Adjuvants restore colistin sensitivity in mouse models of highly colistin-resistant isolates, limiting bacterial proliferation and dissemination.

Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections.

Profiling expression strategies for a type III polyketide synthase in a lysate-based, cell-free system.

Some of the most metabolically diverse species of bacteria (e.g., Actinobacteria) have higher GC content in their DNA, differ substantially in codon usage, and have distinct protein folding environments compared to tractable expression hosts like Escherichia coli.

Profiling Expression Strategies for a Type III Polyketide Synthase in a Lysate-Based, Cell-free System.

Some of the most metabolically diverse species of bacteria (e.g., Actinobacteria) have higher GC content in their DNA, differ substantially in codon usage, and have distinct protein folding environments compared to tractable expression hosts like .

Expression of blue pigment synthetase a from Streptomyces lavenduale reveals insights on the effects of refactoring biosynthetic megasynthases for heterologous expression in Escherichia coli.

High GC bacteria from the genus Streptomyces harbor expansive secondary metabolism. The expression of biosynthetic proteins and the characterization and identification of biological "parts" for synthetic biology purposes from such pathways are of interest. However, the high GC content of proteins from actinomycetes in addition to the large size and multi-domain architecture of many biosynthetic proteins (such as non-ribosomal peptide synthetases; NRPSs, and polyketide synthases; PKSs often called "megasynthases") often presents issues with full-length translation and folding.

Investigating and Optimizing the Lysate-Based Expression of Nonribosomal Peptide Synthetases Using a Reporter System.

Lysate-based cell-free expression (CFE) systems are accessible platforms for expressing proteins that are difficult to synthesize , such as nonribosomal peptide synthetases (NRPSs). NRPSs are large (>100 kDa), modular enzyme complexes that synthesize bioactive peptide natural products. This synthetic process is analogous to transcription/translation (TX/TL) in lysates, resulting in potential resource competition between NRPS expression and NRPS activity in cell-free environments.

Torsades de Pointes With a Normal Magnesium Level in the Setting of Short Bowel Syndrome.

Torsades de pointes (TdP) is a potentially fatal arrhythmia, typically presenting with a congenital or acquired etiology. Low serum magnesium level is a known cause leading to this arrhythmia. However, it has been found that even in the setting of a normal serum magnesium level and with no other foreseeable etiology, TdP may still occur, especially in those with chronic electrolyte deficiencies.

The relationship of semantic intrusions to different etiological subtypes of MCI and cognitively healthy older adults.

Introduction: There is increasing evidence that susceptibility to proactive semantic interference (PSI) and the failure to recover from PSI (frPSI) as evidenced by intrusion errors may be early cognitive markers of both preclinical and prodromal Alzheimer's disease (AD).

Methods: One hundred forty-five participants were administered extensive clinical and neuropsychological evaluations including the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive cognitive stress test measuring PSI and frPSI. Participants also underwent structural magnetic resonance imaging (MRI) and amyloid positron emission tomography/computed tomography (PET/CT) imaging.

Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram-negative bacteria.

The mounting threat of multi-drug-resistant (MDR) bacteria places a tremendous strain on the antimicrobial clinical arsenal, forcing physicians to revert to near-obsolete antibiotics to treat otherwise intractable infections. Antibiotic adjuvant therapy has emerged as a viable alternative to the development of novel antimicrobial agents. This method uses combinations of an existing antibiotic and a non-antimicrobial small molecule, where the combination either breaks drug resistance or further potentiates antibiotic activity.

Structure-Function Studies on IMD-0354 Identifies Highly Active Colistin Adjuvants.

Infections caused by multidrug-resistant (MDR) bacteria, particularly Gram-negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last-resort antibiotic colistin; however, colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram-negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics.

Repurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-Negative Bacteria.

Kinase inhibitors comprise a diverse cohort of chemical scaffolds that are active in multiple biological systems. Currently, thousands of eukaryotic kinase inhibitors are commercially available, have well-characterized targets, and often carry pharmaceutically favorable toxicity profiles. Recently, our group disclosed that derivatives of the natural product meridianin D, a known inhibitor of eukaryotic kinases, modulated behaviors of both Gram-positive and Gram-negative bacteria.

Second-Generation Tryptamine Derivatives Potently Sensitize Colistin Resistant Bacteria to Colistin.

Antibiotic resistance has significantly increased since the beginning of the 21st century. Currently, the polymyxin colistin is typically viewed as the antibiotic of last resort for the treatment of multidrug resistant Gram-negative bacterial infections. However, increased colistin usage has resulted in colistin-resistant bacterial isolates becoming more common.

