We present a detailed investigation of Hubble Space Telescope rest-frame UV/optical observations of 22 short gamma-ray burst (GRB) host galaxies and sub-galactic environments. Utilizing the high ...angular resolution and depth of HST we characterize the host galaxy morphologies, measure precise projected physical and host-normalized offsets between the bursts and host centers, and calculate the locations of the bursts with respect to their host light distributions (rest-frame UV and optical). We calculate a median short GRB projected physical offset of 4.5 kpc, about 3.5 times larger than that for long GRBs, and find that approx =25% of short GRBs have offsets of > ~10 kpc. When compared to their host sizes, the median offset is 1.5 half-light radii (re), about 1.5 times larger than the values for long GRBs, core-collapse supernovae, and Type Ia supernovae. In addition, approx =20% of short GRBs having offsets of > ~5re, and only approx =25% are located within 1re. We further find that short GRBs severely under-represent their hosts' rest-frame optical and UV light, with approx =30%-45% of the bursts located in regions of their host galaxies that have no detectable stellar light, and approx =55% in the regions with no UV light. Therefore, short GRBs do not occur in regions of star formation or even stellar mass. This demonstrates that the progenitor systems of short GRBs must migrate from their birth sites to their eventual explosion sites, a signature of kicks in compact object binary systems. Utilizing the full sample of offsets, we estimate natal kick velocities of approx =20-140 km s super(-1). These independent lines of evidence provide the strongest support to date that short GRBs result from the merger of compact object binaries (NS-NS/NS-BH).
Non-fullerene acceptors based organic solar cells represent the frontier of the field, owing to both the materials and morphology manipulation innovations. Non-radiative recombination loss ...suppression and performance boosting are in the center of organic solar cell research. Here, we developed a non-monotonic intermediate state manipulation strategy for state-of-the-art organic solar cells by employing 1,3,5-trichlorobenzene as crystallization regulator, which optimizes the film crystallization process, regulates the self-organization of bulk-heterojunction in a non-monotonic manner, i.e., first enhancing and then relaxing the molecular aggregation. As a result, the excessive aggregation of non-fullerene acceptors is avoided and we have achieved efficient organic solar cells with reduced non-radiative recombination loss. In PM6:BTP-eC9 organic solar cell, our strategy successfully offers a record binary organic solar cell efficiency of 19.31% (18.93% certified) with very low non-radiative recombination loss of 0.190 eV. And lower non-radiative recombination loss of 0.168 eV is further achieved in PM1:BTP-eC9 organic solar cell (19.10% efficiency), giving great promise to future organic solar cell research.
Graded bulk-heterojunction (G-BHJ) with well-defined vertical phase separation has potential to surpass classical BHJ in organic solar cells (OSCs). In this work, an effective G-BHJ strategy via ...nonhalogenated solvent sequential deposition is demonstrated using nonfullerene acceptor (NFA) OSCs. Spin-coated G-BHJ OSCs deliver an outstanding 17.48% power conversion efficiency (PCE). Depth-profiling X-ray photoelectron spectroscopy (DP-XPS) and angle-dependent grazing incidence X-ray diffraction (GI-XRD) techniques enable the visualization of polymer/NFA composition and crystallinity gradient distributions, which benefit charge transport, and enable outstanding thick OSC PCEs (16.25% for 300 nm, 14.37% for 500 nm), which are among the highest reported. Moreover, the nonhalogenated solvent enabled G-BHJ OSC via open-air blade coating and achieved a record 16.77% PCE. The blade-coated G-BHJ has drastically different D-A crystallization kinetics, which suppresses the excessive aggregation induced unfavorable phase separation in BHJ. All these make G-BHJ a feasible and promising strategy towards highly efficient, eco- and manufacture friendly OSCs.
Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs ...such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A new molecular model for the permeability of drugs and other physiologically important compounds to cross the blood–brain barrier has been developed. Permeability (log
PS
) is dependant on ...desolvation, lipophilicity, molecular volume and dipole moment. Previous models for BBB permeability have not considered desolvation and dipole moment as critical factors. The model applies to passive diffusion processes, and some facilitated diffusion processes. Passive permeability models may not apply to active transport processes, where complex membrane protein binding processes (e.g. stereoselectivity) are involved. Model phosphatidylcholine lipid bilayer membranes have been used to evaluate how charged or polar neutral compounds can interact through their molecular dipoles with the cell membrane to induce electromechanical changes in the cell membrane which facilitate permeation. The free energy of solvation in
n
-octanol has been shown to be a good measure of membrane lipophilicity by calculating the solvation free energy of a model PC lipid membrane in a series of closely related alcohols. The passive diffusion model for alcohols correlates with the known modulation of membrane bilayers which showed a size-dependent “cut-off” point in potency. For most drugs and related molecules, the neutral species are the permeating species.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The literature on the anti-neoplastic effects of Pt drugs provides substantial evidence that free radical may be involved in the formation of Pt-DNA adducts and other cytotoxic effects. The ...conditions specific to cancerous tumours are more conducive to free radical mechanisms than the commonly accepted hydrolysis nucleophilic–electrophilic mechanism of Pt-DNA adduct formation. Molecular orbital studies of the adiabatic attachment of hydrated electrons to Pt drugs reveal that there is a significant lengthening of the Pt–X bond (where X is Cl, O in cisplatin, carboplatin and some pyrophosphate-Pt drugs but not oxaliplatin) in the anion radical species. This observation is consistent with a dissociative electron transfer (DET) mechanism for the formation of Pt-DNA adducts. A DET reaction mechanism is proposed for the reaction of Pt drugs with guanine which involves a quasi-inner sphere 2 electron transfer process involving a transient intermediate 5 co-ordinated activated anion radical species {R2Pt---Cl(G)(Cl)•}*− (where R is an ammine group, and G is guanine) and the complex has an elongated Pt---Cl (or Pt---O) bond. A DET mechanism is also proposed when Pt drugs are activated by reaction with free radicals such as HO•, CO3•−, O2•− but do not react with DNA bases to form adducts, but form Pt-protein adducts with proteins such ezrin, FAS, DR5, TNFR1 etc. The DET mechanism may not occur with oxaliplatin.
