Universality in long-distance geometry and quantum complexity.

In physics, two systems that radically differ at short scales can exhibit strikingly similar macroscopic behaviour: they are part of the same long-distance universality class1. Here we apply this viewpoint to geometry and initiate a program of classifying homogeneous metrics on group manifolds2 by their long-distance properties. We show that many metrics on low-dimensional Lie groups have markedly different short-distance properties but nearly identical distance functions at long distances, and provide evidence that this phenomenon is even more robust in high dimensions. An application of these ideas of particular interest to physics and computer science is complexity geometry3-7-the study of quantum computational complexity using Riemannian geometry. We argue for the existence of a large universality class of definitions of quantum complexity, each linearly related to the other, a much finer-grained equivalence than typically considered. We conjecture that a new effective metric emerges at larger complexities that describes a broad class of complexity geometries, insensitive to various choices of microscopic penalty factors. We discuss the implications for recent conjectures in quantum gravity.

Forest regeneration within Earth system models: current process representations and ways forward.

Earth system models must predict forest responses to global change in order to simulate future global climate, hydrology, and ecosystem dynamics. These models are increasingly adopting vegetation demographic approaches that explicitly represent tree growth, mortality, and recruitment, enabling advances in the projection of forest vulnerability and resilience, as well as evaluation with field data. To date, simulation of regeneration processes has received far less attention than simulation of processes that affect growth and mortality, in spite of their critical role maintaining forest structure, facilitating turnover in forest composition over space and time, enabling recovery from disturbance, and regulating climate-driven range shifts. Our critical review of regeneration process representations within current Earth system vegetation demographic models reveals the need to improve parameter values and algorithms for reproductive allocation, dispersal, seed survival and germination, environmental filtering in the seedling layer, and tree regeneration strategies adapted to wind, fire, and anthropogenic disturbance regimes. These improvements require synthesis of existing data, specific field data-collection protocols, and novel model algorithms compatible with global-scale simulations. Vegetation demographic models offer the opportunity to more fully integrate ecological understanding into Earth system prediction; regeneration processes need to be a critical part of the effort.

Simulating environmentally-sensitive tree recruitment in vegetation demographic models.

Vegetation demographic models (VDMs) endeavor to predict how global forests will respond to climate change. This requires simulating which trees, if any, are able to recruit under changing environmental conditions. We present a new recruitment scheme for VDMs in which functional-type-specific recruitment rates are sensitive to light, soil moisture and the productivity of reproductive trees. We evaluate the scheme by predicting tree recruitment for four tropical tree functional types under varying meteorology and canopy structure at Barro Colorado Island, Panama. We compare predictions to those of a current VDM, quantitative observations and ecological expectations. We find that the scheme improves the magnitude and rank order of recruitment rates among functional types and captures recruitment limitations in response to variable understory light, soil moisture and precipitation regimes. Our results indicate that adopting this framework will improve VDM capacity to predict functional-type-specific tree recruitment in response to climate change, thereby improving predictions of future forest distribution, composition and function.

Hyperbolic Inflation.

A model of cosmological inflation is proposed in which field space is a hyperbolic plane. The inflaton never slow-rolls, and instead orbits the bottom of the potential, buoyed by a centrifugal force. Though initial velocities redshift away during inflation, in negatively curved spaces angular momentum naturally starts exponentially large and remains relevant throughout. Quantum fluctuations produce perturbations that are adiabatic and approximately scale invariant; strikingly, in a certain parameter regime the perturbations can grow double exponentially during horizon crossing.

Holographic Complexity Equals Bulk Action?

We conjecture that the quantum complexity of a holographic state is dual to the action of a certain spacetime region that we call a Wheeler-DeWitt patch. We illustrate and test the conjecture in the context of neutral, charged, and rotating black holes in anti-de Sitter spacetime, as well as black holes perturbed with static shells and with shock waves. This conjecture evolved from a previous conjecture that complexity is dual to spatial volume, but appears to be a major improvement over the original. In light of our results, we discuss the hypothesis that black holes are the fastest computers in nature.

Krüppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling.

