Crisis in Ukraine: Humanitarian and Human Rights Imperatives

The Refugees International Investigation:From March 2 through March 9, 2022, a Refugees International (RI) team traveled to Poland in the wake of the renewed Russian invasion of Ukraine. The team traveled some 600 miles in eastern Poland, visiting border crossings and reception areas in cities hosting people who had fled Ukraine. They met with refugees; members of Polish civil society; and United Nations, U.S. government, and Polish officials.The Ukraine Crisis:As a result of the Russian invasion, Ukraine is in a human rights and humanitarian crisis. About 6.48 million people are estimated to be displaced within the borders of Ukraine, and more than 3.3 million people have fled Ukraine, becoming refugees. The vast majority of refugees are women and children, who are at particular risk of trafficking, sexual exploitation, and gender-based violence. More than 2 million of the refugees are in Poland.The Global Response:The speed and breadth of the international response to the crisis has been unprecedented and generous, with the European Union, the United States, and other donor governments contributing generously to aid efforts. The EU is providing legal status and protections to people who have sought or are seeking refuge from the war in EU countries. A very welcome development, it stands in sharp contrast to European responses to refugee flight from outside the continent—but should be the norm.Refugees in Poland (And Elsewhere in the Region):In Poland and other receiving countries, the UN, EU, and other donors must support governments and civil society to meet refugees' reception and integration needs in the immediate and longer term. These include safe accommodation, medical and mental healthcare, and access to education and employment. An effective response will be grounded in local civil society organizations, investing in their capacity to scale existing services. Swiftly developing government initiatives to responsibly collect and share information about aid efforts within and across borders is necessary to strengthen protections and avoid trafficking, exploitation, and other rights abuses in the region.Unfortunately, non-Ukrainians—in particular Black and brown individuals—who have fled Ukraine have faced greater obstacles in reception and integration, with problems emerging on both sides of borders. The Office of the United Nations High Commissioner for Refugees (UNHCR), the EU, and other leaders have publicly urged that everyone fleeing Ukraine be allowed into the EU, regardless of race or nationality.The Humanitarian Crisis within Ukraine's Borders:Even as States take on the responsibility of welcoming refugees fleeing Ukraine—a challenge Europe can manage—they must give urgent attention to what is emerging as a far more formidable challenge: the humanitarian emergency within Ukraine. Conflict, and especially the Russian bombardment of civilian institutions and inability of civilians to flee in safety, has created an overwhelming internal crisis, exacerbating an already dire situation. Moreover, several factors suggest that the situation will become even more desperate. In particular, as the Russian military's offensive has become frustrated, it is laying siege to population centers and creating enormous suffering.War Crimes and Crimes Against Humanity in Ukraine:Refugees International is persuaded that the Russian military and the Russian government are responsible for war crimes and crimes against humanity in Ukraine. They must end such abuses and must be held accountable for a broad range of widespread, indiscriminate, and what clearly appear to be cruel, deliberate, and unprovoked attacks against civilians in Ukraine and against civilian institutions

DNA cruciform arms nucleate through a correlated but non-synchronous cooperative mechanism

Inverted repeat (IR) sequences in DNA can form non-canonical cruciform structures to relieve torsional stress. We use Monte Carlo simulations of a recently developed coarse-grained model of DNA to demonstrate that the nucleation of a cruciform can proceed through a cooperative mechanism. Firstly, a twist-induced denaturation bubble must diffuse so that its midpoint is near the centre of symmetry of the IR sequence. Secondly, bubble fluctuations must be large enough to allow one of the arms to form a small number of hairpin bonds. Once the first arm is partially formed, the second arm can rapidly grow to a similar size. Because bubbles can twist back on themselves, they need considerably fewer bases to resolve torsional stress than the final cruciform state does. The initially stabilised cruciform therefore continues to grow, which typically proceeds synchronously, reminiscent of the S-type mechanism of cruciform formation. By using umbrella sampling techniques we calculate, for different temperatures and superhelical densities, the free energy as a function of the number of bonds in each cruciform along the correlated but non-synchronous nucleation pathways we observed in direct simulations.Comment: 12 pages main paper + 11 pages supplementary dat

A perfect palindrome in the Escherichia coli chromosome forms DNA hairpins on both leading- and lagging-strands

