Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult β-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in β-cell insulin secretion.

Yan Xing, Hongling Wei, Xiumei Xiao, Zekun Chen, Hui Liu, Xiaomei Tong, and Wei Zhou

Infants with intrauterine growth retardation (IUGR) have a high risk of developing bronchial asthma in childhood, but the underlying mechanisms remain unclear. This study aimed to disclose the role of vascular non-inflammatory molecule 1 (vannin-1, encoded by the Vnn1 gene) and its downstream signaling in IUGR asthmatic mice induced by ovalbumin. Significant histological alterations and an increase of vannin-1 expression were revealed in IUGR asthmatic mice, accompanied by elevated methylation of Vnn1 promoter regions. In IUGR asthmatic mice, we also found (i) a direct binding of HNF4α and PGC1α to Vnn1 promoter by ChIP assay; (ii) a direct interaction of HNF4α with PGC1α; (iii) upregulation of phospho-PI3K p85/p55 and phospho-Akt^Ser473 and downregulation of phospho-PTENT^yr366, and (iv) an increase in nuclear NFB p65 and a decrease in cytosolic IB-α. In primary cultured bronchial epithelial cells derived from the IUGR asthmatic mice, knockdown of Vnn1 prevented upregulation of phospho-Akt^Ser473 and an increase of reactive oxygen species (ROS) and TGF-β production. Taken together, we demonstrate that elevated vannin-1 activates the PI3K/Akt/NFB signaling pathway, leading to ROS and inflammation reactions responsible for asthma occurrence in IUGR individuals. We also disclose that interaction of PGC1α and HNF4α promotes methylation of Vnn1 promoter regions and then upregulates vannin-1 expression.

Background:

Historically, some chiropractors have been critical of vaccination, and this has been the subject of recent media attention in Canada. We explored the association between media attention and public dissemination of vaccination information on Canadian chiropractors’ websites.

Tigecycline serves as one of the antibiotics of last resort to treat multidrug-resistant (including carbapenem-resistant) pathogens. However, the recently emerged plasmid-mediated tigecycline resistance mechanism, Tet(X), challenges the clinical efficacy of this class of antibiotics. In this study, we detected 180 tet(X)-harboring Acinetobacter isolates (8.9%, n = 180) from 2,018 samples collected from avian farms and adjacent environments in China. Eighteen tet(X)-harboring isolates (10.0%) were found to cocarry the carbapenemase gene bla_NDM-1, mostly from waterfowl samples (94.4%, 17/18). Interestingly, among six Acinetobacter strains, tet(X) and bla_NDM-1 were found to colocalize on the same plasmids. Moreover, whole-genome sequencing (WGS) revealed a novel orthologue of tet(X) in the six isolates coharboring tet(X) and bla_NDM-1. Inverse PCR suggested that the two tet(X) genes form a single transposable unit and may be cotransferred. Sequence comparison between six tet(X)- and bla_NDM-1-coharboring plasmids showed that they shared a highly homologous plasmid backbone even though they were isolated from different Acinetobacter species (three from Acinetobacter indicus, two from Acinetobacter schindleri, and one from Acinetobacter lwoffii) from various sources and from different geological regions, suggesting the horizontal genetic transfer of a common tet(X)- and bla_NDM-1-coharboring plasmid among Acinetobacter species in China. Emergence and spread of such plasmids and strains are of great clinical concern, and measures must be implemented to avoid their dissemination.

Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4⁺ T cells, remains a major obstacle to viral eradication. The "shock and kill" strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although some latency-reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vital to seek novel and effective LRAs. Here, we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4⁺ T cells from ART-suppressed individuals ex vivo. TSR does not induce global T cell activation, severe cytotoxicity, or CD8⁺ T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when TSR was combined with JQ1, prostratin, or bryostatin-1. Interestingly, six TSR analogues also show reactivation abilities that are similar to or more effective than that of TSR. We further verified that TSR upregulated expression of heat shock proteins (HSPs) in CD4⁺ T cells, which subsequently activated positive transcriptional elongation factor b (p-TEFb) and NF-B signals, leading to viral reactivation. In summary, we identify TSR as a novel LRA which could have important significance for applications to an HIV-1 functional cure in the future.

