A Nation Going Under: Legal Protection for “Climate Change Refugees”

Climate change-related disasters displace millions of people each year. Small island states in the Pacific have become emblematic of the problem because they are among the most impacted and the most vulnerable. Often portrayed by global media as drowning beneath the sea, these states are struggling for their very survival. Many of their residents are looking to move overseas, but face a lack of legal options to migrate. A test case in New Zealand from a Kiribati national claiming to be a “climate change refugee” highlights the difficulty of fitting climate-induced migrants into the Refugee Convention mold. To grant refuge, deemed the persecutor, would have turned the refugee paradigm on its head. This case reveals the wide protection gap left by existing domestic and international laws for those hoping to flee their sinking homes. To fill this gap, it will be essential for domestic, regional, and multilateral bodies to proactively work together in developing and implementing effective strategies for migration

The Buck Stops Here: Fundamental Rights Infringements Can No Longer Be Ignored When Transferring Asylum Seekers Under \u3cem\u3eDublin II\u3c/em\u3e

Many asylum seekers entering the European Union (EU) cross more than one Member State border before lodging their asylum claims. In response, the EU adopted Dublin II to designate the point of first entry, rather than the point of application, as the State responsible for examining the claim. Unfortunately, this allocation of examination responsibilities overburdens States on the frontline of entry, such as Greece, and has exacerbated the systemic deficiencies in these states’ asylum systems. The Court of Justice of the European Union’s decision in the Joined Cases C-411/10 & C-493/10 helped clarify that a receiving state cannot transfer asylum seekers to the responsible state if they would be subjected to inhumane treatment there. Although this decision halted Dublin II transfers to states where fundamental rights risked being violated, the EU continues to struggle with an unbalanced distribution of asylum claims. Until the principle of solidarity is put into practice and more claims are shifted to lesser-burdened states, the EU will not meet its goal of creating a fair and effective Common European Asylum Policy

Distinguishing Look-Alike Innocent and Vulnerable Code by Subtle Semantic Representation Learning and Explanation

Though many deep learning (DL)-based vulnerability detection approaches have been proposed and indeed achieved remarkable performance, they still have limitations in the generalization as well as the practical usage. More precisely, existing DL-based approaches (1) perform negatively on prediction tasks among functions that are lexically similar but have contrary semantics; (2) provide no intuitive developer-oriented explanations to the detected results. In this paper, we propose a novel approach named SVulD, a function-level Subtle semantic embedding for Vulnerability Detection along with intuitive explanations, to alleviate the above limitations. Specifically, SVulD firstly trains a model to learn distinguishing semantic representations of functions regardless of their lexical similarity. Then, for the detected vulnerable functions, SVulD provides natural language explanations (e.g., root cause) of results to help developers intuitively understand the vulnerabilities. To evaluate the effectiveness of SVulD, we conduct large-scale experiments on a widely used practical vulnerability dataset and compare it with four state-of-the-art (SOTA) approaches by considering five performance measures. The experimental results indicate that SVulD outperforms all SOTAs with a substantial improvement (i.e., 23.5%-68.0% in terms of F1-score, 15.9%-134.8% in terms of PR-AUC and 7.4%-64.4% in terms of Accuracy). Besides, we conduct a user-case study to evaluate the usefulness of SVulD for developers on understanding the vulnerable code and the participants' feedback demonstrates that SVulD is helpful for development practice.Comment: Accepted By FSE'2

Overexpression of DNA damage-induced 45 α gene contributes to esophageal squamous cell cancer by promoter hypomethylation

<p>Abstract</p> <p>Background</p> <p>Environmental factors-induced dysfunction of esophageal squamous epithelium, including genomic DNA impairment and apoptosis, play an important role in the pathogenesis of esophageal squamous cell cancer. DNA damage-induced 45α (GADD45α) has been found promoting DNA repair and removing methylation marker, Therefore, in this study we will investigate whether GADD45α expression is induced and its mechanism in esophageal squamous cell cancer.</p> <p>Methods</p> <p>Two human esophageal squamous cell lines (ESCC), ECA109 and KYSE510 were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). Lipofectamine 2000 was used to transfect cells. mRNA level of GADD45α was measured by reverse transcription-quantitive PCR (RT-qPCR), protein level of GADD45α was detected by western blot and Immunohistochemistry. Global DNA methylation of tissue sample was measured using the Methylamp Global DNA Methylation Quantification Ultra kit (Epigentek Group) and promoter methylation was measured by bisulfite sequencing.</p> <p>Results</p> <p>GADD45a mRNA and protein levels were increased significantly in tumor tissue than that in adjacent normal tissue. Hypomethylation of global genomic DNA and GADD45α promoter were found in ESCC. The cell sensitivity to Cisplatin DDP was decreased significantly in Eca109 and Kyse510 cells, in which GADD45α expression was down-regulated by RNA interference (RNAi). In addition, silence of GADD45a expression in ESCC cells inhibited proliferation and promoted apoptosis.</p> <p>Conclusion</p> <p>Overexpression of GADD45α gene is due to DNA hypomethylation in ESCC. GADD45α may be a protective factor in DDP chemotherapy for esophageal squamous cell carcinoma.</p

