation of amyloid fibrils in various organs. TTR is an important protein in the central nervous system physiology for the maintenance of normal cognitive process during aging, amidated neuropeptide processing, and nerve regeneration. The neuroprotective effect of transthyretin has been widely documented in animal models. Cognitive consequences of the mutant TTR in hereditary ATTRv amyloidosis patients remain still to be elucidated. We designed this study to investigate the cognitive involvement in ATTRv amyloidosis. Methods Detailed neuropsychological tests and cranial MRIs were performed. Biomarkers including amyloid beta 1-42, total tau, and phosphorylated tau were investigated in the cerebrospinal fluid samples. Results Median age of the cohort was 52 years (ranges 34-72). Neuropsychological assessment results were compatible with impaired executive functions (in all patients except one with only bilateral carpal tunnel syndrome, long-term visual and long-term verbal memory (severe in four patients and moderate in one). Visuospatial judgment and perception were impaired in six. Mean cerebrospinal fluid Aβ1-42 (pg/ml) was 878.0 ± 249.5 in patients with cortical atrophyin MRI whereas 1210.0 ± 45.9 in patients without any cortical atrophy. Cranial MRI showed cortical atrophy in six patients (6/10). Conclusion Our data showed the significance of the TTR protein in cognitive functions and highlighted the importance of the close follow-up of cognitive functions in ATTRv amyloidosis patients.

Enoyl-CoA carboxylases/reductases (ECRs) are some of the most efficient CO

Enoyl-CoA carboxylases/reductases (ECRs) are some of the most efficient CO2-fixing enzymes described to date. However, the molecular mechanisms underlying the extraordinary catalytic activity of ECRs on the level of the protein assembly remain elusive. Here we used a combination of ambient-temperature X-ray free electron laser (XFEL) and cryogenic synchrotron experiments to study the structural organization of the ECR from Kitasatospora setae. The K. setae ECR is a homotetramer that differentiates into a pair of dimers of open- and dosed-form subunits in the catalytically active state. Using molecular dynamics simulations and structure-based mutagenesis, we show that catalysis is synchronized in the K. setae ECR across the pair of dimers. This conformational coupling of catalytic domains is conferred by individual amino acids to achieve high CO2-fixation rates. Our results provide unprecedented insights into the dynamic organization and synchronized inter- and intrasubunit communications of this remarkably efficient CO2-fixing enzyme during catalysis., NSF Science and Technology Center Grant; Biology with X-ray Lasers, BioXFEL; Scientific and Technological Research Council of Turkey (TÜBİTAK); 2232 International Fellowship for Outstanding Researchers Program; 1001 Scientific and Technological Research Projects Funding Program; U.S. Department of Energy; Office of Science; Office of Basic Energy Sciences; European Union (EU); Horizon 2020 ; European Research Council (ERC); SYBORG; U.S. Department of Energy Joint Genome Institute; DOE Office of Science User Facility; Max Planck Society; a Max-Planck-Partner Group; CONICYT; CONICYT Doctorado Nacional Grant; Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt) Postdoctoral Fellowship; DOE Office of Science, Biological Environmental Research; National Institutes of Health; National Science Foundation Major Research Instrument Grant; NIGMS; Stanford PRECOURT Institute