Helicobacter pylori is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori. Inspired by the microaerophilic characteristics of H. pylori, we aimed at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori. The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo. During oral administration and after drug withdrawal, H. pylori counts were evaluated by Giemsa staining in animal cohorts. An oxygen-enriched environment in which H. pylori could not survive was successfully established by adding hydrogen peroxide into several solutions and rabbit gastric juice. Hydrogen peroxide effectively killed H. pylori in Columbia blood agar and special peptone broth. Minimum inhibition concentrations and minimum bactericidal concentrations of hydrogen peroxide were both relatively stable after promotion of resistance for 30 generations, indicating that hydrogen peroxide did not easily promote resistance in H. pylori. In models of Mongolian gerbils and Kunming mice, hydrogen peroxide has been shown to significantly eradicate and effectively prevent the recurrence of H. pylori without toxicity and damage to the gastric mucosa. The mechanism of hydrogen peroxide causing H. pylori death was related to the disruption of bacterial cell membranes. The oxygen-enriched environment achieved by hydrogen peroxide eradicates and prevents the recurrence of H. pylori by damaging bacterial cell membranes. Hydrogen peroxide thus provides an attractive candidate for anti-H. pylori treatment.

A fosfomycin-resistant and carbapenemase (OXA-48)-producing Klebsiella pneumoniae isolate was recovered, and whole-genome sequencing revealed ISEcp1-bla_CTX-M-14b tandemly inserted upstream of the chromosomally encoded lysR-fosA locus. Quantitative evaluation of the expression of lysR and fosA genes showed that this insertion brought a strong hybrid promoter leading to overexpression of the fosA gene, resulting in fosfomycin resistance. This work showed the concomitant acquisition of resistance to broad-spectrum cephalosporins and fosfomycin due to a single genetic event.

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.

Tumor-derived retinoic acid promotes monocyte differentiation into immunosuppressive macrophages.

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer.Significance:This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.Significance:NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.See related commentary by Hayward, p. 1799

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17–1.36; P = 2.57 × 10–9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer–promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology.Significance:This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer–promoter interaction loops.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.

BACKGROUND AND PURPOSE:

The massa intermedia is a normal midline transventricular thalamic connection. Massa intermedia aberrations are common in schizophrenia, Chiari II malformation, X-linked hydrocephalus, Cornelia de Lange syndrome, and diencephalic-mesencephalic junction dysplasia, among others. We have noticed that massa intermedia abnormalities often accompany other midline malformations. The massa intermedia has never been formally evaluated in a group of exclusively pediatric patients, to our knowledge. We sought to compare and contrast the prevalence, size, and location of the massa intermedia in pediatric patients with and without congenital midline brain abnormalities.

An analysis of the media consumption habits of people in the US shows that fake news makes up a tiny fraction of what they watch or read every day

There has been talk for some time now about easing labour laws, already seen in industry circles as being too rigid and acting as a drag on growth, specifically to facilitate emerging from the lockdown. And it’s not just a question of emerging from it, there’s also the issue of surviving what looks like being a brutal and prolonged global economic downturn. It was reported on Friday that ordinances were being issued in some states.

The apparent Democratic nominee called for an immediate $13 minimum wage increase for essential workers and criticized President Trump for viewing these front-liners as “disposable."

Asian giant hornet, which became more active in the state in April, is the world’s largest and can kill humans with multiple stings

• Alarm over deaths of bees from rapidly spreading viral disease
  

Researchers and citizens in Washington state are on a careful hunt for invasive “murder hornets”, after the insect made its first appearance in the US.

The Asian giant hornet is the world’s largest and can kill humans. But it is most dangerous for the European honeybee, which is defenseless in the face of the hornet’s spiky mandibles, long stinger and potent venom.

British Lawn Tennis Association president Roger Draper condemned a fifth successive Davis Cup defeat as unacceptable on Monday and called for an immediate inquiry into the humiliating loss to Lithuania.

Fox News Media, a unit of Fox Corp, said on Tuesday it has partnered with digital streaming services company Spotify Technology SA to distribute its podcast catalogue featuring more than 20 original series.

In today's Diary: Rishi Sunak's secret weapon / A question setter's worst nightmare / Billy Porter on the piece of art he wants most / Liberal Tories hope for immigration change

Coronavirus: the symptoms Read our LIVE updates on the coronavirus here

Virgin Media, one of the UK's largest internet providers, has apologised after its broadband service crashed for thousands of customers.

Virgin Media customers are still complaining about issues with their broadband despite the provider saying the issue has been fixed.

The day has been marked every year since 2011

Millions of people had difficulty accessing the internet yesterday as Virgin Media had a series of outages across the country.

Most parents don't want to send their children back to school as soon as the coronavirus lockdown is lifted, a new study has found.

