Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in DYSF (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in MYOF (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in OTOF (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer. This review provides a detailed description of functions of the vertebrate ferlins with a focus on muscle ferlins and discusses the mechanisms leading to disease development. Full article

Glaucoma is one of the leading causes of irreversible blindness in the world and remains a major public health problem. To date, incomplete knowledge of this disease’s pathophysiology has resulted in current therapies (pharmaceutical or surgical) unfortunately having only a slowing effect on disease progression. Recent research suggests that glaucomatous optic neuropathy is a disease that shares common neuroinflammatory mechanisms with “classical” neurodegenerative pathologies. In addition to the death of retinal ganglion cells (RGCs), neuroinflammation appears to be a key element in the progression and spread of this disease. Indeed, early reactivity of glial cells has been observed in the retina, but also in the central visual pathways of glaucoma patients and in preclinical models of ocular hypertension. Moreover, neuronal lesions are not limited to retinal structure, but also occur in central visual pathways. This review summarizes and puts into perspective the experimental and clinical data obtained to date to highlight the need to develop neuroprotective and immunomodulatory therapies to prevent blindness in glaucoma patients. Full article

Accumulating evidence suggests that iron homeostasis is disturbed in tumors. We aimed at clarifying the distribution of iron in renal cell carcinoma (RCC). Considering the pivotal role of macrophages for iron homeostasis and their association with poor clinical outcome, we investigated the role of macrophage-secreted iron for tumor progression by applying a novel chelation approach. We applied flow cytometry and multiplex-immunohistochemistry to detect iron-dependent markers and analyzed iron distribution with atomic absorption spectrometry in patients diagnosed with RCC. We further analyzed the functional significance of iron by applying a novel extracellular chelator using RCC cell lines as well as patient-derived primary cells. The expression of iron-regulated genes was significantly elevated in tumors compared to adjacent healthy tissue. Iron retention was detected in tumor cells, whereas tumor-associated macrophages showed an iron-release phenotype accompanied by enhanced expression of ferroportin. We found increased iron amounts in extracellular fluids, which in turn stimulated tumor cell proliferation and migration. In vitro, macrophage-derived iron showed pro-tumor functions, whereas application of an extracellular chelator blocked these effects. Our study provides new insights in iron distribution and iron-handling in RCC. Chelators that specifically scavenge iron in the extracellular space confirmed the importance of macrophage-secreted iron in promoting tumor growth. Full article

Chromosome instability (CIN), or progressive changes in chromosome numbers, is an enabling feature of many cancers; however, the mechanisms giving rise to CIN remain poorly understood. To expand our mechanistic understanding of the molecular determinants of CIN in humans, we employed a cross-species approach to identify 164 human candidates to screen. Using quantitative imaging microscopy (QuantIM), we show that silencing 148 genes resulted in significant changes in CIN-associated phenotypes in two distinct cellular contexts. Ten genes were prioritized for validation based on cancer patient datasets revealing frequent gene copy number losses and associations with worse patient outcomes. QuantIM determined silencing of each gene-induced CIN, identifying novel roles for each as chromosome stability genes. SKP1 was selected for in-depth analyses as it forms part of SCF (SKP1, CUL1, FBox) complex, an E3 ubiquitin ligase that targets proteins for proteolytic degradation. Remarkably, SKP1 silencing induced increases in replication stress, DNA double strand breaks and chromothriptic events that were ascribed to aberrant increases in Cyclin E1 levels arising from reduced SKP1 expression. Collectively, these data reveal a high degree of evolutionary conservation between human and budding yeast CIN genes and further identify aberrant mechanisms associated with increases in chromothriptic events. Full article

Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer. Full article

The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2. Full article

Masonry structures are notoriously vulnerable to horizontal actions caused by earthquakes. Given the high seismicity of the European region, and that the European building stock comprises a lot of masonry buildings, knowledge about their structural response to seismic excitation is particularly important, but at the same time difficult to determine, due to the heterogenous nature of materials and/or constructional techniques in use. An additional issue is represented by the current methods for mechanical properties assessment, that do not provide a reliable framework for accurate structural estimations of existing buildings characterized by different typological properties. Every structure, in other words, should be separately inspected in regard to its mechanical behaviour, based on dedicated approaches able to capture potential critical issues. In this review paper, an insight on the Croatian ARES project is presented (Assessment and Rehabilitation of Existing Structures), including a state-of-the-art of the actual building stock and giving evidence of major difficulties concerning the assessment of existing structures. The most commonly used techniques and tools are compared, with a focus on their basic features and field of application. A brief overview of prevailing structural behaviours and Finite Element numerical modelling issues are also mentioned. As shown, the general tendency is to ensure “sustainable” and energy-efficient building systems. The latter, however, seem in disagreement with basic principles of structural maintenance and renovation. The aim of the ongoing ARES project, in this context, is to improve the current knowledge regarding the assessment and strengthening of structures, with a focus on a more reliable design and maintenance process for existing masonry buildings. Full article

