Miracle-dz/UniFAR-FTUs huggingface dataset:
Glycolysis supports embryonic muscle growth by promoting myoblast fusion

Significance We report that glycolytic genes are synchronously activated in midembryogenesis in developing Drosophila muscles and that muscle-targeted attenuation of their expression leads to reduced muscle size and the presence of unfused myoblasts. Importantly, a “thin muscle” phenotype is also observed in fast muscle fibers of pgam2 zebrafish morphants, strongly suggesting a conserved role of glycolysis in promoting myoblast fusion-based muscle growth. We also show that insulin positively regulates glycolysis and that blocking the insulin pathway phenocopies the loss of function phenotypes of glycolytic genes, leading to myoblast fusion arrest and reduced muscle size. These findings led us to propose that setting metabolism to glycolysis-based high-rate biomass production is part of a core myogenic program that promotes formation of syncytial muscles. Muscles ensure locomotion behavior of invertebrate and vertebrate organisms. They are highly specialized and form using conserved developmental programs. To identify new players in muscle development we screened Drosophila and zebrafish gene expression databases for orthologous genes expressed in embryonic muscles. We selected more than 100 candidates. Among them is the glycolysis gene Pglym78/pgam2, the attenuated expression of which results in the formation of thinner muscles in Drosophila embryos. This phenotype is also observed in fast muscle fibers of pgam2 zebrafish morphants, suggesting affected myoblast fusion. Indeed, a detailed analysis of developing muscles in Pglym78 RNAi embryos reveals loss of fusion-associated actin foci and an inefficient Notch decay in fusion competent myoblasts, both known to be required for fusion. In addition to Pglym78, our screen identifies six other genes involved in glycolysis or in pyruvate metabolism (Pfk, Tpi, Gapdh, Pgk, Pyk, and Impl3). They are synchronously activated in embryonic muscles and attenuation of their expression leads to similar muscle phenotypes, which are characterized by fibers with reduced size and the presence of unfused myoblasts. Our data also show that the cell size triggering insulin pathway positively regulates glycolysis in developing muscles and that blocking the insulin or target of rapamycin pathways phenocopies the loss of function phenotypes of glycolytic genes, leading to myoblast fusion arrest and reduced muscle size. Collectively, these data suggest that setting metabolism to glycolysis-stimulated biomass production is part of a core myogenic program that operates in both invertebrate and vertebrate embryos and promotes formation of syncytial muscles.
Higher-order interactions bridge the nitric oxide receptor and catalytic domains of soluble guanylate cyclase

Nitric oxide (NO) signaling pathways mediate diverse physiological functions, including vasodilation and neurotransmission. Soluble guanylate cyclase (sGC), the primary NO receptor, triggers downstream signaling cascades by producing the second messenger cGMP. NO binds the sGC heme cofactor to stimulate cyclase activity, yet the molecular mechanisms of cyclase activation remain obscure. Although structural models of the individual sGC domains are available, the structure of the full sGC heterodimer is unknown. Understanding the higher-order domain architecture of sGC is a prerequisite to elucidating the mechanisms of NO activation. We used protein footprinting to map interdomain interaction surfaces of the sGC signaling domains. Hydrogen/deuterium exchange mass spectrometry revealed direct interactions between the Per/Arnt/Sim domain and the heme-associated signaling helix of the heme-NO/O2 binding (H-NOX) domain. Furthermore, interfaces between the H-NOX and catalytic domains were mapped using domain truncations and full-length sGC. The H-NOX domain buries surfaces of the α1 catalytic domain proximal to the cyclase active site, suggesting a signaling mechanism involving NO-induced derepression of catalytic activity. Together, our data reveal interdomain interactions responsible for communicating NO occupancy from H-NOX heme to the catalytic domain active site.
Attenuation of the posttranslational oscillator via transcription–translation feedback enhances circadian-phase shifts in Synechococcus