Turkey has a great number of karstic caves which are unexplored and have unknown microbial diversity. The biodiversity characterisation of these caves has not yet been systematically studied from the molecular point of view. Çal Cave in Trabzon, Turkey is one of the important karstic caves. In the present study, a metagenomic approach was used to explore the microbial diversity of Çal Cave for the first time to assess the potential of gene sources. Detailed taxonomic profiling was defined by sequencing all environmental genomes instead of a specific marker gene such as 16S rRNA which only targets prokaryotes. Taxonomic analysis revealed that the Çal Cave soil sample was represented as 98% Bacteria, 2% Eukaryota, 0.3% Archaea, and 0.01% Virus. Results showed that, the 31 distinct bacterial phyla represented in the Çal Cave soil sample were dominated by Actinobacteria (65%) and Proteobacteria (31%). The most dominant bacterial genus was Streptomyces. Among the 2% Eukaryotic population, the largest phylum was Ascomycota and it was mostly represented as Sordariomycetes. It was determined that 77% of Archaea was Halobacteria. The most abundant class of viruses dwelling in Çal Cave was Caudovirales. 91.61% of total readings could not be classified into any specific kingdom. Overall, classified and unclassified data verify that there exists vast microbial biodiversity in Çal Cave which could not be identified with classical microbiology techniques, and this microbial diversity provides a promising gene source for novel enzyme and bioactive compounds to be used in biotechnological applications., Türkiye henüz araştırılmamış ve mikrobiyal çeşitliliği belirlenmemiş çok sayıda karstik mağaraya sahiptir. Bu mağaraların biyoçeşitlilik karakterizasyonu henüz moleküler bakış açısıyla ele alınarak sistematik bir şekilde incelenmemiştir. Trabzon’da yer alan Çal Mağarası önemli karstik mağaralardan biridir. Bu çalışmada Çal Mağarası’nın gen kaynaklarının biyoteknolojik potansiyelini değerlendirmek amacıyla, mağaranın mikrobiyal çeşitliliği ilk kez metagenomik yaklaşım ile araştırılmıştır. Detaylı taksonomik sınıflandırma 16S rRNA gibi sadece prokaryotları hedef alan spesifik bir markör gen yerine tüm çevresel genomların dizilenmesi ile gerçekleştirilmiştir. Taksonomik analize göre Çal Mağarası toprağındaki mikrobiyal çeşitliliğin %98’ni bakteriler, %2’sini ökaryotlar, %0.3’ünü arkealar ve %0.01’ini virüsler temsil etmektedir. Sonuçlar, Çal Mağarası toprak örneğinde temsil edilen 31 farklı bakteri filumunun %65’inin Actinobacteria ve %31’inin Proteobacteria olduğunu göstermektedir. Bunlar arasında en baskın bakteri cinsi Streptomyces olarak tespit edilmiştir. %2’lik ökaryotik popülasyon arasında en geniş filum Ascomycota’dır ve bu filumun toprak örneği içindeki en yaygın temsilcisinin Sordariomycetes olduğu görülmüştür. Arkeaların %77’sinin Halobacteria olduğu belirlenmiştir. Çal Mağarası toprağında yaşayan en yaygın virüs sınıfının Caudovirales olduğu ortaya çıkmıştır. Toplam okumaların %91.61’i için ise herhangi bir spesifik sınıflandırma yapılamamıştır. Sınıflandırılmış ve sınıflandırılmamış tüm verilere bakıldığında Çal Mağarası’nda klasik mikrobiyoloji teknikleriyle tanımlanamayacak olan çok büyük bir mikrobiyal biyoçeşitliliğin olduğunu ve bu mikrobiyal çeşitliliğin biyoteknolojik uygulamalarda kullanılacak yeni enzim ve biyoaktif bileşenlerin keşfi için umut verici bir gen kaynağı sağladığı doğrulanmaktadır.

The aim of this study is to determine the amount of total aflatoxins and aflatoxin B1 (AFB1) in tomato and pepper pastes sold in farmer’s markets in Istanbul to evaluate whether aflatoxin levels were within the standards regarded as safe (, Bu çalışmanın amacı, İstanbul'daki semt pazarlarında satılan domates ve biber salçalarında bulunan toplam aflatoksin ve aflatoksin B1 (AFB1) miktarını belirlemek ve aflatoksin düzeylerinin güvenli kabul edilen standartlar (

Multimeric protein assemblies are abundant in nature. Streptavidin is an attractive protein that provides a paradigm system to investigate the intra- and intermolecular interactions of multimeric protein complexes. Also, it offers a versatile tool for biotechnological applications. Here, we present two apo-streptavidin structures, the first one is an ambient temperature Serial Femtosecond X-ray crystal (Apo-SFX) structure at 1.7 Å resolution and the second one is a cryogenic crystal structure (Apo-Cryo) at 1.1 Å resolution. These structures are mostly in agreement with previous structural data. Combined with computational analysis, these structures provide invaluable information about structural dynamics of apo streptavidin. Collectively, these data further reveal a novel cooperative allostery of streptavidin which binds to substrate via water molecules that provide a polar interaction network and mimics the substrate biotin which displays one of the strongest affinities found in nature.

Three of six arginine codons (CGU, CGC and CGA) are decoded by two Escherichia coli tRNA(Arg) isoacceptors. The anticodon stem and loop (ASL) domains of tRNA(Arg1) and tRNA(Arg2) both contain inosine and 2-methyladenosine modifications at positions 34 (I(34)) and 37 (m(2)A(37)). tRNA(Arg1) is also modified from cytidine to 2-thiocytidine at position 32 (s(2)C(32)). The s(2)C(32) modification is known to negate wobble codon recognition of the rare CGA codon by an unknown mechanism, while still allowing decoding of CGU and CGC. Substitution of s(2)C(32) for C(32) in the Saccharomyces cerevisiae tRNA(Ile)(IAU) anticodon stem and loop domain (ASL) negates wobble decoding of its synonymous A-ending codon, suggesting that this function of s(2)C at position 32 is a generalizable property. X-ray crystal structures of variously modified ASL(Arg1)(ICG) and ASL(Arg2)(ICG) constructs bound to cognate and wobble codons on the ribosome revealed the disruption of a C(32-)A(38) cross-loop interaction, but failed to fully explain the means by which s(2)C(32) restricts I(34) wobbling. Computational studies revealed that the adoption of a spatially broad inosine-adenosine base pair at the wobble position of the codon cannot be maintained simultaneously with the canonical ASL U-turn motif. C(32-)A(38) cross-loop interactions are required for stability of the anticodon/codon interaction in the ribosomal A-site.

