A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity.

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

Improved production of palitantin by design of experiments and semi-synthesis of palitantin derivatives for bioactivity assessment.

A new method for the production and isolation of (+)-palitantin (1) is herein reported, from cultures of the fungal strain Penicillium sp. AMF1a. (+)-Palitantin was isolated in 160 mg/L yield, as an alternative procedure to obtain 1 at a larger scale.

Structure and Biosynthesis of Perochalasins A-C, Open-Chain Merocytochalasans Produced by the Marine-Derived Fungus sp. M16.

Novel open-chain merocytochalasans, perochalasins A-C (-), containing an unusual N-O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived sp. M16 fungus, along with cytochalasin Z (), cytochalasin Z (), [12]-cytochalasin (), and phenochalasin B (). The structures of compounds - were established by analysis of the spectroscopic data.

[1-7-NαC]-Crocaorb A1 and A2, orbitides from the latex of Croton campanulatus.

Two new heptapeptides, [1-7-NαC]-crocaorbs A1 (1) and A2 (2), were isolated from the latex of Croton campanulatus. Their structures were determined using NMR spectroscopic techniques, ESI-HRMS data, Marfey's method, and further refined using molecular dynamics with simulated annealing (MD/SA). Molecular dynamics calculations of peptides 1 and 2 demonstrated greater stability in simulations using a biological solvent compared to those using DMSO.

Ferroelectric AlScN and HfZrO Domain Switching Dynamics.

The capability to reliably program partial polarization states with nanosecond programming speed and femtojoule energies per bit in ferroelectrics makes them an ideal candidate to realize multibit memory elements for high-density crossbar arrays, which could enable neural network models with a large number of parameters at the edge. However, a thorough understanding of the domain switching dynamics involved in the polarization reversal is required to achieve full control of the multibit capability. Transient current integration measurements are adopted to investigate the domain dynamics in aluminum scandium nitride (AlScN) and hafnium zirconium oxide (HfZrO).

Genetic Algorithm for Feature Selection Applied to Financial Time Series Monotonicity Prediction: Experimental Cases in Cryptocurrencies and Brazilian Assets.

Since financial assets on stock exchanges were created, investors have sought to predict their future values. Currently, cryptocurrencies are also seen as assets. Machine learning is increasingly adopted to assist and automate investments.

Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus.

Objectives: The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results.

Methods: Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines.

Enduring Consensus Guidelines for Cervical Cancer Screening and Management: Introduction to the Scope and Process.

Objectives: The Enduring Consensus Cervical Cancer Screening and Management Guidelines (Enduring Guidelines) effort is a standing committee to continuously evaluate new technologies and approaches to cervical cancer screening, management, and surveillance.

Methods And Results: The Enduring Guidelines process will selectively incorporate new technologies and approaches with adequate supportive data to more effectively improve cancer prevention for high-risk individuals and decrease unnecessary procedures in low-risk individuals. This manuscript describes the structure, process, and methods of the Enduring Guidelines effort.

Analysis of survival rate and persistence predictors of baricitinib in real-world data from a large cohort of rheumatoid arthritis patients.

Objectives: The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years.

Kinetics of N- to M-Polar Switching in Ferroelectric AlScN Capacitors.

Ferroelectric wurtzite-type aluminum scandium nitride (AlScN) presents unique properties that can enhance the performance of non-volatile memory technologies. The realization of the full potential of AlScN requires a comprehensive understanding of the mechanism of polarization reversal and domain structure dynamics involved in the ferroelectric switching process. In this work, transient current integration measurements performed by a pulse switching method are combined with domain imaging by piezoresponse force microscopy (PFM) to investigate the kinetics of domain nucleation and wall motion during polarization reversal in AlScN capacitors.

Discovery of new piperaquine hybrid analogs linked by triazolopyrimidine and pyrazolopyrimidine scaffolds with antiplasmodial and transmission blocking activities.

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates.

2019 ASCCP Risk-Based Management Consensus Guidelines: Updates Through 2023.

This Research Letter summarizes all updates to the 2019 Guidelines through September 2023, including: endorsement of the 2021 Opportunistic Infections guidelines for HIV+ or immunosuppressed patients; clarification of use of human papillomavirus testing alone for patients undergoing observation for cervical intraepithelial neoplasia 2; revision of unsatisfactory cytology management; clarification that 2012 guidelines should be followed for patients aged 25 years and older screened with cytology only; management of patients for whom colposcopy was recommended but not completed; clarification that after treatment for cervical intraepithelial neoplasia 2+, 3 negative human papillomavirus tests or cotests at 6, 18, and 30 months are recommended before the patient can return to a 3-year testing interval; and clarification of postcolposcopy management of minimally abnormal results.