Circadian rhythms are endogenous biological timing processes that are ubiquitous in organisms ranging from cyanobacteria to humans. In the photoautotrophic unicellular cyanobacterium Synechococcus elongatus PCC 7942, under continuous light (LL) conditions, the transcription–translation feedback loop (TTFL) of KaiC generates a rhythmic change in the accumulation of KaiC relative to KaiA clock proteins (KaiC/KaiA ratio), which peak and trough at subjective dawn and dusk, respectively. However, the role of TTFL in the cyanobacterial circadian system remains unclear because it is not an essential requirement for the basic oscillation driven by the Kai-based posttranslational oscillator (PTO) and the transcriptional output mechanisms. Here, we show that TTFL is important for the circadian photic resetting property in Synechococcus. The robustness of PTO, which is exemplified by the amplitude of the KaiC phosphorylation cycle, changed depending on the KaiC/KaiA ratio, which was cyclic under LL. After cells were transferred from LL to the dark, the clock protein levels remained constant in the dark. When cells were transferred from LL to continuous dark at subjective dawn, the KaiC phosphorylation cycle was attenuated with a lower KaiC/KaiA ratio, a higher KaiC phosphorylation level, and a lower amplitude than that in cells transferred at subjective dusk. We also found that the greater the degree to which PTO was attenuated in continuous dark, the greater the phase shifts upon the subsequent light exposure. Based on these results, we propose that TTFL enhances resetting of the Kai-based PTO in Synechococcus.
An immunofluorescence test for phospholipase-A₂-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis.

BACKGROUND The recent finding that phospholipase-A(2)-receptor antibodies (PLA(2)R-AB) may play a role in the development of primary membranous glomerulonephritis (MGN) offers the opportunity to measure a marker to help diagnose, classify and eventually monitor the course of patients with MGN. METHODS We developed an immunofluorescence test, which allows the easy and specific analysis of the presence of PLA(2)R-AB in serum. The usefulness of this test was studied in 153 healthy blood donors, 90 patients with non-membranous glomerular injuries, 17 patients with a secondary form of MGN and 100 patients with biopsy-proven primary MGN. In addition, in five patients with biopsy-proven MGN, PLA(2)R-AB levels were monitored prospectively for up to 18 months following a single dose of rituximab (RTX) (375 mg/m(2) body surface). RESULTS PLA(2)R-AB were not found in healthy controls or patients with glomerular lesions other than biopsy-proven primary MGN. Fifty-two patients with primary MGN (52%) were positive for PLA(2)R-AB. The levels ranged from 1:10 to 1:3200. In patients who had MGN and were treated with RTX the fall in PLA(2)R-AB levels was followed by a decrease in proteinuria, whereas an increase in PLA(2)R-AB levels was associated with an increase in proteinuria. CONCLUSIONS These studies show that the new test allows the monitoring of PLA(2)R-AB levels in patients with MGN and may help in making therapeutic decisions for these patients.
The interaction of HIV and tuberculosis

An apparatus and method for producing extruded elongate pasta of substantially even lengths. The apparatus includes: an extruder; a first cutter for cutting uneven tip portions of the bunches of elongate pasta; a second cutter for cutting the bunches of the elongate pasta, whose uneven tip portions have been cut, into an even length; and a sorting part for selectively sorting the bunches of elongate pasta having been cut into the even length with the second cutter from the uneven tip portions having been cut with the first cutter.
Inhibition of pluripotent stem cell-derived teratoma formation by small molecules

Significance We found that quercetin/YM155-induced selective cell death is sufficient to completely inhibit teratoma formation after transplantation of human pluripotent stem cell (hPSC)-derived cells. These data provide the first “proof of concept” that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy. The future of safe cell-based therapy rests on overcoming teratoma/tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC-derived cells. Taken together, these results provide the “proof of concept” that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.
Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Significance Both lamin B1 and lamin B2 have farnesyl lipid anchors, but the importance of this lipid modification has been unclear. We addressed that issue with knock-in mouse models. Mice expressing nonfarnesylated lamin B2 developed normally and were healthy. In contrast, mice expressing nonfarnesylated lamin B1 exhibited a severe neurodevelopmental abnormality accompanied by a striking defect in the cell nucleus. During the migration of neurons, the nuclear lamina was pulled free of the chromatin. Thus, farnesylation of lamin B1—but not lamin B2—is crucial for neuronal migration in the brain and for the retention of chromatin within the nuclear lamina. The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left “naked” (free from the nuclear lamina). Thus, farnesylation of lamin B1—but not lamin B2—is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.
Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues

The functions of intrinsically disordered proteins (IDPs) are governed by relationships between information encoded in their amino acid sequences and the ensembles of conformations that they sample as autonomous units. Most IDPs are polyampholytes, with sequences that include both positively and negatively charged residues. Accordingly, we focus here on the sequence–ensemble relationships of polyampholytic IDPs. The fraction of charged residues discriminates between weak and strong polyampholytes. Using atomistic simulations, we show that weak polyampholytes form globules, whereas the conformational preferences of strong polyampholytes are determined by a combination of fraction of charged residues values and the linear sequence distributions of oppositely charged residues. We quantify the latter using a patterning parameter κ that lies between zero and one. The value of κ is low for well-mixed sequences, and in these sequences, intrachain electrostatic repulsions and attractions are counterbalanced, leading to the unmasking of preferences for conformations that resemble either self-avoiding random walks or generic Flory random coils. Segregation of oppositely charged residues within linear sequences leads to high κ-values and preferences for hairpin-like conformations caused by long-range electrostatic attractions induced by conformational fluctuations. We propose a scaling theory to explain the sequence-encoded conformational properties of strong polyampholytes. We show that naturally occurring strong polyampholytes have low κ-values, and this feature implies a selection for random coil ensembles. The design of sequences with different κ-values demonstrably alters the conformational preferences of polyampholytic IDPs, and this ability could become a useful tool for enabling direct inquiries into connections between sequence–ensemble relationships and functions of IDPs.
SARS as a “Health Scare”

Permission received as follows:From: Wiley Global Permissions Date: 17 July 2015 at 18:51 Subject: FW: FW: book chapter To: "clairehookerwork@gmail.com" Dear Dr Claire Hooker, Further to your email below, I have corresponded with the editor of the book in which your chapter was published and she has agreed to you depositing the accepted version of your work in your institutional repository. Please note that While many of our journals allow authors to self-archive articles in institutional repositories, please note that the same situation does not automatically apply to material published in our books, so any future requests relating to book chapters will need to be sent to us for review. Our journals policies for author self-archiving can be found via the following link: http://olabout.wiley. com/WileyCDA/Section/id-820227.html . I hope this answers your query, but please do not hesitate to get in contact if there is anything further we can assist with, Yours Sincerely, Rebecca Cook Permissions Assistant John Wiley & Sons Ltd The Atrium Southern Gate, Chichester West Sussex, PO19 8SQ UK Description: Description: cid:image001.jpg@01CD4ED1.91DE0370
Importance of normohydration for the long-term survival of haemodialysis patients.

BACKGROUND Fluid overload and hypertension are among the most important risk factors for haemodialysis (HD) patients. The aim of this study was to analyse the impact of fluid overload for the survival of HD patients by using a selected reference population from Tassin. METHODS A positively selected HD population (n = 50) from Tassin (Lyon-France) was used as a reference for fluid status and all-cause mortality. This population was compared to one dialysis centre from Giessen (Germany) which was separated into a non-hyperhydrated (n = 123) and a hyperhydrated (n = 35) patient group. The hydration status (ΔHS) of all patients was objectively measured with whole-body bioimpedance spectroscopy in 2003. All-cause mortality was analysed after a 6.5-year follow-up. RESULTS Most of the reference patients from Tassin were normohydrated (ΔHS = 0.25 ± 1.15 L) at the start of the HD session. The hydration status of the Tassin patients was not different to the non-hyperhydrated Giessen patients (ΔHS = 0.8 ± 1.1 L) but significantly lower than in the hyperhydrated Giessen group (ΔHS = 3.5 ± 1.2 L). Multivariate adjusted all-cause mortality was significantly increased in the hyperhydrated patient group (hazard ratio = 3.41)- no difference in mortality could be observed between the Tassin and the non-hyperhydrated group from Giessen-even considering the fact that Tassin patients presented a significantly lower blood pressure. CONCLUSIONS Fluid overload has a very high predictive value for all-cause mortality and seems to be one of the major killers in the HD population. Patients might strongly benefit from active management of fluid overload.
Structural evidence for a bifurcated mode of action in the antibody-mediated neutralization of hepatitis C virus