Offshore wind farms are a collection of offshore wind turbines (OWTs) and are currently being installed in seismically active regions. An OWT consists of a long slender tower with a top-heavy fixed mass (Nacelle) together with a heavy rotating mass (Hub and blades) and is always exposed to variable environmental wind and wave loads. For dynamic analysis, an OWT can also be seen as an inverted pendulum (with over 25%–50% of the total mass concentrated in the upper 3rd of the tower), yet it is not granted that their seismic response is dominated by the first mode. Guidelines for the design of such special structures are not explicitly mentioned in current codes of practice. The aim of this technical note is to identify the design issues and provide a rational background for the seismic analysis. Where feasible, further research work that is needed is also identified and discussed.

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of Montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of the Montelukast both on the main protease enzyme inhibition and virus entry into the host cell (Spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with Montelukast for 20 hours on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and if its effect is proven in clinical phase studies, it should be used against COVID-19., Graphical abstract, In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast that simultaneously targets two important drug targets of SARS-CoV-2. Montelukast shows its effect both on the main protease and Spike/ACE2. The virus neutralization assay results showed that SARS-CoV-2 activity was delayed with Montelukast for 20 hours on the infected cells.

Oligomerization of Pr55(Gag) is a critical step of the late stage of the HIV life cycle. It has been known that the binding of IP6, an abundant endogenous cyclitol molecule at the MA domain, has been linked to the oligomerization of Pr55(Gag). However, the exact binding site of IP6 on MA remains unknown and the structural details of this interaction are missing. Here, we present three high-resolution crystal structures of the MA domain in complex with IP6 molecules to reveal its binding mode. Additionally, extensive Differential Scanning Fluorimetry analysis combined with cryo- and ambient-temperature X-ray crystallography and GNM-based transfer entropy calculations identify the key residues that participate in IP6 binding. Our data provide novel insights about the multilayered HIV-1 virion assembly process that involves the interplay of IP6 with PIP2, a phosphoinositide essential for the binding of Pr55(Gag) to membrane. IP6 and PIP2 have neighboring alternate binding sites within the same highly basic region (residues 18-33). This indicates that IP6 and PIP2 bindings are not mutually exclusive and may play a key role in coordinating virion particles' membrane localization. Based on our three different IP6-MA complex crystal structures, we propose a new model that involves IP6 coordination of the oligomerization of outer MA and inner CA domain's 2D layers during assembly and budding., National Science Foundation (NSF) Science and Technology Centers Grant; BioXFEL; Scientific and Technological Research Council of Turkey (TÜBİTAK); 2232 International Fellowship for Outstanding Researchers Program; Grant-in-Aid for Scientific Research; Grant-in-Aid for Research Activity Start-up; Japanese Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research; Grant-in and Aid for JSPS Research Fellow; Japan Agency for Medical Research and Development Basis for Supporting Innovative Drug Discovery and Life Science Research; Platform for Drug Discovery, Informatics, and Structural Life Science (MEXT); Japan Agency for Medical Research and Development (AMED)

The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2., Graphical abstract, Durdağı et al. represent radiation damage-free high-resolution SARS-CoV-2 main protease SFX structures obtained at near-physiological temperature and performed MD simulation of apo-form proteins and three known main protease inhibitors. The structures reveal alternate conformation, while MD simulation indicates asymmetric behavior of the protein, which is invaluable information for immediate drug-repurposing studies.

Objective: to compare the effectiveness of different mask types in limiting the dispersal of coughed air. Method: the Schlieren method with a single curved mirror was used in this study. Coughed air has a slightly higher temperature than ambient air, which generates a refractive index gradient. A curved mirror with a radius of curvature of 10 m and a diameter of 60 cm was used. The spread of the cough wavefront was investigated among five subjects wearing: (1) no mask; (2) a single surgical mask; (3) a double surgical mask; (4) a cloth mask; (5) a valveless N95 mask; and (6) a valved N95 mask. Results: all mask types reduced the size of the contaminated region significantly. The percentage reduction in the cross-sectional area of the contaminated region for the same mask types on different subjects revealed by normalized data suggests that the fit of a mask plays an important role. Conclusions: no significant difference in the spread of coughed air was found between the use of a single surgical mask or a double surgical mask. Cloth masks may be effective, depending on the quality of the cloth. Valved N95 masks exclusively protect the user. The fit of a mask is an important factor to minimize the contaminated region., 2232 International Fellowship for Outstanding Researchers Program; Scientific and Technological Research Council of Turkey (TÜBİTAK)

