Interventions against variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Stable and potent nanobodies (Nbs) that target the receptor binding domain (RBD) of SARS-CoV-2 spike are promising therapeutics. However, it is unknown if Nbs broadly neutralize circulating variants. We found that RBD Nbs are highly resistant to variants of concern (VOCs). High-resolution cryoelectron microscopy determination of eight Nb-bound structures reveals multiple potent neutralizing epitopes clustered into three classes: Class I targets ACE2-binding sites and disrupts host receptor binding. Class II binds highly conserved epitopes and retains activity against VOCs and RBDSARS-CoV. Cass III recognizes unique epitopes that are likely inaccessible to antibodies. Systematic comparisons of neutralizing antibodies and Nbs provided insights into how Nbs target the spike to achieve high-affinity and broadly neutralizing activity. Structure-function analysis of Nbs indicates a variety of antiviral mechanisms. Our study may guide the rational design of pan-coronavirus vaccines and therapeutics.

Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin’s Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin’s assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10–20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer’s disease and malaria.

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ObjectiveWe aimed to compare rescuer fatigue and cardiopulmonary resuscitation (CPR) quality between standard 30:2 CPR (ST-CPR) and chest compression only CPR (CO-CPR) performed for 8 minutes on a realistic manikin by following the 2010 CPR guidelines.MethodsAll 36 volunteers (laypersons; 18 men and 18 women) were randomized to ST-CPR or CO-CPR at first, and then each CPR technique was performed for 8 minutes with a 3-hour rest interval. We measured the mean blood pressure (MBP) of the volunteers before and after performing each CPR technique, and continuously monitored the heart rate (HR) of the volunteers during each CPR technique using the MRx monitor. CPR quality measures included the depth of chest compression (CC) and the number of adequate CCs per minute.ResultsThe adequate CC rate significantly differed between the 2 groups after 2 minutes, with it being higher in the ST-CPR group than in the CO-CPR group. Additionally, the adequate CC rate significantly differed between the 2 groups during 8 minutes for male volunteers (p =0.012). The number of adequate CCs was higher in the ST-CPR group than in the CO-CPR group after 3 minutes (p =0.001). The change in MBP before and after performing CPR did not differ between the 2 groups. However, the change in HR during 8 minutes of CPR was higher in the CO-CPR group than in the ST-CPR group (p =0.007).ConclusionsThe rate and number of adequate CCs were significantly lower with the CO-CPR than with the ST-CPR after 2 and 6 minutes, respectively, and performer fatigue was higher with the CO-CPR than with the ST-CPR during 8 minutes of CPR.

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Diabetic retinopathy progression can occur in patients with or without before DR after bariatric surgery, regardless of remission of T2DM. All patients with T2DM should be examined regularly by an ophthalmologist postoperatively, and more carefully patients with previous DR or albuminuria.

The evolutionarily conserved TREX complex plays central roles during mRNP (messenger ribonucleoprotein) maturation and export from the nucleus to the cytoplasm. In yeast, TREX is composed of the THO sub-complex (Tho2, Hpr1, Tex1, Mft1, and Thp2), the DEAD box ATPase Sub2, and Yra1. Here we present a 3.7 Å cryo-EM structure of the yeast THO•Sub2 complex. The structure reveals the intimate assembly of THO revolving around its largest subunit Tho2. THO stabilizes a semi-open conformation of the Sub2 ATPase via interactions with Tho2. We show that THO interacts with the SR-like protein Gbp2 through both the RS domain and RRM domains of Gbp2. Crosslinking mass spectrometry analysis supports the extensive interactions between THO and Gbp2, further revealing that RRM domains of Gbp2 are in close proximity to the C-terminal domain of Tho2. We propose that THO serves as a landing pad to configure Gbp2 to facilitate its loading onto mRNP.

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