Notes

COVID-19 in Cladribine-treated individual with ms.
Glacial landforms, including lobate debris aprons, are a global water ice reservoir on Mars preserving ice from past periods when high orbital obliquity permitted nonpolar ice accumulation. Numerous studies have noted morphological similarities between lobate debris aprons and terrestrial debris-covered glaciers, an interpretation supported by radar observations. On Earth and Mars, these landforms consist of a core of flowing ice covered by a rocky lag. Terrestrial debris-covered glaciers advance in response to climate forcing driven by obliquity-paced changes to ice mass balance. However, on Mars, it is not known whether glacial landforms emplaced over the past 300 to 800 formed during a single, long deposition event or during multiple glaciations. Here, we show that boulders atop 45 lobate debris aprons exhibit no evidence of monotonic comminution but are clustered into bands that become more numerous with increasing latitude, debris apron length, and pole-facing flow orientation. Boulder bands are prominent at glacier headwalls, consistent with debris accumulation during the current Martian interglacial. Terrestrial glacier boulder bands occur near flow discontinuities caused by obliquity-driven hiatuses in ice accumulation, forming internal debris layers. By analogy, we suggest that Martian lobate debris aprons experienced multiple cycles of ice deposition, followed by ice destabilization in the accumulation zone, leading to boulder-dominated lenses and subsequent ice deposition and continued flow. Correlation between latitude and boulder clustering suggests that ice mass-balance works across global scales on Mars. Lobate debris aprons may preserve ice spanning multiple glacial/interglacial cycles, extending Mars climate records back hundreds of millions of years.In biosynthesis of the pancreatic cancer drug streptozotocin, the tridomain nonheme-iron oxygenase SznF hydroxylates Nδ and Nω' of Nω-methyl-l-arginine before oxidatively rearranging the triply modified guanidine to the N-methyl-N-nitrosourea pharmacophore. A previously published structure visualized the monoiron cofactor in the enzyme's C-terminal cupin domain, which promotes the final rearrangement, but exhibited disorder and minimal metal occupancy in the site of the proposed diiron cofactor in the N-hydroxylating heme-oxygenase-like (HO-like) central domain. We leveraged our recent observation that the N-oxygenating µ-peroxodiiron(III/III) intermediate can form in the HO-like domain after the apo protein self-assembles its diiron(II/II) cofactor to solve structures of SznF with both of its iron cofactors bound. These structures of a biochemically validated member of the emerging heme-oxygenase-like diiron oxidase and oxygenase (HDO) superfamily with intact diiron cofactor reveal both the large-scale conformational change required to assemble the O2-reactive Fe2(II/II) complex and the structural basis for cofactor instability-a trait shared by the other validated HDOs. During cofactor (dis)assembly, a ligand-harboring core helix dynamically (un)folds. The diiron cofactor also coordinates an unanticipated Glu ligand contributed by an auxiliary helix implicated in substrate binding by docking and molecular dynamics simulations. The additional carboxylate ligand is conserved in another N-oxygenating HDO but not in two HDOs that cleave carbon-hydrogen and carbon-carbon bonds to install olefins. Among ∼9,600 sequences identified bioinformatically as members of the emerging HDO superfamily, ∼25% conserve this additional carboxylate residue and are thus tentatively assigned as N-oxygenases.We analyze the zero-temperature phases of an array of neutral atoms on the kagome lattice, interacting via laser excitation to atomic Rydberg states. Density-matrix renormalization group calculations reveal the presence of a wide variety of complex solid phases with broken lattice symmetries. In addition, we identify a regime with dense Rydberg excitations that has a large entanglement entropy and no local order parameter associated with lattice symmetries. From a mapping to the triangular lattice quantum dimer model, and theories of quantum phase transitions out of the proximate solid phases, we argue that this regime could contain one or more phases with topological order. Our results provide the foundation for theoretical and experimental explorations of crystalline and liquid states using programmable quantum simulators based on Rydberg atom arrays.Variation in gene regulation is ubiquitous, yet identifying the mechanisms producing such variation, especially for complex traits, is challenging. read more Snake venoms provide a model system for studying the phenotypic impacts of regulatory variation in complex traits because of their genetic tractability. Here, we sequence the genome of the Tiger Rattlesnake, which possesses the simplest and most toxic venom of any rattlesnake species, to determine whether the simple venom phenotype is the result of a simple genotype through gene loss or a complex genotype mediated through regulatory mechanisms. We generate the most contiguous snake-genome assembly to date and use this genome to show that gene loss, chromatin accessibility, and methylation levels all contribute to the production of the simplest, most toxic rattlesnake venom. We provide the most complete characterization of the venom gene-regulatory network to date and identify key mechanisms mediating phenotypic variation across a polygenic regulatory network.We have studied the role of protein dynamics in chemical catalysis in the enzyme dihydrofolate reductase (DHFR), using a pump-probe method that employs pulsed-laser photothermal heating of a gold nanoparticle (AuNP) to directly excite a local region of the protein structure and transient absorbance to probe the effect on enzyme activity. Enzyme activity is accelerated by pulsed-laser excitation when the AuNP is attached close to a network of coupled motions in DHFR (on the FG loop, containing residues 116-132, or on a nearby alpha helix). No rate acceleration is observed when the AuNP is attached away from the network (distal mutant and His-tagged mutant) with pulsed excitation, or for any attachment site with continuous wave excitation. We interpret these results within an energy landscape model in which transient, site-specific addition of energy to the enzyme speeds up the search for reactive conformations by activating motions that facilitate this search.
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