Limits to timescale dependence in erosion rates: Quantifying glacial and fluvial erosion across timescales.

Earth's topography and climate result from the competition between uplift and erosion, but it has been debated whether rivers or glaciers are more effective erosional agents. We present a global compilation of fluvial and glacial erosion rates alongside simple numerical experiments, which show that the "Sadler effect," wherein geological rates show an inverse relationship with measurement timescale, comprises three distinct effects: a measurement thickness bias, a bias of erosion and redeposition, and a bias introduced by not observing quiescent intervals. Furthermore, we find that, globally, average glacial erosion rates exceed fluvial erosion rates through time by an order of magnitude, and that this difference cannot be explained by Sadlerian biases or by variations in hillslope, precipitation, or latitude.

DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras.

Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases.

Erratum: Author Correction: High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity.

[This corrects the article DOI: 10.1038/s42003-019-0587-z.].

High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity.

Expression of human asparagine synthetase (ASNS) promotes metastatic progression and tumor cell invasiveness in colorectal and breast cancer, presumably by altering cellular levels of L-asparagine. Human ASNS is therefore emerging as a drug target for cancer therapy. Here we show that a slow-onset, tight binding inhibitor, which exhibits nanomolar affinity for human ASNS in vitro, exhibits excellent selectivity at 10 μM concentration in HCT-116 cell lysates with almost no off-target binding.

Acute effect of a supplemented milk drink on bone metabolism in healthy postmenopausal women is influenced by the metabolic syndrome.

Background: Dietary factors acutely influence the rate of bone resorption, as demonstrated by changes in serum bone resorption markers. Dietary calcium exerts its effect by reducing parathyroid hormone levels while other components induce gut incretin hormones both of which reduce bone resorption markers. The impact of dietary calcium on bone turnover when energy metabolism is modulated such as in metabolic syndrome has not been explored.

ATP Acyl Phosphate Reactivity Reveals Native Conformations of Hsp90 Paralogs and Inhibitor Target Engagement.

Hsp90 is an ATP-dependent chaperone of widespread interest as a drug target. Here, using an LC-MS/MS chemoproteomics platform based on a lysine-reactive ATP acyl phosphate probe, several Hsp90 inhibitors were profiled in native cell lysates. Inhibitor specificities for all four human paralogs of Hsp90 were simultaneously monitored at their endogenous relative abundances.

Global Human-Kinase Screening Identifies Therapeutic Host Targets against Influenza.

During viral infection of human cells, host kinases mediate signaling activities that are used by all viruses for replication; therefore, targeting of host kinases is of broad therapeutic interest. Here, host kinases were globally screened during human influenza virus (H1N1) infection to determine the time-dependent effects of virus infection and replication on kinase function. Desthiobiotin-labeled analogs of adenosine triphosphate and adenosine diphosphate were used to probe and covalently label host kinases in infected cell lysates, and probe affinity was determined.

Comparison of 2 weight-loss diets of different protein content on bone health: a randomized trial.

Background: It has been hypothesized that hip-fracture rates are higher in developed than in developing countries because high-protein (HP) Western diets induce metabolic acidosis and hypercalciuria. Confounders include interactions between dietary protein and calcium, sodium, and potassium.

Objective: We determined whether an HP or a high-normal-protein (HNP) weight-loss diet caused greater loss in bone mineral density (BMD) over 24 mo.

In situ kinase profiling reveals functionally relevant properties of native kinases.

Protein kinases are intensely studied mediators of cellular signaling, yet important questions remain regarding their regulation and in vivo properties. Here, we use a probe-based chemoprotemics platform to profile several well studied kinase inhibitors against >200 kinases in native cell proteomes and reveal biological targets for some of these inhibitors. Several striking differences were identified between native and recombinant kinase inhibitory profiles, in particular, for the Raf kinases.

The calcium scare--what would Austin Bradford Hill have thought?

Unlabelled: Detailed consideration of the suggested association between calcium supplementation and heart attacks has revealed weakness in the evidence which make the hypothesis highly implausible.

Introduction: The aim of this study was to evaluate the strength of the evidence that calcium supplementation increases the risk of myocardial infarction.

Methods: This study used critical examination of a meta-analysis of the effects of calcium supplements on heart attacks in five prospective trials on 8,016 men and women, and consideration of related publications by the same author.

Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways.

A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen.

Recalculation of the calcium requirement of adult men.

Background: There is uncertainty about the calcium requirement with particular respect to age and sex differences and the calculation of skin calcium losses.

Objective: We calculated the calcium requirement of adult men from a homogenous set of calcium balances and a robust estimate of calcium loss through the skin.

Design: We reviewed available high-quality published calcium balances in men and retrieved 219 balances; we noted a fall in calcium absorption in individuals >60 y of age.

Evolution of the calcium paradigm: the relation between vitamin D, serum calcium and calcium absorption.

Osteoporosis is the index disease for calcium deficiency, just as rickets/osteomalacia is the index disease for vitamin D deficiency, but there is considerable overlap between them. The common explanation for this overlap is that hypovitaminosis D causes malabsorption of calcium which then causes secondary hyperparathyroidism and is effectively the same thing as calcium deficiency. This paradigm is incorrect.

Suppression of C-terminal telopeptide in hypovitaminosis D requires calcium as well as vitamin D.

We compared the effects of oral calcium and vitamin D separately and together on relevant variables in 22 postmenopausal volunteers with initial serum 25OHD levels below 60 nmol/L. Subjects were allocated randomly to two regimens: group 1 received 1 week of calcium 1,000 mg, followed by 7 weeks with additional vitamin D3 1,000 i.u.

Calcium malabsorption does not cause secondary hyperparathyroidism.

We challenge the widespread assumption that malabsorption of calcium per se causes secondary hyperparathyroidism. Serum parathyroid hormone (PTH) does not rise at the menopause despite the fall in calcium absorption, nor is it raised in osteoporotic women with vertebral fractures despite their low calcium absorption. The age-related rise in serum PTH can be accounted for by the age-related fall in serum 25(OH)D and/or decline in renal function with consequent loss of the calcemic action of vitamin D on bone.

The effect of calcium supplementation on bone loss in 32 controlled trials in postmenopausal women.

Summary: In 32 controlled trials of calcium supplementation (700-2000 mg) in 3,169 postmenopausal women, mean bone loss in the controls was -1.07% p.a.