A new β-class carbonic anhydrase was cloned and purified from the filamentous ascomycete Sordaria macrospora, CAS3. This enzyme has a higher catalytic activity compared to the other two such enzymes from this fungus, CAS1 and CAS2, which were reported earlier, with the following kinetic parameters: k_cat of (7.9 ± 0.2) × 10⁵ s⁻¹, and k_cat/K_m of (9.5 ± 0.12) × 10⁷ M⁻¹∙s⁻¹. An inhibition study with a panel of sulfonamides and one sulfamate was also performed. The most effective CAS3 inhibitors were benzolamide, brinzolamide, dichlorophnamide, methazolamide, acetazolamide, ethoxzolamide, sulfanilamide, methanilamide, and benzene-1,3-disulfonamide, with K_Is in the range of 54–95 nM. CAS3 generally shows a higher affinity for this class of inhibitors compared to CAS1 and CAS2. As S. macrospora is a model organism for the study of fruiting body development in fungi, these data may be useful for developing antifungal compounds based on CA inhibition. Full article

This study aimed to evaluate the chemical composition by gas chromatography-mass spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR) analyses, the antioxidant activities evaluated by different in vitro assays namely 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), Ferric Reducing Ability Power (FRAP), and β-carotene bleaching tests, and the inhibitory effects of enzymes linked to obesity (lipase, α-amylase, and α-glucosidase) of fixed seed oil of Ceiba speciosa (A. St.-Hil.). Fourteen compounds were identified. Linoleic acid (28.22%) was the most abundant followed by palmitic acid (19.56%). Malvalic acid (16.15%), sterculic acid (11.11%), and dihydrosterculic acid (2.74%) were also detected. C. speciosa fixed oil exerted a promising ABTS radicals scavenging activity with an IC₅₀ value of 10.21 µg/mL, whereas an IC₅₀ of 77.44 µg/mL against DPPH⁺ radicals was found. C. speciosa fixed oil inhibited lipase with an IC₅₀ value of 127.57 µg/mL. The present investigation confirmed the functional properties of C. speciosa fixed oil, and proposes its use as valuable source of bioactive constituents. Full article

Natural compounds extracted from plants have gained immense importance in the fight against cancer cells due to their lesser toxicity and potential therapeutic effects. Raddeanin A (RA), an oleanane type triterpenoid is a major compound isolated from Anemone raddeana Regel. As an anticancer agent, RA induces apoptosis, cell cycle arrest, inhibits invasion, migration and angiogenesis in malignant cell lines as well as in preclinical models. In this systemic review, the pharmacological effects of RA and its underlying molecular mechanisms were carefully analyzed and potential molecular targets have been highlighted. The apoptotic potential of RA can be mediated through the modulation of Bcl-2, Bax, caspase-3, caspase-8, caspase-9, cytochrome c and poly-ADP ribose polymerase (PARP) cleavage. PI3K/Akt signaling pathway serves as the major molecular target affected by RA. Furthermore, RA can block cell proliferation through inhibition of canonical Wnt/β-catenin signaling pathway in colorectal cancer cells. RA can also alter the activation of NF-κB and STAT3 signaling pathways to suppress invasion and metastasis. RA has also exhibited promising anticancer potential against drug resistant cancer cells and can enhance the anticancer effects of several chemotherapeutic agents. Overall, RA may function as a promising compound in combating cancer, although further in-depth study is required under clinical settings to validate its efficacy in cancer patients. Full article

This paper investigates the thermohydraulic performance of finned-tube supercritical carbon dioxide (sCO₂) gas coolers operating with refrigerant pressures near the critical point. A distributed modelling approach combined with the ε-NTU method has been developed for the simulation of the gas cooler. The heat transfer and pressure drop for each evenly divided segment are calculated using empirical correlations for Nusselt number and friction factor. The model was validated against test results and then used to investigate the influence of design and operating parameters on local and overall gas cooler performance. The results show that the refrigerant heat-transfer coefficient increases with decreasing temperature and reaches its maximum close to the pseudocritical temperature before beginning to decrease. The pressure drop increases along the flow direction with decreasing temperature. Overall performance results illustrate that higher refrigerant mass flow rate and decreasing finned-tube diameter lead to improved heat-transfer rates but also increased pressure drops. Design optimization of gas coolers should take into consideration their impact on overall refrigeration performance and life cycle cost. This is important in the drive to reduce the footprint of components, energy consumption, and environmental impacts of refrigeration and heat-pump systems. The present work provides practical guidance to the design of finned-tube gas coolers and can be used as the basis for the modelling of integrated sCO₂ refrigeration and heat-pump systems. Full article

