MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration.

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015.

Substrate interactions guide cyclase engineering and lasso peptide diversification.

Lasso peptides are a diverse class of naturally occurring, highly stable molecules kinetically trapped in a distinctive [1]rotaxane conformation. How the ATP-dependent lasso cyclase constrains a relatively unstructured substrate peptide into a low entropy product has remained a mystery owing to poor enzyme stability and activity in vitro. In this study, we combined substrate tolerance data with structural predictions, bioinformatic analysis, molecular dynamics simulations and mutational scanning to construct a model for the three-dimensional orientation of the substrate peptide in the lasso cyclase active site.

Advances in lasso peptide discovery, biosynthesis, and function.

Lasso peptides are a large and sequence-diverse class of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products characterized by their slip knot-like shape. These unique, highly stable peptides are produced by bacteria for various purposes. Their stability and sequence diversity make them a potentially useful scaffold for biomedically relevant folded peptides.

Digital Technology in Community Engagement: Impacts and Implications.

Health professionals are increasingly using digital technology as a strategy to maximize community engagement and effectively implement health interventions, a phenomenon evidenced by the COVID-19 pandemic. While technology has improved health information dissemination, communication, and data management, it cannot replace the human-based interactions offered by traditional grassroots outreach that can influence long-term health behavior change, particularly for underserved communities. Digital community engagement can be part of the digital divide, often widening disparities by excluding those without access or limited access to technology.

The role of doulas in providing breastfeeding support during the COVID-19 pandemic.

Background: Doulas have been instrumental in providing breastfeeding support to nursing mothers before and during the COVID-19 pandemic, as they can significantly impact a mother's ability to initiate and maintain breastfeeding. However, the COVID-19 pandemic, subsequent lockdowns, and social isolation created challenges for nursing mothers to access doulas' services, usually provided in person. In this study, we examined the role of doulas in providing breastfeeding support during the COVID-19 pandemic, exploring adaptation to COVID-19 guidelines and the challenges doulas face in providing breastfeeding support during the pandemic.

Peptidase Activation by a Leader Peptide-Bound RiPP Recognition Element.

The RiPP precursor recognition element (RRE) is a conserved domain found in many prokaryotic ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthetic gene clusters (BGCs). RREs bind with high specificity and affinity to a recognition sequence within the N-terminal leader region of RiPP precursor peptides. Lasso peptide biosynthesis involves an RRE-dependent leader peptidase, which is discretely encoded or fused to the RRE as a di-domain protein.

A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial of Radiopaque Islatravir-Eluting Subdermal Implants for Pre-exposure Prophylaxis Against HIV-1 Infection.

Background: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP).

Setting: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.

Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial.

Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal.

Drug eluting implants in pharmaceutical development and clinical practice.

: Drug eluting implants offer patient convenience and improved compliance through less frequent dosing, eliminating repeated, painful injections and providing localized, site specific delivery with applications in contraception, ophthalmology, and oncology.: This review provides an overview of available implant products, design approaches, biodegradable and non-biodegradable polymeric materials, and fabrication techniques with a focus on commercial applications and industrial drug product development. Developing trends in the field, including expanded availability of suitable excipients, development of novel materials, scaled down manufacturing process, and a wider understanding of the implant development process are discussed and point to opportunities for differentiated drug eluting implant products.

Accurate and Efficient One-Pot Reverse Transcription and Amplification of 2'-Fluoro-Modified Nucleic Acids by Commercial DNA Polymerases.

DNA is a foundational tool in biotechnology and synthetic biology but is limited by sensitivity to DNA-modifying enzymes. Recently, researchers have identified DNA polymerases that can enzymatically synthesize long oligonucleotides of modified DNA (M-DNA) that are resistant to DNA-modifying enzymes. Most applications require M-DNA to be reverse transcribed, typically using a RNA reverse transcriptase, back into natural DNA for sequence analysis or further manipulation.

An Imaging Toolkit for Physical Characterization of Long-Acting Pharmaceutical Implants.

In pharmaceutical development alternative drug delivery modalities are being increasingly employed. One example is an implant, which achieves gradual drug release in patients over a period of many months or years. Due to the complexity of these long-acting formulations, advanced physical characterization methods are desirable as screening tools during protracted formulation development.

Islatravir Case Study for Enhanced Screening of Thermodynamically Stable Crystalline Anhydrate Phases in Pharmaceutical Process Development by Hot Melt Extrusion.

The emergence of new active pharmaceutical ingredient (API) polymorphs in pharmaceutical development presents significant risks. Even with thorough polymorph screening, new pathways toward alternate crystal phases can present themselves over the course of formulation development; thus, further improvements in phase screening methods are needed. Herein, a case study is presented of a thermodynamically stable crystalline phase of the HIV drug Islatravir (MK-8591, EFdA) that was not isolated from initial pharmaceutical polymorph screening.