The back-and-forth continues.The Department of Homeland Security said Friday the United States will shorten the visa length for Chinese journalists working for non-American news outlets to 90 days. Previously, journalists with Chinese passports were granted open-ended visas. They can apply for extensions under the new rules, but renewed visas will also last just 90 days. The new limit won't apply to reporters from Hong Kong Macau, or to mainland Chinese citizens who hold green cards.It's the latest development in a media war between Washington and Beijing that has intensified during the coronavirus pandemic. American officials said the rules were meant to counterbalance the "suppression of independent journalism" in China, whose government expelled journalists from The Wall Street Journal, The New York Times, and The Washington Post in March. Before that, the U.S. reduced the number of Chinese citizens employed by multiple state-controlled Chinese news organizations to work in the country. The New York Times notes the move wasn't unexpected; U.S. intelligence officials have long believed some journalists at Beijing-run outlets are spies, and the Trump administration has designated some Chinese news agencies foreign government functionaries.The heightened tensions between the world's two biggest powers didn't just show up in the media world Friday. U.S. lawmakers wrote to nearly 60 countries asking them to support Taiwan's participation in the World Health Organization, a move that likely won't sit well with China. And Washington also blocked a United Nations security council resolution calling for a global ceasefire during the pandemic because it indirectly referenced the WHO, which the U.S. has blamed in conjunction with China for failing to suppress the outbreak.More stories from theweek.com Outed CIA agent Valerie Plame is running for Congress, and her launch video looks like a spy movie trailer 7 scathing cartoons about America's rush to reopen Trump says he couldn't have exposed WWII vets to COVID-19 because the wind was blowing the wrong way

1. Coronavirus Lockdown 3.0: Suspension of labour laws by fiat can only be an immediate-term response to the...  Firstpost
2. Odisha govt extends work shift to 12 hours  The Hindu
3. Now, Maharashtra tweaks labour laws to increase working hours  The Hindu
4. View Full coverage on Google News

Derek Herbert had been due to appear at Hever Castle in Kent but will instead perform on social media.

Publishers of several of Canada’s major newspapers signed a joint letter to the federal government this month, taking aim at the advertising revenue earned by Google and Facebook.

The investigation into bullying accusations against Priti Patel must be released "as soon as possible", Labour has demanded.

It is the new must-try food

Not much has changed for Ricky Gervais in lockdown. He didn't go out much anyway, and he's got enough booze in the house for a nuclear winter. Dave Itzkoff took the chance to speak to him about targeting celebrity culture at the Golden Globes and the new series of 'After Life'

Billie Henry was given a five-year restraining order

Davidson is currently quarantining in his mother's basement

Will Hislop engaged in a pretend argument with his neighbour, 'Karen', over whether one of them had broken lockdown rules

News Corp is campaigning full-bore for the US president, with reports of a Wuhan lab ‘intelligence’ dossier being seeded across its empire

In liberal democracies, the integrity, impartiality and professionalism of intelligence agencies matters. That’s why it is essential that intelligence agencies remain aloof, not only from the political debates of the day, but also from the policy decisions that individual governments may take. The intelligence community’s core task is to provide brutally realistic analysis on the threat environments we face so that governments can then make the best-informed policy decisions possible to preserve our common security.

The failures of the intelligence community before the Iraq war, the gullibility of much of the western media, as well as the cynical manipulation of both by the political class of the day, provide us with a stark reminder of what can go radically wrong. On 8 September 2002 the New York Times published one of this century’s most consequential news articles. The front-page story, supplied by the Bush administration, claimed that Saddam Hussein had stepped up his quest for weapons of mass destruction by acquiring key components for a nuclear weapon. In the UK, the Blair government’s “dodgy dossier” compounded the error. John Howard did the same in Australia. The problem was that it just wasn’t true. These were over-egged stories designed to soften the public up for what would become a disastrous war.

Lord Sugar has been criticised for sharing a conspiracy theory on social media which stated that Covid-19 was man-made.

The lockdown has us turning to the stars for guidance

Judge Alison J. Nathan has ruled that the 66-year-old comedian is the creator of the show.

Crunch talks between league two chairmen may have knock-on effect up to Premier League

Manchester United are only pursuing an extension to Odion Ighalo's loan deal and have no immediate plans to negotiate a permanent move.

Bill Maher’s final “New Rule” on Friday’s Real Time With Bill Maher was, as usual, a doozie. “The liberal media and liberal party,” said Maher, “is doing…exactly what Republicans want: for us to go down the rabbit hole of ‘Joe Biden, sex monster.'” Maher was of course referring to allegations made by Tara Reade, who […]

The former Leafs forward commented on the physical appearances of Vancouver forward Tanner Pearson’s wife and Edmonton captain Connor McDavid’s girlfriend. He also called Capitals linemates Garnet Hathaway and Nick Dowd losers.

Mike Bloomberg has hired hundreds of paid "digital organizers" to boost his presidential bid on social media. A look inside the operation reveals potential downsides to this approach.