UNLABELLED: Expression of the transcription factor Krüppel-like factor 9 (KLF9) is frequently reduced in colorectal cancers, although a tumor suppressive role has not been established. To determine if KLF9 suppresses intestinal adenoma formation, we generated mice of distinct Klf9 genotypes in the background of the Apc (Min/+) mouse and compared their adenoma burdens at 16 weeks of age. While small intestine adenoma burden remained unchanged among Klf9 genotypes, male and female Apc(Min/+)/Klf9(-/-) and Apc(Min/+)/Klf9(+/-) mice exhibited significantly more colon adenomas than their Apc(Min/+)/Klf9(+/+) counterparts. Microarray analysis showed significant increases in the expression of interferon-induced genes in the colon mucosa of female Apc (Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) compared to Apc(Min/+)/Klf9(+/+) mice, prior to overt adenoma occurrence. Gene upregulation was confirmed by qPCR of colon mucosa and by siRNA knockdown of KLF9 in human HT29 colorectal cancer cells. Increases in expression of these genes were further augmented by supplementation with Interferon ß1. Circulating levels of the cytokine, interferon-stimulated gene 15 (ISG15) were increased in Apc(Min/+)/Klf9(+/-) and Apc(Min/+)/Klf9(-/-) mice relative to Apc(Min/+)/Klf9(+/+). Additionally, colon mucosal levels of ISG15 were increased in Apc(Min/+)/Klf9(+/-) mice. Chromatin immunoprecipitation demonstrated KLF9 recruitment to the ISG15 promoter. Lastly, treatment with ISG15 suppressed apoptosis in HT29 cells, in the presence and absence of 5-fluorouracil (5FU). Results show KLF9 to be a haploinsufficient suppressor of colon tumorigenesis in Apc(Min/+) mice in part, by repression of ISG15 and the latter's antiapoptotic function. SUMMARY: Krüppel-like factor 9 (KLF9) is a haploinsufficient tumor suppressor in the ApcMin/+ mouse colon by suppressing expression of ISG15, an apoptosis-inhibiting cytokine.

Developmentally regulated neurosteroid synthesis enhances GABAergic neurotransmission in mouse thalamocortical neurones.

KEY POINTS: During neuronal development synaptic events mediated by GABAA receptors are progressively reduced in their duration, allowing for rapid and precise network function. Here we focused on ventrobasal thalamocortical neurones, which contribute to behaviourally relevant oscillations between thalamus and cortex. We demonstrate that the developmental decrease in the duration of inhibitory phasic events results predominantly from a precisely timed loss of locally produced neurosteroids, which act as positive allosteric modulators of the GABAA receptor. The mature thalamus retains the ability to synthesise neurosteroids, thus preserving the capacity to enhance both phasic and tonic inhibition, mediated by synaptic and extrasynaptic GABAA receptors, respectively, in physiological and pathophysiological scenarios associated with perturbed neurosteroid levels. Our data establish a potent, endogenous mechanism to locally regulate the GABAA receptor function and thereby influence thalamocortical activity. During brain development the duration of miniature inhibitory postsynaptic currents (mIPSCs) mediated by GABAA receptors (GABAA Rs) progressively reduces, to accommodate the temporal demands required for precise network activity. Conventionally, this synaptic plasticity results from GABAA R subunit reorganisation. In particular, in certain developing neurones synaptic α2-GABAA Rs are replaced by α1-GABAA Rs. However, in thalamocortical neurones of the mouse ventrobasal (VB) thalamus, the major alteration to mIPSC kinetics occurs on postnatal (P) day 10, some days prior to the GABAA R isoform change. Here, whole-cell voltage-clamp recordings from VB neurones of mouse thalamic slices revealed that early in postnatal development (P7-P8), the mIPSC duration is prolonged by local neurosteroids acting in a paracrine or autocrine manner to enhance GABAA R function. However, by P10, this neurosteroid 'tone' rapidly dissipates, thereby producing brief mIPSCs. This plasticity results from a lack of steroid substrate as pre-treatment of mature thalamic slices (P20-24) with the GABAA R-inactive precursor 5α-dihydroprogesterone (5α-DHP) resulted in markedly prolonged mIPSCs and a greatly enhanced tonic conductance, mediated by synaptic and extrasynaptic GABAA Rs, respectively. In summary, endogenous neurosteroids profoundly influence GABAergic neurotransmission in developing VB neurones and govern a transition from slow to fast phasic synaptic events. Furthermore, the retained capacity for steroidogenesis in the mature thalamus raises the prospect that certain physiological or pathophysiological conditions may trigger neurosteroid neosynthesis, thereby providing a local mechanism for fine-tuning neuronal excitability.

