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Model-based prioritization for acquiring protection
No full textProtection often involves the capacity to prospectively plan the actions needed to mitigate harm. The computational architecture of decisions involving protection remains unclear, as well as whether these decisions differ from other beneficial prospective actions such as reward acquisition. Here we compare protection acquisition to reward acquisition and punishment avoidance to examine overlapping and distinct features across the three action types. Protection acquisition is positively valenced similar to reward. For both protection and reward, the more the actor gains, the more benefit. However, reward and protection occur in different contexts, with protection existing in aversive contexts. Punishment avoidance also occurs in aversive contexts, but differs from protection because punishment is negatively valenced and motivates avoidance. Across three independent studies (Total N = 600) we applied computational modeling to examine model-based reinforcement learning for protection, reward, and punishment in humans. Decisions motivated by acquiring protection evoked a higher degree of model-based control than acquiring reward or avoiding punishment, with no significant differences in learning rate. The context-valence asymmetry characteristic of protection increased deployment of flexible decision strategies, suggesting model-based control depends on the context in which outcomes are encountered as well as the valence of the outcome
Pohlite, a new lead iodate hydroxide chloride from Sierra Gorda, Chile
No full textThe new mineral pohlite (IMA2022–043), Pb₇(IO₃)(OH)₄Cl₉, was found at La Compania mine, Sierra Gorda, Antofagasta Province, Antofagasta, Chile, where it occurs in cavities in an oxidised portion of a quartz vein in association with massive aragonite and anhydrite. Pohlite crystals are transparent, colourless to pale grey blades, up to 4 mm in length. The mineral has a white streak, adamantine lustre and is nonfluorescent. It is brittle with irregular, conchoidal fracture. The Mohs hardness is ~2½ and it has no cleavage. The calculated density is 5.838(2) g cm⁻³. Optically, the mineral is biaxial (+) with α v dispersion; orientation: Y ∧ a ≈ 20°, Z ∧ b ≈ 30°; and is nonpleochroic. The Raman spectrum exhibits bands consistent with IO₃⁻ and O–H. Electron microprobe analysis provided the empirical formula Pb_(6.74)I_(1.00)Cl_(9.29)O_(6.71)H_(4.23). The five strongest powder X-ray diffraction lines are [d_(obs) Å(I)(hkl)]: 3.818(91)(023, 122, 11), 3.674(85)(1, 22, 200, 104), 3.399(47)(10, 210, 04), 2.378(100)(302, 041, 24) and 1.9943(45)(multiple). Pohlite is triclinic, P, a = 7.3366(5), b = 9.5130(9), c = 16.2434(15) Å, α = 81.592(7), β = 84.955(7), γ = 89.565(6)°, V = 1117.13(17) Å3 and Z = 2. The structure of pohlite (R1 = 0.0328 for 3394 I > 2σI) contains two types of clusters, a [Pb₄(OH)₃]⁵⁺ cluster formed by short Pb–O bonds and a [Pb₃(OH)(IO₃)]₂⁸⁺ ‘double cluster’ formed by short I–O bonds and short- to medium-length Pb–O bonds. Long Pb–Cl and I–Cl bonds link the clusters together in three dimensions
Analysis of Gene Expression Heterogeneity Reveals Therapeutic Targets and Novel Regulators of Metastasis
No full textTumor cell heterogeneity has been implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. We hypothesized that genes with low cell-to-cell transcriptional variability may be effective therapeutic targets, and that analysis of variability may facilitate identification of new metastatic regulators. Here we demonstrate, using single cell RNA sequencing, that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) reduced overall transcriptional variability in TNBC xenograft tumors. Focusing on genes with reduced variability in response to RKIP, we identified targetable gene sets such as oxidative phosphorylation and showed that metformin could inhibit RKIP-expressing but not control tumor growth. We also found many regulators of cancer progression including a novel epigenetic metastasis suppressor, KMT5C. These studies demonstrate that a metastatic regulator can alter transcriptional variability in tumors and reveal the importance of genes involved in heterogeneity as potential therapeutic targets and regulators of metastatic progression in cancer
Annotation-agnostic discovery of associations between novel gene isoforms and phenotypes
No full textWe present a novel method for associating phenotypes with RNA expression, that can identify expression associations resulting from a wide variety of underlying transcriptional and post-transcriptional events, without relying on annotations of these events. We show that we can reliably detect,de novo, phenotypically relevant transcriptional structure
Differential Stability of Task Variable Representations in Retrosplenial Cortex
No full textCortical neurons store information across different timescales, from seconds to years. Although information stability is variable across regions, it can vary within a region as well. Association areas are known to multiplex behaviorally relevant variables, but the stability of their representations is not well understood. Here, we longitudinally recorded the activity of neuronal populations in the retrosplenial cortex (RSC) during the performance of a context-choice association task. We found that the activity of neurons exhibits different levels of stability across days. Using linear classifiers, we quantified the stability of three task relevant variables. We find that RSC representations of context and trial outcome display higher stability than motor choice, both at the single cell and population levels. Together, our findings show an important characteristic of association areas, where diverse information is stored with varying levels of stability, maintaining an adequate balance between stability and flexibility to subserve behavioral demands
Transient and delay chemical master equations