Types of errors on a semantic interference task in mild cognitive impairment and dementia.

Objective: This research aimed to determine whether qualitative analysis of different types of intrusion errors on a verbal cognitive task was useful in detecting subtle cognitive impairment in preclinical stages prior to the progression to dementia.

Method: Different types of semantic intrusions on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L) were compared across 160 individuals diagnosed as cognitively normal (CN), amnestic Mild Cognitive Impairment (aMCI), and dementia. The sample included Hispanics and non-Hispanic European Americans.

Tryptamine derivatives disarm colistin resistance in polymyxin-resistant gram-negative bacteria.

The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains.

Effects of Bilingualism on Verbal and Nonverbal Memory Measures in Mild Cognitive Impairment.

Objectives: Maintaining two active languages may increase cognitive and brain reserve among bilingual individuals. We explored whether such a neuroprotective effect was manifested in the performance of memory tests for participants with amnestic mild cognitive impairment (aMCI).

Methods: We compared 42 bilinguals to 25 monolinguals on verbal and nonverbal memory tests.

Utilizing semantic intrusions to identify amyloid positivity in mild cognitive impairment.

Objective: Semantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology [SNAP]) or persons who are diagnosed with other brain disorders affecting cognition.

Methods: Eighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy-), or other neurological/psychiatric diagnosis (Amy-). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning).

Meridianin D Analogues Display Antibiofilm Activity against MRSA and Increase Colistin Efficacy in Gram-Negative Bacteria.

In the last 30 years, development of new classes of antibiotics has slowed, increasing the necessity for new options to treat multidrug resistant bacterial infections. Development of antibiotic adjuvants that increase the effectiveness of currently available antibiotics is a promising alternative approach to classical antibiotic development. Reports of the ability of the natural product meridianin D to modulate bacterial behavior have been rare.

Semantic Intrusions and Failure to Recover From Semantic Interference in Mild Cognitive Impairment: Relationship to Amyloid and Cortical Thickness.

Background: Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer's disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory.

Objectives: We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI).

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria.

Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance-1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr.

Laparoscopic repair of paraesophageal hernias.

Background And Objectives: Laparoscopy has quickly become the standard surgical approach to repair paraesophageal hernias. Although many centers routinely perform this procedure, relatively high recurrence rates have led many surgeons to question this approach. We sought to evaluate outcomes in our cohort of patients with an emphasis on recurrence rates and symptom improvement and their correlation with true radiologic recurrence seen on contrast imaging.

An electron transfer series of octahedral chromium complexes containing a redox non-innocent α-diimine ligand.

An electron-transfer series of octahedral α-diimine complexes [((H)L(Cy))3Cr](n+)(BARF)n (n = 2, 1, 0) has been synthesized and crystallographically characterized. Cyclic voltammetry indicated additional formation of [((H)L(Cy))3Cr](3+). The molecular structures suggested that all redox processes were ligand-based.

Sharing knowledge, saving time: an online toolbox to aid junior doctors.

Junior doctors are too often frustrated by not being able to quickly find information for how to make referrals, book investigations and contact other professionals at hospital. To make matters worse, much of the knowledge gained by doctors throughout the year is lost during the August rotation. There is an unmet need for retaining such knowledge, in order to facilitate a smoother and safer handover.

Time-calibrated phylogeny of the woody Australian genus Hakea (Proteaceae) supports multiple origins of insect-pollination among bird-pollinated ancestors.

Premise Of The Study: A past study based on morphological data alone showed that the means by which plants of the Australian genus Hakea reduce florivory is related to the evolution of bird pollination. For example, bird pollination was shown to have arisen only in insect-pollinated lineages that already produced greater amounts of floral cyanide, a feature that reduces florivory. We examine a central conclusion of that study, and a common assumption in the literature, that bird pollination arose in insect-pollinated lineages, rather than the reverse.

Factors predicting discharge of Huntington's disease patients from a neuropsychiatry unit.

Background: We explored phenotypic parameters of people with Huntington's disease who had been admitted to a psychiatric unit and then discharged, with a view to determining prognostic factors for discharge to higher levels of care.

Methods: A cross-sectional study was carried out on 19 patients admitted to a psychiatric unit with Huntington's disease. Data on the Unified Huntington's Disease Rating Scale (UHDRS) of behavior and function, global assessment of presence of depression and dementia as well as discharge outcomes were collated.