The aim of this study was to investigate the protective effects of selenium yeast (Se-Y) against hepatotoxicity induced by ochratoxin A (OTA). The OTA-induced liver injury model was established in chickens by daily oral gavage of 50 µg/kg OTA for 21 days. Serum biochemistry analysis, antioxidant analysis, as well as the qRT-PCR and Western blot (WB) analyses were then used to evaluate oxidative damage and apoptosis in chicken liver tissue. The results showed that Se-Y significantly increased liver coefficient induced by OTA (P < 0.05). OTA + Se-Y treated group revealed that Se-Y reduced the OTA-induced increase in glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and malonaldehyde (MDA) content, and reversed the decrease in antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) (P < 0.05). In this study, we found that OTA is involved in the mRNA expression levels about Nrf2/Keap1 and PI3K/AKT signaling pathways, such as oxidative stress-related genes (Nrf2, GSH-Px, GLRX2 and Keap1) and apoptosis-related genes (Bax, Caspase3, P53, AKT, PI3K and Bcl-2). Besides, significant downregulations of protein expression of HO-1, MnSOD, Nrf2 and Bcl-2, as well as a significant upregulation of Caspase3 and Bax levels were observed after contaminated with OTA (P < 0.05). Notably, OTA-induced apoptosis and oxidative damage in the liver of chickens were reverted back to normal level in the OTA + Se-Y group. Our findings indicate that pretreatment with Se-Y effectively ameliorates OTA-induced hepatotoxicity. Full article

The journal Reproductive Medicine just started as an open access journal with an excellent editorial team. As founding editor-in-chief it is my belief that this new journal will find its specific niche in the field of reproduction. It is not only the free access to scientific data that is very important today and that comes with this journal; this journal also builds the bridge between IVF (In Vitro Fertilization) and ART (Assisted Reproductive Technology) on the one hand and pregnancy and pregnancy pathologies on the other hand, combined in one journal. This interdisciplinary approach is needed as the last decade has shown that there are more links between the mode of conception and the outcome of pregnancy than we ever thought. We encourage our readers to scroll through the list of papers that will be published in this journal to open their view for all aspects of reproduction from the ovarian reserve to the epigenetic changes of a newborn due to fetal programming. Full article

Three-dimensional (3D) printed anatomical models are valuable visual aids that are widely used in clinical and academic settings to teach complex anatomy. Procedures for converting human biomedical image datasets, like X-ray computed tomography (CT), to printable 3D files were explored, allowing easy reproduction of highly accurate models; however, these largely remain monochrome. While multi-color 3D printing is available in two accessible modalities (binder-jetting and poly-jet/multi-jet systems), studies embracing the viability of these technologies in the production of anatomical teaching models are relatively sparse, especially for sub-structures within a segmentation of homogeneous tissue density. Here, we outline a strategy to manually highlight anatomical subregions of a given structure and multi-color 3D print the resultant models in a cost-effective manner. Readily available high-resolution 3D reconstructed models are accessible to the public in online libraries. From these databases, four representative files (of a femur, lumbar vertebra, scapula, and innominate bone) were selected and digitally color enhanced with one of two strategies (painting or splitting) guided by Feneis and Dauber’s Pocket Atlas of Human Anatomy. Resulting models were created via 3D printing with binder-jet and/or poly-jet machines with important features, such as muscle origin and insertion points, highlighted using multiple colors. The resulting multi-color, physical models are promising teaching tools that will enhance the anatomical learning experience. Full article

Antimicrobial resistance (AMR) is the major issue posing a serious global health threat. Low- and middle-income countries are likely to be the most affected, both in terms of impact on public health and economic burden. Recent studies highlighted the role of resistance networks on the transmission of AMR organisms, with this network being driven by complex interactions between clinical (e.g., human health, animal husbandry and veterinary medicine) and other components, including environmental factors (e.g., persistence of AMR in wastewater). Many studies have highlighted the role of wastewater as a significant environmental reservoir of AMR as it represents an ideal environment for AMR bacteria (ARB) and antimicrobial resistant genes (ARGs) to persist. Although the treatment process can help in removing or reducing the ARB load, it has limited impact on ARGs. ARGs are not degradable; therefore, they can be spread among microbial communities in the environment through horizontal gene transfer, which is the main resistance mechanism in most Gram-negative bacteria. Here we analysed the recent literature to highlight the contribution of wastewater to the emergence, persistence and transmission of AMR under different settings, particularly those associated with mass gathering events (e.g., Hajj and Kumbh Mela). Full article