Characterizing human stem cell-derived sensory neurons at the single-cell level reveals their ion channel expression and utility in pain research.

The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell-derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders.

Extrasynaptic GABA(A) receptors couple presynaptic activity to postsynaptic inhibition in the somatosensory thalamus.

Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and generate pathological activities during absence epilepsy. Inhibitory control of thalamocortical (TC) relay neurons is partially mediated by GABA released from neurons of the thalamic reticular nucleus (nRT), acting predominantly via synaptic α1ß2γ2 GABA(A) receptors (GABA(A)Rs). Importantly, TC neurons also express extrasynaptic α4ß2δ GABA(A)Rs, although how they cooperate with synaptic GABA(A)Rs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABA(A)R-lacking, α4 "knock-out" (α4(0/0)) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in α4(0/0) pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynaptic GABA(A)Rs. Furthermore, the influence of nRT tonic firing frequency on VB holding current is also greatly reduced in α4(0/0) pairs, implying that the α4-GABA(A)R-mediated tonic conductance of relay neurons is dynamically influenced, in an activity-dependent manner, by nRT tonic firing intensity. Collectively, our data reveal that extrasynaptic GABA(A)Rs of the somatosensory thalamus do not merely provide static tonic inhibition but can also be dynamically engaged to couple presynaptic activity to postsynaptic excitability. Moreover, these processes are highly sensitive to the δ-selective allosteric modulator, DS2 and manipulation of GABA transport systems, revealing novel opportunities for therapeutic intervention in thalamocortical network disorders.

Enantioselective thiourea-catalyzed intramolecular cope-type hydroamination.

Catalysis of Cope-type rearrangements of bis-homoallylic hydroxylamines is demonstrated using chiral thiourea derivatives. This formal intramolecular hydroamination reaction provides access to highly enantioenriched α-substituted pyrrolidine products and represents a complementary approach to metal-catalyzed methods.

Tensile strength and the mining of black holes.

There are a number of important thought experiments that involve raising and lowering boxes full of radiation in the vicinity of black hole horizons. This Letter looks at the limitations placed on these thought experiments by the null energy condition, which imposes a fundamental bound on the tensile-strength-to-weight ratio of the materials involved, makes it impossible to build a box near the horizon that is wider than a single wavelength of the Hawking quanta, and puts a severe constraint on the operation of "space elevators" near black holes. In particular, it is shown that proposals for mining black holes by lowering boxes near the horizon, collecting some Hawking radiation, and dragging it out to infinity cannot proceed nearly as rapidly as has previously been claimed. As a consequence of this limitation, the boxes and all the moving parts are superfluous and black holes can be destroyed equally rapidly by threading the horizon with strings.

The role of thyroid hormone signaling in the prevention of digestive system cancers.

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVß3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVß3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Mechanism of formation of palladium nanoparticles: Lewis base assisted, low-temperature preparation of monodisperse nanoparticles.

Small and cool: The mechanism of formation of amine-capped Pd nanoparticles from [Pd(acac)(2)] (acac=acetylacetonate) is elucidated, and shown to involve Pd-amido and Pd-hydride intermediates. The addition of a Lewis base results in a significant reduction in the temperature at which highly monodisperse nanoparticles are isolated.

Krüppel-like Factor 9 (KLF9) Suppresses Hepatocellular Carcinoma (HCC)-Promoting Oxidative Stress and Inflammation in Mice Fed High-Fat Diet.

Obesity, oxidative stress, and inflammation are risk factors for hepatocellular carcinoma (HCC). We examined, in mice, the effects of Krüppel-like factor 9 (KLF9) knockout on: adiposity, hepatic and systemic oxidative stress, and hepatic expression of pro-inflammatory and NOX/DUOX family genes, in a high-fat diet (HFD) context. Male and female Klf9+/+ (wild type, WT) and Klf9-/- (knockout, KO) mice were fed HFD (beginning at age 35 days) for 12 weeks, after which liver and adipose tissues were obtained, and serum adiponectin and leptin levels, liver fat content, and markers of oxidative stress evaluated. Klf9-/- mice of either sex did not exhibit significant alterations in weight gain, adipocyte size, adipokine levels, or liver fat content when compared to WT counterparts. However, Klf9-/- mice of both sexes had increased liver weight/size (hepatomegaly). This was accompanied by increased hepatic oxidative stress as indicated by decreased GSH/GSSG ratio and increased homocysteine, 3-nitrotyrosine, 3-chlorotyrosine, and 4HNE content. Decreased GSH to GSSG ratio and a trend toward increased homocysteine levels were observed in the corresponding Klf9-/- mouse serum. Gene expression analysis showed a heightened pro-inflammatory state in livers from Klf9-/- mice. KLF9 suppresses hepatic oxidative stress and inflammation, thus identifying potential mechanisms for KLF9 suppression of HCC and perhaps cancers of other tissues.