No full textThe serial nature of reactions involved in the RNA life-cycle motivates the incorporation of delays in models of transcriptional dynamics. The models couple a bursty or switching promoter to a fairly general set of Markovian or deterministically delayed monomolecular RNA interconversion reactions with no feedback. We provide numerical solutions for the RNA copy number distributions the models induce, and solve several systems with splicing and degradation. An analysis of single-cell and single-nucleus RNA sequencing data using these models reveals that the kinetics of nuclear export do not appear to require invocation of a non-Markovian waiting time
The Phosphate Deprivation Response is Mediated by an Interaction between Brassinosteroid Signaling and Zinc in Tomato
No full textPhosphate is a necessary macronutrient for basic biological processes, plant growth, and agriculture. Plants modulate their root system architecture and cellular processes to adapt to phosphate deprivation albeit with a growth penalty. Excess application of phosphate fertilizer, on the other hand, leads to eutrophication and has a negative environmental impact. Moreover, phosphate mined from rock reserves is a finite and non-recyclable resource and its levels are nearing complete depletion. Here, we show that Solanum pennellii, a wild relative of tomato, is partially insensitive to phosphate deprivation. Furthermore, it mounts a constitutive response under phosphate sufficiency. We demonstrate that activated brassinosteroid signaling through a tomato BZR1 ortholog gives rise to the same constitutive phosphate deficiency response, which is dependent on zinc over-accumulation. Collectively, these results reveal an additional strategy by which plants can adapt to phosphate starvation
Prediction and experimental validation of drug candidates that bind specifically to the SARS-CoV-2 receptor-binding domain to prevent entry via Angiotensin-converting enzyme 2 (ACE2)
No full textThe COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (SARS-CoV-2) virus has created enormous public health and economic crises. The SARS-CoV-2 spike protein binds to its host receptor, human angiotensin-converting enzyme 2 (hACE2), through its receptor binding domain (RBD) and is proteolytically activated by human protease TMPRSS2 to process the SARS-CoV-2 spike protein to facilitate host cell entry. To identify new candidate drugs to inhibit binding of the RBD to hACE2 (the first step of virus entry), we used in silico screening (Phase VS from Schrӧdinger) to predict the RBD binding site and energetics for molecules in the ZINC FDA approved Drug Bank database (1,657 drugs), which includes clinical trial drugs approved by FDA. Using a pharmacophore (1 acceptor, 1 donor, 3 negatively charged, 1 positively charged) derived from the 2.5-Å X-ray structure SARS-CoV-2 RBD complexed with hACE2 (PDB ID: 6LZG), we found 29 unique hits. To refine the binding energies and bonding sites, we applied our DarwinDock complete sampling method, predicting that 4 of these 29 should bind strongly to the RBD site. Next, we tested 3 of these experimentally using FLOWER, a label-free optical whispering gallery mode sensing technique that can measure ligand-receptor binding affinities down to attomolar levels. We measure that methotrexate (MTX) and Diethylenetriamine pentaacetate (DTPA) bind with an inhibitory constant (Ki) of 0.2 pM in Tricine buffer, which is 1.832 million fold increase in binding strength compared to hACE2 (Kd: 366.4 nM). We then tested these ligands against common mutations: alpha, delta, and omicron. Our measured binding studies demonstrate that MTX provides inhibition against all four variants of SARS-coV-2. Indeed, the clinical and experimental data have shown that humans taking WT MTX are protected against infection by SARS-CoV-2
Toward liquid cell quantum sensing: Ytterbium complexes with ultra-narrow absorption
No full textIn quantum technology (such as atomic vapor cells used in precision magnetometry), the energetic disorder induced by a fluctuating liquid environment acts in direct opposition to the precise control required for coherence-based sensing. Overcoming fluctuations requires a protected quantum subspace that only weakly interacts with the local environment. Herein, we report a ferrocene-supported ytterbium complex ((thiolfan)YbCl(THF), thiolfan = 1,1′-bis(2,4-di-tert-butyl-6-thiomethylenephenoxy)ferrocene) that exhibits an extraordinarily narrow absorption linewidth in solution at room temperature with a full-width at half-maximum of 0.625 ± 0.006 meV. A detailed spectroscopic analysis allows us to assign all near infrared (NIR) transitions to atom-centered f-f transitions, protected from the solvent environment. A combination of density functional theory and multireference methods match experimental transition energies and oscillator strengths, illustrating the role of spin-orbit coupling and asymmetric ligand field in enhancing absorption and pointing toward molecular design principles that create well-protected yet observable electronic transitions in lanthanide complexes. Narrow linewidths allow for a demonstration of extremely low-field magnetic circular dichroism at room temperature, employed to sense and image magnetic fields, down to Earth scale. We term this system an ‘atom-like molecular sensor’ (ALMS), and propose approaches to improve its performance
A scalable and continuous access to pure cyclic polymers enabled by quarantined heterogeneous catalysts
No full textCyclic polymers are topologically interesting and envisioned as a lubricant material. However, scalable synthesis of pure cyclic polymers remains elusive. The most straightforward way is to recycle a used catalyst for the synthesis of cyclic polymers. Unfortunately, it is demanding because of the catalyst’s vulnerability and inseparability from polymers, which depreciates the practicality of the process. Here, we develop a continuous process streamlined in a circular way that polymerization, polymer separation, and catalyst recovery happen in situ, to dispense a pure cyclic polymer after bulk ring-expansion metathesis polymerization of cyclopentene. It is enabled by introducing silica-supported ruthenium catalysts and a newly-designed glassware. Also, different depolymerization kinetics of the cyclic polymer from its linear analogue is discussed. This process minimizes manual labor, maximizes security of vulnerable catalysts, and guarantees purity of cyclic polymers, thereby showcasing a prototype of a scalable access to cyclic polymers with increased reusability of precious catalysts (≥415,000 turnovers)