Hepatitis C virus (HCV) envelope glycoprotein E2 has been considered as a major target for vaccine design. Epitope II, mapped between residues 427–446 within the E2 protein, elicits antibodies that are either neutralizing or nonneutralizing. The fundamental mechanism of antibody-mediated neutralization at epitope II remains to be defined at the atomic level. Here we report the crystal structure of the epitope II peptide in complex with a monoclonal antibody (mAb#8) capable of neutralizing HCV. The complex structure revealed that this neutralizing antibody engages epitope II via interactions with both the C-terminal α-helix and the N-terminal loop using a bifurcated mode of action. Our structural insights into the key determinants for the antibody-mediated neutralization may contribute to the immune prophylaxis of HCV infection and the development of an effective HCV vaccine.
High‐Performance Pseudocapacitive Microsupercapacitors from Laser‐Induced Graphene

All-solid-state, flexible, symmetric, and asymmetric microsupercapacitors are fabricated by a simple method in a scalable fashion from laser-induced graphene on commercial polyimide films, followed by electrodeposition of pseudocapacitive materials on the interdigitated in-plane architectures. These microsupercapacitors demonstrate comparable energy density to commercial lithium thin-film batteries, yet exhibit more than two orders of magnitude higher power density with good mechanical flexibility.
Structure of the 26S proteasome with ATP-γS bound provides insights into the mechanism of nucleotide-dependent substrate translocation

The 26S proteasome is a 2.5-MDa, ATP-dependent multisubunit proteolytic complex that processively destroys proteins carrying a degradation signal. The proteasomal ATPase heterohexamer is a key module of the 19S regulatory particle; it unfolds substrates and translocates them into the 20S core particle where degradation takes place. We used cryoelectron microscopy single-particle analysis to obtain insights into the structural changes of 26S proteasome upon the binding and hydrolysis of ATP. The ATPase ring adopts at least two distinct helical staircase conformations dependent on the nucleotide state. The transition from the conformation observed in the presence of ATP to the predominant conformation in the presence of ATP-γS induces a sliding motion of the ATPase ring over the 20S core particle ring leading to an alignment of the translocation channels of the ATPase and the core particle gate, a conformational state likely to facilitate substrate translocation. Two types of intersubunit modules formed by the large ATPase domain of one ATPase subunit and the small ATPase domain of its neighbor exist. They resemble the contacts observed in the crystal structures of ClpX and proteasome-activating nucleotidase, respectively. The ClpX-like contacts are positioned consecutively and give rise to helical shape in the hexamer, whereas the proteasome-activating nucleotidase-like contact is required to close the ring. Conformational switching between these forms allows adopting different helical conformations in different nucleotide states. We postulate that ATP hydrolysis by the regulatory particle ATPase (Rpt) 5 subunit initiates a cascade of conformational changes, leading to pulling of the substrate, which is primarily executed by Rpt1, Rpt2, and Rpt6.
Impact of Film Stoichiometry on the Ionization Energy and Electronic Structure of CH3NH3PbI3 Perovskites

The electronic structure of a large sample set of CH3 NH3 PbI3 -based perovskites is studied. Combined investigations by UV/X-ray photoelectron spectroscopy and X-ray diffraction reveal that interstitials present in the film lead to changes in the occupied density of states close to the valence band, which in turn influences the performance of solar cells. Changes in elemental composition tune the ionization energy of the perovskite film by almost 1 eV without introducing significant amounts of gap states.
Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.
Recent advances in the understanding and management of diffuse large B‐cell lymphoma in children

Diffuse large B‐cell lymphomas (DLBCL) are neoplasms of transformed mature B cells, accounting for approximately 10% of non‐Hodgkin lymphomas (NHL) of childhood. Increasing evidence indicates that DLBCL are composed of biologically distinct subsets. Clinical features of children with DLBCL differ from those with other NHL entities, e.g. by a lower frequency of bone‐marrow and central nervous sytem involvement. Treatment strategies originally designed for Burkitt lymphoma appear to be efficacious for children with DLBCL. However, children with primary mediastinal large B‐cell lymphoma may need a more specific treatment approach, given their inferior outcome in recent studies. The addition of the monoclonal anti‐CD20 antibody rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy improved outcome of adults with DLBCL significantly. However, preliminary data suggest differences between DLBCL of children and adults concerning cell of origin, genetic abnormalities and responsiveness to current treatments. Thus, the potential role of monoclonal antibodies in the treatment of children with DLBCL remains to be determined. The availability of new methodological tools, such as gene expression profiling, will greatly enhance our insights into the biology of childhood DLBCL and its similarities and disparities compared to adult DLBCL. Furthermore, these tools may enable a more risk‐adapted and rationally targeted subtype‐specific therapy in the future.