Estrogens promote misfolded proinsulin degradation to protect insulin production and delay diabetes

Summary: Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and β cell dysfunction. We show that CE prevent insulin-deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-α (ERα), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERα modulator bazedoxifene mimics CE protection of β cells in females but not in males. : Estrogens prevent diabetes in women, but the mechanism is poorly understood. Xu et al. report that estrogens activate the endoplasmic-reticulum-associated protein degradation pathway, which promotes misfolded proinsulin degradation, suppresses endoplasmic reticulum stress, and protects insulin secretion in mice and in human pancreatic β cells. Keywords: estrogens, beta cell, islet, endoplasmic reticulum stress, proinsulin misfolding, diabetes, bazedoxifene, sex dimorphism, ERAD, SER

Comment on "Superconducting gap anisotropy vs. doping level in high-T_c cuprates" by C. Kendziora et al, PRL 77, 727 (1996)

In a recent paper Kendziora et al concluded that the superconducting gap in overdoped Bi-2212 is isotropic. From data obtained from electronic Raman scattering measurements, their conclusion was based on the observation that pair breaking peaks occured at approximately the same frequency in different scattering geometries and that the normalized scattering intensity at low energies was strongly depleted. We discuss a different interpretation of the raw data and present new data which is consistent with a strongly anisotropic gap with nodes. The spectra can be successfully described by a model for Raman scattering in a d_{x^{2}-y^{2}} superconductor with spin fluctuations and impurity scattering included.Comment: 1 page revtex plus 1 postscript figur

The conceptual and practical ethical dilemmas of using health discussion board posts as research data.

Increasing numbers of people living with a long-term health condition are putting personal health information online, including on discussion boards. Many discussion boards contain material of potential use to researchers; however, it is unclear how this information can and should be used by researchers. To date there has been no evaluation of the views of those individuals sharing health information online regarding the use of their shared information for research purposes

Constraints on the Persistent Radio Source Associated with FRB 20190520B Using the European VLBI Network

We present very long baseline interferometry (VLBI) observations of a continuum radio source potentially associated with the fast radio burst source FRB 20190520B. Using the European VLBI network, we find the source to be compact on VLBI scales with an angular size of <2.3 mas (3σ). This corresponds to a transverse physical size of <9 pc (at the z = 0.241 redshift of the host galaxy), confirming it to be as fast radio burst (FRB) persistent radio source (PRS) like that associated with the first-known repeater FRB 20121102A. The PRS has a flux density of 201 ± 34 μJy at 1.7 GHz and a spectral radio luminosity of L1.7 GHz = (3.0 ± 0.5) × 1029 erg s−1 Hz−1 (also similar to the FRB 20121102A PRS). Compared to previous lower-resolution observations, we find that no flux is resolved out on milliarcsecond scales. We have refined the PRS position, improving its precision by an order of magnitude compared to previous results. We also report the detection of the FRB 20190520B burst at 1.4 GHz and find the burst position to be consistent with the PRS position, at ≲20 mas. This strongly supports their direct physical association and the hypothesis that a single central engine powers both the bursts and the PRS. We discuss the model of a magnetar in a wind nebula and present an allowed parameter space for its age and the radius of the putative nebula powering the observed PRS emission. Alternatively, we find that an accretion-powered hypernebula model also fits our observational constraints

Approximability of Capacitated Network Design

In the capacitated survivable network design problem (Cap- SNDP), we are given an undirected multi-graph where each edge has a capacity and a cost. The goal is to find a minimum cost subset of edges that satisfies a given set of pairwise minimum-cut requirements. Unlike its classical special case of SNDP when all capacities are unit, the approximability of Cap-SNDP is not well understood; even in very restricted settings no known algorithm achieves a o(m) approximation, where m is the number of edges in the graph. In this paper, we obtain several new results and insights into the approximability of Cap-SNDP. We give an O(log n) approximation for a special case of Cap-SNDP where the global minimum cut is required to be at least R, by rounding the natural cut-based LP relaxation strengthened with valid knapsackcover inequalities. We then show that as we move away from global connectivity, the single pair case (that is, when only one pair (s, t) has positive connectivity requirement) captures much of the difficulty of Cap-SNDP: even strengthened with KC inequalities, the LP has an Ω(n) integrality gap. Furthermore, in directed graphs, we show that single pair Cap-SNDP is 2log1−3 n-hard to approximate for any fixed constant δ \u3e 0. We also consider a variant of the Cap-SNDP in which multiple copies of an edge can be bought: we give an O(log k) approximation for this case, where k is the number of vertex pairs with non-zero connectivity requirement. This improves upon the previously known O(min{k, log Rmax})-approximation for this problem when the largest minimumcut requirement, namely Rmax, is large. On the other hand, we observe that the multiple copy version of Cap-SNDP is Ω(log log n)-hard to approximate even for the single-source version of the problem

