Structural and Mechanistic Bases for Resistance of the M66I Capsid Variant to Lenacapavir.

Unlabelled: Lenacapavir (LEN) is the first in class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance associated mutations (RAMs) in the vicinity of the hydrophobic CA pocket targeted by LEN. The M66I substitution conferred by far the highest level of resistance to the inhibitor compared to other RAMs.

Crystal structure of the GDP-bound human M-RAS protein in two crystal forms.

M-RAS plays a crucial role in the RAF-MEK signaling pathway. When activated by GTP, M-RAS forms a complex with SHOC2 and PP1C, initiating downstream RAF-MEK signal transduction. In this study, the crystal structure of the GDP-bound human M-RAS protein is presented with two forms of crystal packing.

Enhancing the apo protein tyrosine phosphatase non-receptor type 2 crystal soaking strategy through inhibitor-accessible binding sites.

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) has recently been recognized as a promising target for cancer immunotherapy. Despite extensive structural and functional studies of other protein tyrosine phosphatases, there is limited structural understanding of PTPN2. Currently, there are only five published PTPN2 structures and none are truly unbound due to the presence of a mutation, an inhibitor or a loop (related to crystal packing) in the active site.

Curating an online checklist for Erica L. (Ericaceae): contributing to and supporting global conservation through the World Flora Online.

To support the work of the Global Conservation Consortium for and update the checklist in the World Flora Online (WFO), we have curated the taxonomic backbone in the WFO by expanding it to include updated nomenclatural information from the International Plant Name Index, missing names present in the World Checklist of Vascular Plants (WCVP), the Botanical Database of Southern Africa (BODATSA), and from the "International register of heather names" database, a data source not readily available online. The result is the most robust database of names to date, including 851 species, 111 subspecies, 244 varieties, and 2787 synonyms, which is a reliable reference for initiatives such as the identification aid, conservation prioritisation, and gap analyses. We disambiguate common orthographic variants within the database and present an overview of these.

Quality Improvement to Eliminate Disparities in Developmental Screening for Patients Needing Interpreters.

Unlabelled: Children from households with a preferred language other than English are less likely to receive timely identification and treatment for developmental delay than children of native English speakers. In dismantling this inequity, the role of primary care pediatrics is to establish equitable systems for screening and referral. This project, conducted in a network of twelve pediatric primary care centers, focused on eliminating a small but systematic disparity in developmental screening rates between families who did and did not require interpreters (86% versus 92%).

Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir.

Lenacapavir (LEN) is a long-acting, highly potent HIV-1 capsid (CA) inhibitor. The evolution of viral variants under the genetic pressure of LEN identified Q67H, N74D, and Q67H/N74D CA substitutions as the main resistance associated mutations (RAMs). Here, we determined high-resolution structures of CA hexamers containing these RAMs in the absence and presence of LEN.

Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6.

The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C.

Structural and mechanistic bases for a potent HIV-1 capsid inhibitor.

The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice.

Synthesis and Molecular Properties of Nerve Agent Reactivator HLö-7 Dimethanesulfonate.

The threat of a deliberate release of chemical nerve agents has underscored the need to continually improve field effective treatments for these types of poisonings. The oxime containing HLö-7 is a potential second-generation therapeutic reactivator. A synthetic process for HLö-7 is detailed with improvements to the DIBAL reduction and ion exchange steps.

The structural and biochemical impacts of monomerizing human acetylcholinesterase.

Serving a critical role in neurotransmission, human acetylcholinesterase (hAChE) is the target of organophosphate nerve agents. Hence, there is an active interest in studying the mechanism of inhibition and recovery of enzymatic activity, which could lead to better countermeasures against nerve agents. As hAChE is found in different oligomeric assemblies, certain approaches to studying it have been problematic.

The Cuito catchment of the Okavango system: a vascular plant checklist for the Angolan headwaters.

This paper aims to provide a baseline for conservation planning by documenting patterns of plant diversity and vegetation in the upper catchment of the Cuito River. 417 species are recorded from this region. Nine of these are species potentially new to science.

Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6.

Over 50 years ago, the toxicity of irreversible organophosphate inhibitors targeting human acetylcholinesterase (hAChE) was observed to be stereospecific. The therapeutic reversal of hAChE inhibition by reactivators has also been shown to depend on the stereochemistry of the inhibitor. To gain clarity on the mechanism of stereospecific inhibition, the X-ray crystallographic structures of hAChE inhibited by a racemic mixture of VX (P ) and its enantiomers were obtained.

Insights into the Porcine Reproductive and Respiratory Syndrome Virus Viral Ovarian Tumor Domain Protease Specificity for Ubiquitin and Interferon Stimulated Gene Product 15.

Porcine reproductive and respiratory syndrome (PRRS) is a widespread economically devastating disease caused by PRRS virus (PRRSV). First recognized in the late 1980s, PRRSV is known to undergo somatic mutations and high frequency viral recombination, which leads to many diverse viral strains. This includes differences within viral virulence factors, such as the viral ovarian tumor domain (vOTU) protease, also referred to as the papain-like protease 2.

Oxygen limitation and thermal tolerance in two terrestrial arthropod species.

Recent studies of marine invertebrates and fish have suggested that lower and upper critical temperatures (CT(min) and CT(max)) are coupled by a common mechanism: oxygen and capacity limitation of thermal tolerance (OCLT). Using thermolimit respirometry, we tested the predictions of this theory for terrestrial arthropods by measuring maxima and minima for both critical temperatures and metabolic rate in two arthropods, the isopod Porcellio scaber and the beetle Tenebrio molitor, at 40%, 21%, 10% and 2.5% ambient O(2).

[Infratentorial pathology a pitfall for neonatal cerebral sonography: Additional sonographic imaging through the posterolateral fontanelle, a prospective study].

Background: Routine assessment of the neonatal brain is performed by ultrasound through the anterior fontanelle. The infratentorial structures can be visualised more detailed by sonography through the posterolateral fontanelle. This prospective study was performed to evaluate anterior fontanelle and posterolateral fontanelle for the detection of infratentorial lesions.

Isolated large third-trimester intracranial cyst on fetal ultrasound: fact or fiction?

Objective: To distinguish the fact from artifact of an isolated, large, intracranial cyst on prenatal sonography (PSG).

Background: The use of PSG is rapidly increasing with most obstetric ultrasounds occurring in general community settings like small hospitals and clinics with personnel who have variable training, experience, and interest levels. In contrast, most PSG articles and books are produced in large subspecialty centers with concentrated referral bases plus both highly-trained and experienced personnel.

Bruxism threshold: an explanation for successful treatment of the multifactorial aetiology of bruxism.

Many authors claim successful treatment of bruxism by various treatment modalities. This paper presents a review of the nature of bruxism, the multifactorial aetiology of bruxism and a discussion of successful treatment of bruxism by various treatment modalities. The aim of this paper is to provide an explanation for successful treatment of bruxism on the basis of decreasing or eliminating any one or more of the aetiological stimuli to a combined level below the bruxism threshold.

The effect of airborne particle abrasion on the dentin smear layer and dentin: an in vitro investigation.

This study investigated the effect of airborne particle abrasion on the exposed dentin surfaces of 40 extracted teeth. A Siroflow abrasion unit was used to treat four groups of ten specimens that were subjected to 5, 10, 20, and 40 seconds of abrasion respectively. Statistical analysis (Spearman Rank Order) showed a significant difference between all groups (P < .

The communicative effectiveness index: development and psychometric evaluation of a functional communication measure for adult aphasia.

Groups of aphasic patients and their spouses generated a series of communication situations that they felt were important in their day-to-day life. Using criteria to ensure that the situations were generalizable across people, times, and places, we reduced the number of situations to 36 and constructed an index that allowed the significant others of 11 recovering and 11 stable aphasic individuals to rate their partners' performance in the situations on two occasions 6 weeks apart. These data were then used to evaluate the psychometric properties of the Communicative Effectiveness Index (CETI) as a measure of change in functional communication ability.