Recognition of cavitation characteristics in non-clogging pumps based on the improved Lévy flight bat algorithm

The performance and operational stability of non-clogging pumps can be affected by cavitation. To accurately identify the cavitation state of the non-clogging pump and provide technical references for monitoring its operation, a study was conducted on the optimization of Elman neural networks for cavitation monitoring and identification using the Improved Lévy Flight Bat Algorithm (ILBA) on the basis of the traditional Bat Algorithm (BA). The ILBA employs multiple bats to interact and search for targets and utilizes the local search strategy of Lévy flight, effectively avoiding local minima by taking advantage of the non-uniform random walk characteristics of large jumps. The ILBA algorithm demonstrates superior performance compared to other traditional algorithms through simulation testing and comparative calculations with eight benchmark test functions. On this basis, the optimization of the weights and thresholds of the Elman neural network was carried out by the improved bat algorithm. This leads to an enhancement in the accuracy of the neural network for identifying and classifying cavitation data, and the establishment of the ILBA-Elman cavitation diagnosis model was achieved. Collect pressure pulsation signals at the tongue of the non-clogging pump volute through cavitation tests. Through the cavitation feature extraction method based on Variational Mode Decomposition (VMD) and Multi-scale Dispersion Entropy (MDE), the interference signal can be effectively suppressed and the complexity of the time series can be measured from multiple angles, thereby creating a cavitation feature data set. The improved cavitation diagnosis model (ILBA-Elman) can realize the effective identification of the cavitation characteristics of non-clogging pumps through a variety of algorithm comparison experiments

Crystal structure and centromere binding of the plasmid segregation protein ParB from pCXC100

Plasmid pCXC100 from the Gram-positive bacterium Leifsonia xyli subsp. cynodontis uses a type Ib partition system that includes a centromere region, a Walker-type ATPase ParA and a centromere-binding protein ParB for stable segregation. However, ParB shows no detectable sequence homology to any DNA-binding motif. Here, we study the ParB centromere interaction by structural and biochemical approaches. The crystal structure of the C-terminal DNA-binding domain of ParB at 1.4 Å resolution reveals a dimeric ribbon–helix–helix (RHH) motif, supporting the prevalence of RHH motif in centromere binding. Using hydroxyl radical footprinting and quantitative binding assays, we show that the centromere core comprises nine uninterrupted 9-nt direct repeats that can be successively bound by ParB dimers in a cooperative manner. However, the interaction of ParB with a single subsite requires 18 base pairs covering one immediate repeat as well as two halves of flanking repeats. Through mutagenesis, sequence specificity was determined for each position of an 18-bp subsite. These data suggest an unique centromere recognition mechanism by which the repeat sequence is jointly specified by adjacent ParB dimers bound to an overlapped region

Inflammatory osteolysis is regulated by site-specific ISGylation of the scaffold protein NEMO

Inflammatory osteolysis is governed by exacerbated osteoclastogenesis. Ample evidence points to central role of NF-κB in such pathologic responses, yet the precise mechanisms underpinning specificity of these responses remain unclear. We propose that motifs of the scaffold protein IKKγ/NEMO partly facilitate such functions. As proof-of-principle, we used site-specific mutagenesis to examine the role of NEMO in mediating RANKL-induced signaling in mouse bone marrow macrophages, known as osteoclast precursors. We identified lysine (K)270 as a target regulating RANKL signaling as K270A substitution results in exuberant osteoclastogenesis in vitro and murine inflammatory osteolysis in vivo. Mechanistically, we discovered that K270A mutation disrupts autophagy, stabilizes NEMO, and elevates inflammatory burden. Specifically, K270A directly or indirectly hinders binding of NEMO to ISG15, a ubiquitin-like protein, which we show targets the modified proteins to autophagy-mediated lysosomal degradation. Taken together, our findings suggest that NEMO serves as a toolkit to fine-tune specific signals in physiologic and pathologic conditions

Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays.

Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development.This work is part of the ‘‘SpatioTemporal Omics Consortium’’ (STOC) paper package. A list of STOC members is available at: http://sto-consortium.org. We would like to thank the MOTIC China Group, Rongqin Ke (Huaqiao University, Xiamen, China), Jiazuan Ni (Shenzhen University, Shenzhen, China), Wei Huang (Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China), and Jonathan S. Weissman (Whitehead Institute, Boston, USA) for their help. This work was supported by the grant of Top Ten Foundamental Research Institutes of Shenzhen, the Shenzhen Key Laboratory of Single-Cell Omics (ZDSYS20190902093613831), and the Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011); Longqi Liu was supported by the National Natural Science Foundation of China (31900466) and Miguel A. Esteban’s laboratory at the Guangzhou Institutes of Biomedicine and Health by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502), National Natural Science Foundation of China (92068106), and the Guangdong Basic and Applied Basic Research Foundation (2021B1515120075).S

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data