We are doing what we do best when something threatens the consumer supply chain: rushing to buy mountains of toilet paper. Experts say the dockworkers' strike won't result in shortages, but the panic-buying might so long as the panic-buying lasts.

"They cleaned out the toilet paper at my local Walmart in Virginia.

— Read the rest

The post Toilet paper buying panic recommences as dockworkers strike appeared first on Boing Boing.

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The Springboks will continue to evolve their attack, but they must do so within the framework of what has made them so successful, says attack coach Tony Brown.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

Ivan Matic
Jan 1, 2008; 7:132-144
Research

Jacek R. Wiśniewski
Dec 1, 2014; 13:3497-3506
Research

Sinwar’s death does not make Hamas–Fatah reconciliation more likely, whoever his successor may be Expert comment jon.wallace 22 October 2024

The killing may aid Hamas recruitment – but it will not make agreement with Fatah any easier to achieve.

Western political leaders were quick to argue that Israel’s killing of Hamas leader Yahya Sinwar on 17 October presented an opportunity for a ceasefire in Gaza and the return of Israeli hostages.

US President Joe Biden immediately called on Israeli prime minister Benjamin Netanyahu to seize the moment to negotiate, now that Israel has achieved one of its war aims.

However, that ‘moment’ has already passed. Israel’s military assault on Gaza has intensified since Sinwar was killed, leading UN Peace Process Co-ordinator Tor Wennesland to say that ‘nowhere is safe in Gaza’. It is abundantly clear Netanyahu is intent on further degrading Hamas, resetting a new ‘power balance’ and carving out a buffer zone, no matter the cost in Palestinian lives or Israeli hostages. 

But there are other implications of Sinwar’s assassination beyond the zero-sum analysis of will there or won’t there be a ceasefire.

Hamas’s ability to fight

At present, everyone has an opinion on how Sinwar’s killing will affect Hamas and its ability to resist and respond to Israel’s military. His death will have been a major blow – symbolically, operationally, and psychologically. Hamas has been downgraded and its capacity to respond compromised.

But it will recover, regenerate and retaliate in time – and Sinwar’s death will have been no surprise to Palestinians in Gaza or elsewhere. Hamas is accustomed to seeing its leaders assassinated. Since its formation in 1987, it has been ‘decapitated’ many times, only to continue with its mission to ‘liberate Palestine’.

Hamas’s portrayal of Sinwar dying in his fatigues, head wrapped in a keffiyeh and resisting until the end will persuade many young Palestinians that he died as a martyr serving the Palestinian cause. Many will be inspired to join and fortify the ranks of Hamas as a result.

The IDF’s release of drone footage showing Sinwar’s last moments will have done nothing to undermine his credibility. 

On the contrary, it will serve as a rallying call to disaffected and disenfranchised young Palestinians horrified by Israel’s bombing of civilian targets in Gaza and disaffected with Fatah’s inability to prevent Israeli settler expansion and violence in the West Bank.

Reconciliation

Some hope that if Sinwar is replaced by a more ‘moderate’ leader, his killing may smooth the path to Hamas–Fatah reconciliation – and that this could provide a foundation for a patchwork political solution when Israel and Gaza arrive at the ‘day after.’  

But the idea that a downgraded and ‘leaderless’ Hamas will be susceptible to international pressure to reconcile with Fatah is divorced from reality.  

Prospective new Hamas leaders such as Khaled al Meshaal and Khalil al-Hayya are based in Qatar. 

They may be more pliable to external pressure to reconcile with Fatah in search of a political outcome, but their ability to influence events on the ground in Gaza will be limited. That was demonstrated by the Sinwar-orchestrated attacks on 7 October 2023, which took place without the blessing of the exiled leadership in Doha.

Hamas has long gone to ground in Gaza and become far more decentralized than it was before 7 October. It is now more typical of an insurgency, where Hamas cadres exercise a great degree of operational autonomy.

In other words, the disconnect between Hamas in Gaza and its political leadership in Qatar has only grown wider since this round of conflict started.

International efforts

That will undermine international efforts made by Qatar, Egypt, Saudi Arabia, China, Russia and others to bring about a reconciliation. Moscow and Beijing already hosted reconciliation talks in February and April early this year but made no progress in closing the chasm between the two parties. Saudi Arabia has also hosted talks.

The three Arab states, none of which have so far commented publicly on Sinwar’s killing, will likely view his death as an opportunity to bolster the political wing of Hamas – backing it with pledges of political, diplomatic and financial support.

Saudi Arabia and Egypt will have next to no influence over the succession process, but Qatar’s long-established relationship with the political wing of Hamas affords it leverage over the organization, albeit limited. They may be able to strengthen the hand of those based in Doha by promising to work harder at securing a ceasefire, guaranteeing the provision of humanitarian relief, and working towards a political solution.

Expert

Expert

A. G. Sergeev, A. Kh. Khachatryan and Kh. A. Khachatryan
Trans. Moscow Math. Soc. 83 (), 55-65.
Abstract, references and article information

Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment.

The recent structural elucidation of ex vivo Drosophila Orb2 fibrils revealed a novel amyloid formed by interdigitated Gln and His residue side chains belonging to the prion-like domain. However, atomic-level details on the conformational transitions associated with memory consolidation remain unknown. Here, we have characterized the nascent conformation and dynamics of the prion-like domain (PLD) of Orb2A using a nonconventional liquid-state NMR spectroscopy strategy based on 13C detection to afford an essentially complete set of 13Cα, 13Cβ, 1Hα, and backbone 13CO and 15N assignments. At pH 4, where His residues are protonated, the PLD is disordered and flexible, except for a partially populated α-helix spanning residues 55–60, and binds RNA oligos, but not divalent cations. At pH 7, in contrast, His residues are predominantly neutral, and the Q/H segments adopt minor populations of helical structure, show decreased mobility and start to self-associate. At pH 7, the His residues do not bind RNA or Ca2+, but do bind Zn2+, which promotes further association. These findings represent a remarkable case of structural plasticity, based on which an updated model for Orb2A functional amyloidogenesis is suggested.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

The glycoprotein spike (S) on the surface of SARS-CoV-2 is a determinant for viral invasion and host immune response. Herein, we characterized the site-specific N-glycosylation of S protein at the level of intact glycopeptides. All 22 potential N-glycosites were identified in the S-protein protomer and were found to be preserved among the 753 SARS-CoV-2 genome sequences. The glycosites exhibited glycoform heterogeneity as expected for a human cell-expressed protein subunit. We identified masses that correspond to 157 N-glycans, primarily of the complex type. In contrast, the insect cell-expressed S protein contained 38 N-glycans, completely of the high-mannose type. Our results revealed that the glycan types were highly determined by the differential processing of N-glycans among human and insect cells, regardless of the glycosites’ location. Moreover, the N-glycan compositions were conserved among different sizes of subunits. Our study indicate that the S protein N-glycosylation occurs regularly at each site, albeit the occupied N-glycans were diverse and heterogenous. This N-glycosylation landscape and the differential N-glycan patterns among distinct host cells are expected to shed light on the infection mechanism and present a positive view for the development of vaccines and targeted drugs.

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