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About the Authors: Daniel Lin Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0001-6398-4789 Ramez Kouzy Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0002-1521-0495 Joseph Abi Jaoude Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0002-2283-4765 Sonal S. Noticewala Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America Andrea Y. Delgado Medrano Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0003-0813-3492 Ann H. Klopp Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America Cullen M. Taniguchi * E-mail: ctaniguchi@mdanderson.org (CMT); lcolbert@mdanderson.org (LEC) Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0002-8052-3316 Lauren E. Colbert * E-mail: ctaniguchi@mdanderson.org (CMT); lcolbert@mdanderson.org (LEC) Affiliation: Department of Radiation Oncology, Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ORCID logo http://orcid.org/0000-0001-5806-4339 Introduction Human papillomavirus (HPV) infections account for over 600,000 new cancer cases every year [1]. Factors unique to the individual mucosal sites such as epithelial surface integrity, mucosal secretions, immune regulation, and the local microbiota likely play a role in HPV persistence and progression to cancer [2–4]. Insights into the potential influence of the microbiome on viral persistence, immune response, host-mucosal environment, and cancer treatments for HPV-related cancers are just beginning to emerge. All of these bacterial, mucosal, and immune complications related to BV can result in an increased susceptibility to HPV infection and the development of high-grade intraepithelial lesions.

There has been increasing interest in phenomena emerging from relativistic electrons in a solid, which have a potential impact on spintronics and magnetoelectrics. One example is the Rashba effect, which lifts the electron-spin degeneracy as a consequence of spin–orbit interaction under broken inversion symmetry. A high-energy-scale Rashba spin splitting is highly desirable for enhancing the coupling between electron spins and electricity relevant for spintronic functions. Here we describe the finding of a huge spin–orbit interaction effect in a polar semiconductor composed of heavy elements, BiTeI, where the bulk carriers are ruled by large Rashba-like spin splitting. The band splitting and its spin polarization obtained by spin- and angle-resolved photoemission spectroscopy are well in accord with relativistic first-principles calculations, confirming that the spin splitting is indeed derived from bulk atomic configurations. Together with the feasibility of carrier-doping control, the giant-Rashba semiconductor BiTeI possesses excellent potential for application to various spin-dependent electronic functions. A very large Rashba-type spin splitting, which is a consequence of spin–orbit interaction, has been observed in the heavy-element semiconductor BiTeI. The results show the possibility, in principle, of using the material in spintronics devices in which the electron spin is controlled by electric currents.

In the hole-doped cuprates, a small number of carriers suppresses antiferromagnetism and induces superconductivity. In the electron-doped cuprates, on the other hand, superconductivity appears only in a narrow window of high-doped Ce concentration after reduction annealing, and strong antiferromagnetic correlation persists in the superconducting phase. Recently, Pr 1.3− x La 0.7 Ce x CuO 4 (PLCCO) bulk single crystals annealed by a protect annealing method showed a high critical temperature of around 27 K for small Ce content down to 0.05. Here, by angle-resolved photoemission spectroscopy measurements of PLCCO crystals, we observed a sharp quasi-particle peak on the entire Fermi surface without signature of an antiferromagnetic pseudogap unlike all the previous work, indicating a dramatic reduction of antiferromagnetic correlation length and/or of magnetic moments. The superconducting state was found to extend over a wide electron concentration range. The present results fundamentally challenge the long-standing picture on the electronic structure in the electron-doped regime. In cuprates, superconductivity exists in a narrow window at high electron doping concentration with strong antiferromagnetic correlations. Here, the authors demonstrate superconductivity with no effect of antiferromagnetic order in a cuprate for a wide electron doping range following a protect anneal process.

The concept of 'critical nodes' has been used to define the main junctions in physiologically important, complex signalling networks. Several critical nodes of the insulin network have been identified and shown to have important roles in normal physiology and disease states. Key Points Cell-signalling networks are complex systems that allow for the specific biological response to a defined stimulus. We argue that it is possible to qualitatively identify the important mediators of any ligand–receptor system through a method that conceptualizes the most important genes as critical nodes. A 'critical node' is defined as a group of related proteins (for example, gene isoforms) that are essential for the receptor-mediated signal, and in which two or more of these related proteins might have unique biological roles within a signalling network and therefore serve as a source of divergence within the signalling system. The node is highly regulated, both positively and negatively, and is a junction for potential crosstalk with other signalling systems. Here, we use the insulin-signalling pathway as a model system. Three groups of genes are used as examples of 'critical nodes': the insulin receptor and its substrates (IR/IRS), phosphatidylinositol 3-kinase (PI3K) and AKT/protein kinase B (PKB). Although many proteins could be considered to be significant players in insulin signalling, only these three have attained sufficient in vivo and in vitro evidence to be considered 'critical nodes'. The IRSs are a critical node because six isoforms exist, with most of insulin's signal being mediated by IRS1 and IRS2. These IRS proteins, and others, have been shown, through knockout and RNAi studies, to have different biological functions in vivo . These proteins are regulated, both positively by the insulin receptor, and negatively through serine phosphorylation and downregulation of protein levels. The IRS proteins also mediate crosstalk with other signalling systems, particularly with the inflammation pathways. PI3K is also a critical node because both of its subunits, p85 and p110, have many different isoforms, many of which have unique biological functions. The p85α isoform is of particular interest because it negatively regulates insulin action independently of its function in the PI3K holoenzyme. This p85α subunit might also mediate crosstalk with the inflammatory pathways through the activation of c-Jun N-terminal kinase (JNK). AKT/PKB is a critical node because it has been shown to be crucial for glucose homeostasis. AKT comes in three isoforms, and is subject to considerable positive and negative regulation, both by other kinases and by proteins that bind to and inhibit AKT. Many of insulin's downstream functions are mediated by AKT, including the activation of glycogen synthesis, the suppression of gluconeogenesis and the regulation of cell growth and cell size. Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role using insulin signalling as a model system.

Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6–12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63–75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3–4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. Galera Therapeutics.

Dopamine in prefrontal cortices is implicated in cognitive and emotional functions, and the dysfunction of prefrontal dopamine has been associated with cognitive and emotional deficits in mental illnesses. These findings have led to clinical trials of dopamine-targeting drugs and brain imaging of dopamine receptors in patients with mental illnesses. Rodent studies have suggested that dopaminergic pathway projecting to the medial prefrontal cortex (mPFC) suppresses stress susceptibility. Although various types of mPFC neurons express several dopamine receptor subtypes, previous studies neither isolated a role of dopamine receptor subtype nor identified the site of its action in mPFC. Using social defeat stress (SDS) in mice, here we identified a role of dopamine D1 receptor subtype in mPFC excitatory neurons in suppressing stress susceptibility. Repeated social defeat stress (R-SDS) reduces the expression of D1 receptor subtype in mPFC of mice susceptible to R-SDS. Knockdown of D1 receptor subtype in whole neuronal populations or excitatory neurons in mPFC facilitates the induction of social avoidance by SDS. Single social defeat stress (S-SDS) induces D1 receptor-mediated extracellular signal-regulated kinase phosphorylation and c-Fos expression in mPFC neurons. Whereas R-SDS reduces dendritic lengths of mPFC layer II/III pyramidal neurons, S-SDS increases arborization and spines of apical dendrites of these neurons in a D1 receptor-dependent manner. Collectively, our findings show that D1 receptor subtype and related signaling in mPFC excitatory neurons mediate acute stress-induced dendritic growth of these neurons and contribute to suppression of stress susceptibility. Therefore, we propose that D1 receptor-mediated dendritic growth in mPFC excitatory neurons suppresses stress susceptibility.

Summary Background Drugs that inhibit the renin–angiotensin–aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease. Methods We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20–79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40–160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328. Findings After a median follow-up of 3·1 years (range 1–3·9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21·3 vs 34·5 per 1000 patient years; hazard ratio 0·61, 95% CI 0·47–0·79, p=0·0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0·60, 0·38–0·95, p=0·028), angina pectoris (19 vs 53; 0·35, 0·20–0·58, p<0·0001), and heart failure (19 vs 36; 0·53, 0·31–0·94, p=0·029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups. Interpretation The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

BMP-7 and obesity Originally identified as a bone inducer, BMP-7 also has potent renal- and neuro-regenerative effects. Now it is reported to regulate energy homeostasis by promoting differentiation of brown, but not white, fat cells. BMP-7 switches on regulators of brown fat, including PRDM16 (see the cover story) and adipogenic transcription factors, and stimulates mitochondrial biogenesis. Ectopic expression of BMP-7 in mice increases brown, but not white, fat mass and leads to an increase in energy expenditure and reduced weight gain. These results have obvious therapeutic implications for the treatment of obesity. A member of the family of bone morphogenetic proteins, BMP-7, promotes the differentiation of brown, not white, fat cells. BMP-7 switches on regulators of brown fat, among which there is PRDM16, adipogenic transcription factors, and mitochondrial biogenesis. BMP-7 can persuade mesenchymal progenitor cells to become brown adipocytes. Without BMP-7 less brown fat develops. Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity 1 . Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood 2 , 3 . Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4 ) and PGC-1α (peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α; ref. 5 ), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARγ and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.

The three-dimensional topological semimetals represent a new quantum state of matter. Distinct from the surface state in the topological insulators that exhibits linear dispersion in two-dimensional momentum plane, the three-dimensional semimetals host bulk band dispersions linearly along all directions. In addition to the gapless points in the bulk, the three-dimensional Weyl/Dirac semimetals are also characterized by “topologically protected” surface state with Fermi arcs on their surface. While Cd 3 As 2 is proposed to be a viable candidate of a Dirac semimetal, more investigations are necessary to pin down its nature. In particular, the topological surface state, the hallmark of the three-dimensional semimetal, has not been observed in Cd 3 As 2 . Here we report the electronic structure of Cd 3 As 2 investigated by angle-resolved photoemission measurements on the (112) crystal surface and detailed band structure calculations. The measured Fermi surface and band structure show a good agreement with the band structure calculations with two bulk Dirac-like bands approaching the Fermi level and forming Dirac points near the Brillouin zone center. Moreover, the topological surface state with a linear dispersion approaching the Fermi level is identified for the first time. These results provide experimental indications on the nature of topologically non-trivial three-dimensional Dirac cones in Cd 3 As 2 .

In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2α to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes. Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain–containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes 1 . Although Hif regulates many metabolic pathways 2 , it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3 , also known as Egln3 , improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.