DNA palindromes are hotspots for DNA double strand breaks, inverted duplications and intra-chromosomal translocations in a wide spectrum of organisms from bacteria to humans. These reactions are mediated by DNA secondary structures such as hairpins and cruciforms. In order to further investigate the pathways of formation and cleavage of these structures, we have compared the processing of a 460 base pair (bp) perfect palindrome in the Escherichia coli chromosome with the same construct interrupted by a 20 bp spacer to form a 480 bp interrupted palindrome. We show here that the perfect palindrome can form hairpin DNA structures on the templates of the leading- and lagging-strands in a replication-dependent reaction. In the presence of the hairpin endonuclease SbcCD, both copies of the replicated chromosome containing the perfect palindrome are cleaved, resulting in the formation of an unrepairable DNA double-strand break and cell death. This contrasts with the interrupted palindrome, which forms a hairpin on the lagging-strand template that is processed to form breaks, which can be repaired by homologous recombination

Unusually Long Palindromes Are Abundant in Mitochondrial Control Regions of Insects and Nematodes

BACKGROUND: Palindromes are known to be involved in a variety of biological processes. In the present investigation we carried out a comprehensive analysis of palindromes in the mitochondrial control regions (CRs) of several animal groups to study their frequency, distribution and architecture to gain insights into the origin of replication of mtDNA. METHODOLOGY/PRINCIPAL FINDINGS: Many species of Arthropoda, Nematoda, Mollusca and Annelida harbor palindromes and inverted repeats (IRs) in their CRs. Lower animals like cnidarians and higher animal groups like chordates are almost devoid of palindromes and IRs. The study revealed that palindrome occurrence is positively correlated with the AT content of CRs, and that IRs are likely to give rise to longer palindromes. CONCLUSIONS/SIGNIFICANCE: The present study attempts to explain possible reasons and gives in silico evidence for absence of palindromes and IRs from CR of vertebrate mtDNA and acquisition and retention of the same in insects. Study of CRs of different animal phyla uncovered unique architecture of this locus, be it high abundance of long palindromes and IRs in CRs of Insecta and Nematoda, or short IRs of 10–20 nucleotides with a spacer region of 12–14 bases in subphylum Chelicerata, or nearly complete of absence of any long palindromes and IRs in Vertebrata, Cnidaria and Echinodermata

A Ligand Peptide Motif Selected from a Cancer Patient Is a Receptor-Interacting Site within Human Interleukin-11

Interleukin-11 (IL-11) is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC). Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i) the peptide mimics a receptor-binding site within IL-11, (ii) the binding of CGRRAGGSC to the IL-11Rα is functionally relevant, (iii) Arg4 and Ser8 are the key residues mediating the interaction, and (iv) the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11Rα has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs

Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA

We develop a statistical mechanical model to analyze the competitive behavior of transitions to multiple alternate conformations in a negatively supercoiled DNA molecule of kilobase length and specified base sequence. Since DNA superhelicity topologically couples together the transition behaviors of all base pairs, a unified model is required to analyze all the transitions to which the DNA sequence is susceptible. Here we present a first model of this type. Our numerical approach generalizes the strategy of previously developed algorithms, which studied superhelical transitions to a single alternate conformation. We apply our multi-state model to study the competition between strand separation and B-Z transitions in superhelical DNA. We show this competition to be highly sensitive to temperature and to the imposed level of supercoiling. Comparison of our results with experimental data shows that, when the energetics appropriate to the experimental conditions are used, the competition between these two transitions is accurately captured by our algorithm. We analyze the superhelical competition between B-Z transitions and denaturation around the c-myc oncogene, where both transitions are known to occur when this gene is transcribing. We apply our model to explore the correlation between stress-induced transitions and transcriptional activity in various organisms. In higher eukaryotes we find a strong enhancement of Z-forming regions immediately 5′ to their transcription start sites (TSS), and a depletion of strand separating sites in a broad region around the TSS. The opposite patterns occur around transcript end locations. We also show that susceptibility to each type of transition is different in eukaryotes and prokaryotes. By analyzing a set of untranscribed pseudogenes we show that the Z-susceptibility just downstream of the TSS is not preserved, suggesting it may be under selection pressure