Bu çalışmanın amacı, Atatürk döneminde Türk Jinekoloji Cemiyeti tarafından 1934-1939 yılları arasında çıkarılmış olan Türk Jinekoloji Arşivi adlı mecmuayı ve mecmuada yer alan haberleri gözler önüne sererek mecmuayı dönemin sağlık politikaları açısından değerlendirmektir. Türk Jinekoloji Arşivi, Cumhuriyet’in ilk yıllarından itibaren kadın sağlığına verilen önem dolayısıyla özellikle Türk kadınını bilinçlendirmek ve Türk sağlığına kadın doğum ve hastalıkları konusunda yeni geliştirilen tedavi yöntemlerini halka duyurmak açısından son derece önem arz etmekteydi. Böylece hem yeni Türkiye Cumhuriyeti devletinde sağlıklı kadınlar, sağlıklı genler doğuracak ve yetiştirecek hem de Türk kadını siyasal ve sosyal alanda olduğu gibi sağlık alanında da layık olduğu yere gelecekti. Bu açıdan bakıldığında Türk Jinekoloji Arşivi, önemli bir görevi de üstlenmiş bulunmaktaydı. Bu sayede bu çalışma, Türk Jinekoloji Arşivi’nin Türkiye Cumhuriyeti tarihi açısından önemini de ortaya koyacaktır. Çalışma meydana getirilirken konuyla ilgili kaynak ve literatür eserler, tarih ilminin öngördüğü şekilde tarafsız ve dönemin şartları içerisinde incelenecektir. Çalışma giriş, iki ana bölüm ve sonuç kısımlarından oluşacaktır. Giriş bölümünde Türkiye’de kadın sağlığının kısa bir tarihçesi verilecek cumhuriyetten önceki dönemlerde kadın sağlığı konusunda neler yapıldığına dikkat çekilecektir. Birinci bölümde mecmuayı çıkaran Türk Jinekoloji Cemiyeti hakkında açıklayıcı mahiyette bilgiler verilecektir. Cemiyetin amacı, neden kurulduğu ve faaliyetleri bu bölümde verilecektir. İkinci bölüm ise Türk Jinekoloji Arşivi mecmuasını ele almaktadır. Bu bölümde mecmuanın niçin ve kimler tarafından çıkarıldığına dair sorulara cevap aranmaya çalışılacaktır. Mecmuanın kaç sayı çıktığı ve ne tür haberlere yer verdiği yine bu bölümde tartışılacaktır. Mecmua hakkında değerlendirmeler yapılarak Atatürk dönemi kadın sağlığı politikaları üzerinden mecmuaya dair bazı çıkarımlarda bulunulacaktır. Sonuç kısmında ise Türk Jinekoloji Arşivi’nin Türk kadın sağlığı açısından yeri ve önemi üzerinden değerlendirmeler yapılacaktır. Türk Jinekoloji Arşivi, 1934-1939 yılları arasında Türk Jinekoloji Cemiyeti tarafından çıkarılmıştır. Mecmuanın mevcut 15 sayısına ulaşılmıştır. Mecmuanın her bir sayısı ortalama 90 sayfadır. Mecmua ilk olarak Ağustos 1934’te neşredilmiş ve üç ayda bir olmak üzere yayınlanmıştır. Mecmuanın sahip ve mesul müdürü M.A. Hadi isimli bir doktordur. Neşir Heyeti ise Kenan Tevfik, Ahmet Asım ve Ali Esat beylerden oluşmaktadır. Mecmua, Türk Jinekoloji Cemiyeti doktorlarının kadın hastalıkları ve doğumuyla ilgili ilmi tedkiklerini yayınlamıştır. Bundan başka Türk Jinekoloji Cemiyeti’nin aylık toplantılarına yer vermiştir. Mecmuanın son sayfalarında ise kadın sağlığına yönelik ilaç reklamları yer almaktadır. Mecmua, kadında frengi, bel soğukluğu, gebelik vs. çeşitli hastalıklara çözümler üretmektedir. Kadın hastalıları ile ilgili konular, alanında doktorlar tarafından ele alınarak özellikle kadınlar bu konuda bilinçlendirilmeye çalışılmış, kadın sağlığına yeni tedavi yöntemleri geliştirilmiş ve bunlar Türk sağlığına kazandırılmıştır. Böylece Türkiye Cumhuriyeti devletinin, sağlıklı nesiller yetiştirme politikası daha iyi bir ivme yakalamıştır.