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•Molecular mechanisms: Pt drugs.•Free radical mechanism.•Dissociative electron transfer.•Pt-DNA and Pt-protein adducts.•Molecular orbital calculations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Transcription is apparently risky business. Its intrinsic mutagenic potential must be kept in check by networks of DNA repair factors that monitor the transcription process to repair DNA lesions that ...could otherwise compromise transcriptional fidelity and genome integrity. Intriguingly, recent studies point to an even more direct function of DNA repair complexes as coactivators of transcription and the unexpected role of “scheduled” DNA damage/repair at gene promoters. Paradoxically, spontaneous DNA double-strand breaks also induce ectopic transcription that is essential for repair. Thus, transcription, DNA damage, and repair may be more physically and functionally intertwined than previously appreciated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We present ground-based optical and Hubble Space Telescope (HST) optical and near-IR observations of the short-hard GRB 130603B at z = 0.356, which demonstrate the presence of excess near-IR emission ...matching the expected brightness and color of an r-process powered transient (a "kilonova"). The early afterglow fades rapidly with alpha <, ~ -2.6 at t approximate 8-32 hr post-burst and has a spectral index of beta approximate -1.5 (F sub(v) proportional, variant t super( alpha ) v super( beta )), leading to an expected near-IR brightness at the time of the first HST observation of m sub(F160W)(t = 9.4 days) > ~ 29.3 AB mag. Instead, the detected source has m sub(F160W) = 25.8 + or - 0.2 AB mag, corresponding to a rest-frame absolute magnitude of M sub(J) approximate -15.2 mag. The upper limit in the HST optical observations is m sub(F606W) > ~ 27.7 AB mag (3sigma), indicating an unusually red color of V -H > ~ 1.9 mag. Comparing the observed near-IR luminosity to theoretical models of kilonovae produced by ejecta from the merger of an NS-NS or NS-BH binary, we infer an ejecta mass of M sub(ej) approximate 0.03-0.08 M sub(middot in circle) for upsilon sub(ej) approximate 0.1-0.3c. The inferred mass matches the expectations from numerical merger simulations. The presence of a kilonova provides the strongest evidence to date that short GRBs are produced by compact object mergers, and provides initial insight on the ejected mass and the primary role that compact object merger may play in the r-process. Equally important, it demonstrates that gravitational wave sources detected by Advanced LIGO/Virgo will be accompanied by optical/near-IR counterparts with unusually red colors, detectable by existing and upcoming large wide-field facilities (e.g., Pan-STARRS, DECam, Subaru, LSST).
Influenza virus infections are believed to spread mostly by close contact in the community. Social distancing measures are essential components of the public health response to influenza pandemics. ...The objective of these mitigation measures is to reduce transmission, thereby delaying the epidemic peak, reducing the size of the epidemic peak, and spreading cases over a longer time to relieve pressure on the healthcare system. We conducted systematic reviews of the evidence base for effectiveness of multiple mitigation measures: isolating ill persons, contact tracing, quarantining exposed persons, school closures, workplace measures/closures, and avoiding crowding. Evidence supporting the effectiveness of these measures was obtained largely from observational studies and simulation studies. Voluntary isolation at home might be a more feasible social distancing measure, and pandemic plans should consider how to facilitate this measure. More drastic social distancing measures might be reserved for severe pandemics.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The transcriptional activators Oct4, Sox2, and Nanog cooperate with a wide array of cofactors to orchestrate an embryonic stem (ES) cell-specific gene expression program that forms the molecular ...basis of pluripotency. Here, we report using an unbiased in vitro transcription-biochemical complementation assay to discover a multisubunit stem cell coactivator complex (SCC) that is selectively required for the synergistic activation of the
Nanog gene by Oct4 and Sox2. Purification, identification, and reconstitution of SCC revealed this coactivator to be the trimeric XPC-nucleotide excision repair complex. SCC interacts directly with Oct4 and Sox2 and is recruited to the
Nanog and
Oct4 promoters as well as a majority of genomic regions that are occupied by Oct4 and Sox2. Depletion of SCC/XPC compromised both pluripotency in ES cells and somatic cell reprogramming of fibroblasts to induced pluripotent stem (iPS) cells. This study identifies a transcriptional coactivator with diversified functions in maintaining ES cell pluripotency and safeguarding genome integrity.
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► Transcriptional activation of
Nanog by Oct4 and Sox2 requires a stem cell coactivator (SCC) ► SCC is identical to the XPC-RAD23B-CETN2 nucleotide excision repair complex ► SCC binds Oct4 and Sox2 and co-occupies many of their target genes in ES cells ► SCC is required for stem cell maintenance and efficient somatic cell reprogramming
Transcription of key pluripotency genes in ESCs relies on Oct4 and Sox2's cooperation with a complex of DNA repair proteins at promoters.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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