Reaching the sparse-sampling limit for reconstructing a single peak in a 2D NMR spectrum using iterated maps.

Many of the ubiquitous experiments of biomolecular NMR, including [Formula: see text], [Formula: see text], and CEST, involve acquiring repeated 2D spectra under slightly different conditions. Such experiments are amenable to acceleration using non-uniform sampling spectral reconstruction methods that take advantage of prior information. We previously developed one such technique, an iterated maps method (DiffMap) that we successfully applied to 2D NMR spectra, including [Formula: see text] relaxation dispersion data.

Accelerating 2D NMR relaxation dispersion experiments using iterated maps.

NMR relaxation dispersion experiments play a central role in exploring molecular motion over an important range of timescales, and are an example of a broader class of multidimensional NMR experiments that probe important biomolecules. However, resolving the spectral features of these experiments using the Fourier transform requires sampling the full Nyquist grid of data, making these experiments very costly in time. Practitioners often reduce the experiment time by omitting 1D experiments in the indirectly observed dimensions, and reconstructing the spectra using one of a variety of post-processing algorithms.

Exploration of long-acting implant formulations of hepatitis B drug entecavir.

Alternative formulations of entecavir, a once daily oral hepatitis B antiretroviral, may improve treatment adherence by patients. We explored the use of biocompatible polymers to control entecavir dissolution in two formats suitable for subcutaneous implantation. Hot melt extrudates were prepared by extruding entecavir-polymer blends at specified weight ratios.

A preparative method for the isolation and fractionation of dissolved organic acids from bitumen-influenced waters.

The surface mining of oil sands north of Fort McMurray, Alberta produces considerable tailings waste that is stored in large tailings ponds on industrial lease sites. Viable strategies for the detoxification of oil sands process affected water (OSPW) are under investigation. In order to assess the toxic potential of the suite of dissolved organics in OSPW, a method for their extraction and fractionation was developed using solid phase extraction.

Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention.

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence.

Observation of Discrete-Time-Crystal Signatures in an Ordered Dipolar Many-Body System.

A discrete time crystal (DTC) is a robust phase of driven systems that breaks the discrete time translation symmetry of the driving Hamiltonian. Recent experiments have observed DTC signatures in two distinct systems. Here we show nuclear magnetic resonance observations of DTC signatures in a third, strikingly different system: an ordered spatial crystal.

Sustained Release Drug Delivery Applications of Polyurethanes.

Since their introduction over 50 years ago, polyurethanes have been applied to nearly every industry. This review describes applications of polyurethanes to the development of modified release drug delivery. Although drug delivery research leveraging polyurethanes has been ongoing for decades, there has been renewed and substantial interest in the field in recent years.

Correlation of apparent diffusion coefficient ratio on 3.0 T MRI with prostate cancer Gleason score.

Introduction: The purpose was to investigate the usefulness of ADC on Diffusion MRI to discriminate between benign and malignant lesions of Prostate.

Methods: Images of patients who underwent in-gantry MRI guided prostate lesion biopsy were retrospectively analyzed. Prostate Cancers with 20% or more Gleason score (GS) pattern 3 + 3 = 6 in each core or any volume of higher Gleason score pattern were included.

Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges.

Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. The duration of treatment required for all forms of tuberculosis (TB) put existing regimens at risk of failure because of early discontinuations and treatment loss to follow-up.

Design and Discovery of New Combinations of Mutant DNA Polymerases and Modified DNA Substrates.

Chemical modifications can enhance the properties of DNA by imparting nuclease resistance and generating more-diverse physical structures. However, native DNA polymerases generally cannot synthesize significant lengths of DNA with modified nucleotide triphosphates. Previous efforts have identified a mutant of DNA polymerase I from Thermus aquaticus DNA (SFM19) as capable of synthesizing a range of short, 2'-modified DNAs; however, it is limited in the length of the products it can synthesize.

Who is in Your Waiting Room? Health Care Professionals as Culturally Responsive and Trauma-Informed First Responders to Human Trafficking.

Evidence-based practice standards are not yet well defined for assisting potential victims of human trafficking. Nonetheless, health care professionals are learning to be first responders in identifying, treating, and referring potential victims. As more public and private sector resources are used to train health care professionals about human trafficking, more evaluation and research are needed to develop an effective standard of care.

Liver-Targeted SiRNA Delivery Using Biodegradable Poly(amide) Polymer Conjugates.

The realization of polymer conjugate-based RNA delivery as a clinical modality requires the development and optimization of novel formulations. Although many literature examples of polymer conjugate-based SiRNA delivery systems exist, the protocols described herein represent a robust and facile way of screening any poly(amine)-based polymer system for SiRNA delivery. In this chapter, we describe the synthetic methods used to prepare poly(amide) polymers using a controlled polymerization method, as well as the preparation of the resulting targeted SiRNA polymer conjugates.