Populating the whole landscape.

Every de Sitter vacuum can transition to every other de Sitter vacuum despite any obstacle, despite intervening anti-de Sitter sinks, despite not being connected by an instanton. Eternal inflation populates the whole landscape.

Aversive, appetitive and flavour avoidance responses in the presence of contextual cues.

Appetitive, aversive and avoidance responses to a flavoured solution in distinct contexts were examined. Rats placed in either a white or black box were given access to saccharin. Consumption was followed by an injection of a toxin in one but not the other box. Rats showed more aversive responses in anticipation of and during the presentation of saccharin in the box paired with the toxin than in the box paired with vehicle. The reverse was true for appetitive responses. The acquisition of conditioned avoidance paralleled the acquisition of aversive and appetitive responses. These findings demonstrate that the toxin does not have to overlap exposure to contextual cues to produce conditioned aversive responses, that the aversive and appetitive responses to a flavour can be modulated by visually distinct environments that predict the toxin, and that conditioned avoidance and conditioned aversions develop simultaneously during acquisition. Thus, environmental cues can modulate anticipatory nausea and may prove helpful in the control of nausea in clinical settings.

Bacterial efflux inhibitors are widely distributed in land plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Secondary metabolites play a critical role in plant defense against disease and are of great importance to ethnomedicine. Bacterial efflux pumps are active transport proteins that bacterial cells use to protect themselves against multiple toxic compounds, including many antimicrobials. Efflux pump inhibitors from plants can block these efflux pumps, increasing the potency of antimicrobial compounds. This study demonstrates that efflux pump inhibition against the Gram-positive bacterial pathogen Staphylococcus aureus is widespread in extracts prepared from individual species throughout the land plant lineage. It therefore suggests a general mechanism by which plants used by indigenous species may be effective as a topical treatment for some bacterial infections. AIM OF THE STUDY: The goal of this research was to evaluate the distribution of efflux pump inhibitors in nine plant extracts with an ethnobotanical use suggestive of an antimicrobial function for the presence of efflux pump inhibitory activity against Staphylococcus aureus. MATERIALS AND METHODS: Plants were collected, dried, extracted, and vouchers submitted to the Herbarium of the University of North Carolina Chapel Hill (NCU). The extracts were analyzed by quantitative mass spectrometry (UPLC-MS) to determine the presence and concentration of flavonoids with known efflux pump inhibitory activity. A mass spectrometry-based assay was employed to measure efflux pump inhibition for all extracts against Staphylococcus aureus. The assay relies on UPLC-MS measurement of changes in ethidium concentration in the spent culture broth when extracts are incubated with bacteria. RESULTS: Eight of these nine plant extracts inhibited toxic compound efflux at concentrations below the MIC (minimum inhibitory concentration) value for the same extract. The most active extracts were those prepared from Osmunda claytoniana L. and Pinus strobes L., which both demonstrated IC50 values for efflux inhibition of 19 ppm. CONCLUSIONS: Our findings indicate that efflux pump inhibitors active against Staphylococcus aureus are common in land plants. By extension, this activity is likely to be important in many plant-derived antimicrobial extracts, including those used in traditional medicine, and evaluation of efflux pump inhibition may often be valuable when studying natural product efficacy.

Enantioselective catalytic alpha-alkylation of aldehydes via an SN1 pathway.

Primary aminothiourea derivatives are shown to catalyze enantioselective alkylation of alpha-arylpriopionaldehdyes with diarylbromomethane. Evidence for a stepwise, S(N)1 mechanism in the substitution reaction induced by anion binding to the catalyst is provided by catalyst structure-activity studies, kinetic isotope effects, linear free-energy relationship studies, and competition experiments.