Codon-based analysis of selection pressure and genetic structure in the Psammobates tentorius (Bell, 1828) species complex, and phylogeny inferred from both codons and amino acid sequences

This study used codon analysis (dN/dS and Tv/Ti) to investigate selection pressure and genetic structure in the highly polymorphic Psammobates tentorius species complex, and amino acid sequences to construct a phylogeny tree for it. Our results revealed a strong selection signal at node ‘C2 + C3’, possibly driven by aridity intensification resulting from the development of the Benguela Current. A similar signal was noticed at C3, possibly due to the same driving force. These findings suggest that environmental selection pressure favoured those groups and that further cladogenic events were possible. Selection pressure was also found to be high at C1, C4 and C7, which may indicate that they are also favoured by the current selection pressure. The codon-based phylogeny did not retrieve any potentially undescribed species, but nonetheless provided support for the validity of the seven distinct clades retrieved with the DNA sequence data. The amino acid sequence-based phylogeny generally supported the seven lineages as valid putative species. Investigation at the genomic scale could, however, help to solve the issue. In general, we found the codon, dN, dS, Tv, Ti and amino acid sequence-based phylogenetic inferences useful in species delimitation and recommend their use in species delimitation studies

Nucleosides rescue replication-mediated genome instability of human pluripotent stem cells

Human pluripotent stem cells (PSCs) are subject to the appearance of recurrent genetic variants on prolonged culture. We have now found that, compared with isogenic differentiated cells, PSCs exhibit evidence of considerably more DNA damage during the S phase of the cell cycle, apparently as a consequence of DNA replication stress marked by slower progression of DNA replication, activation of latent origins of replication, and collapse of replication forks. As in many cancers, which, like PSCs, exhibit a shortened G1 phase and DNA replication stress, the resulting DNA damage may underlie the higher incidence of abnormal and abortive mitoses in PSCs, resulting in chromosomal non-dysjunction or cell death. However, we have found that the extent of DNA replication stress, DNA damage, and consequent aberrant mitoses can be substantially reduced by culturing PSCs in the presence of exogenous nucleosides, resulting in improved survival, clonogenicity, and population growth

Doping dependence of the superconducting gap in Bi2Sr2CaCu2O{8 + delta}

Bi2Sr2CaCu2O{8 + \delta} crystals with varying hole concentrations (0.12 < p < 0.23) were studied to investigate the effects of doping on the symmetry and magnitude of the superconducting gap. Electronic Raman scattering experiments that sample regions of the Fermi surface near the diagonal (B_{2g}) and principal axes (B_{1g}) of the Brillouin Zone have been utilized. The frequency dependence of the Raman response function at low energies is found to be linear for B_{2g} and cubic for B_{1g} (T< T_c). The latter observations have led us to conclude that the doping dependence of the superconducting gap is consistent with d_{x^2-y^2} symmetry, for slightly underdoped and overdoped crystals. Studies of the pair-breaking peak found in the B_{1g} spectra demonstrate that the magnitude of the maximum gap decreases monotonically with increasing hole doping, for p > 0.12. Based on the magnitude of the B_{1g} renormalization, it is found that the number of quasiparticles participating in pairing increases monotonically with increased doping. On the other hand, the B_{2g} spectra show a weak "pair-breaking peak" that follows a parabolic-like dependence on hole concentration, for 0.12 < p < 0.23.Comment: 9 pages REvTex document including 8 eps figures; new table II; changes to Fig. 5 and tex

Human embryonic stem cells passaged using enzymatic methods retain a normal karyotype and express CD30

Human embryonic stem cells (hESCs) are thought to be susceptible to chromosomal rearrangements as a consequence of single cell dissociation. Compared in this study are two methods of dissociation that do not generate single cell suspensions (collagenase and EDTA) with an enzymatic procedure using trypsin combined with the calcium-specific chelator EGTA (TEG), that does generate a single cell suspension, over 10 passages. Cells passaged by single cell dissociation using TEG retained a normal karyotype. However, cells passaged using EDTA, without trypsin, acquired an isochromosome p7 in three replicates of one experiment. In all of the TEG, collagenase and EDTA-treated cultures, cells retained consistent telomere length and potentiality, demonstrating that single cell dissociation can be used to maintain karyotypically and phenotypically normal hESCs. However, competitive genomic hybridization revealed that subkaryotypic deletions and amplifications could accumulate over time, reinforcing that present culture regimes remain suboptimal. In all cultures the cell surface marker CD30, reportedly expressed on embryonal carcinoma but not karyoptically normal ESCs, was expressed on hESCs with both normal and abnormal karyotype, but was upregulated on the latter. © 2008 Mary Ann Liebert, Inc