Optimization of Plasmodium vivax infection of colonized Amazonian Anopheles darlingi.

Obtaining Plasmodium vivax sporozoites is essential for in vitro culture of liver stage parasites, not only to understand fundamental aspects of parasite biology, but also for drug and vaccine development. A major impediment to establish high-throughput in vitro P. vivax liver stage assays for drug development is obtaining sufficient numbers of sporozoites.

Emerging Treatment Options for Cervical Dysplasia and Early Cervical Cancer.

of treatment strategies for cervical cancer precursors, review of medical therapies and emerging therapeutics for treatment of cervical cancers, and updates on new approaches to treating early-stage cervical cancers.

Management of Abnormal Cervical Cancer Screening Test: A Risk-based Approach.

Cervical cancer screening plays a major role in preventing cervical cancer. The field is based on understanding the natural history of human papillomavirus and its role in cervical cancer. Screening has evolved to assessing the risk for cervical intraepithelial neoplasia grade 3, a true cancer precursor, and performing diagnostic tests based on those risks.

Cervical Cancer Screening: A Review.

Importance: Each year in the US, approximately 100 000 people are treated for cervical precancer, 14 000 people are diagnosed with cervical cancer, and 4000 die of cervical cancer.

Observations: Essentially all cervical cancers worldwide are caused by persistent infections with one of 13 carcinogenic human papillomavirus (HPV) genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. HPV vaccination at ages 9 through 12 years will likely prevent more than 90% of cervical precancers and cancers.

Role of Defects in the Breakdown Phenomenon of AlScN: From Ferroelectric to Filamentary Resistive Switching.

Aluminum scandium nitride (AlScN), with its large remanent polarization, is an attractive material for high-density ferroelectric random-access memories. However, the cycling endurance of AlScN ferroelectric capacitors is far below what can be achieved in other ferroelectric materials. Understanding the nature and dynamics of the breakdown mechanism is of the utmost importance for improving memory reliability.

MFCC Parameters of the Speech Signal: An Alternative to Formant-Based Instantaneous Vocal Tract Length Estimation.

On the one hand, the relationship between formant frequencies and vocal tract length (VTL) has been intensively studied over the years. On the other hand, the connection involving mel-frequency cepstral coefficients (MFCCs), which concisely codify the overall shape of a speaker's spectral envelope with just a few cepstral coefficients, and VTL has only been modestly analyzed, being worth of further investigation. Thus, based on different statistical models, this article explores the advantages and disadvantages of the latter approach, which is relatively novel, in contrast to the former which arises from more traditional studies.

An Experimental Analysis on Multicepstral Projection Representation Strategies for Dysphonia Detection.

Biometrics-based authentication has become the most well-established form of user recognition in systems that demand a certain level of security. For example, the most commonplace social activities stand out, such as access to the work environment or to one's own bank account. Among all biometrics, voice receives special attention due to factors such as ease of collection, the low cost of reading devices, and the high quantity of literature and software packages available for use.

Polyketide- and Terpenoid-Derived Metabolites Produced by a Marine-Derived Fungus, sp.

Bioassay-guided investigation of the EtOAc-soluble extract of a culture of the marine-derived fungus sp. M16 led to the isolation of seven new polyketide- and terpenoid-derived metabolites (, , -), along with known polyketides (, -). Structures of compounds , , and - were established by analysis of spectroscopic data.

Copper-Catalyzed Synthesis of Pyrrolo[1,2-]quinazolines and Pyrrolo[2,1-]isoquinolines and Antiplasmodial Evaluation.

Reactions involving C(sp)-H bonds of azaarenes have been widely studied in recent years as they allow direct functionalization of these -heterocycles without the use of harsh reaction conditions. In this work, we describe the C(sp)-H functionalization of 4-methylquinazolines and 1-benzylisoquinolines, employing α-substituted β-nitrostyrenes catalyzed by inexpensive copper acetate. Under the optimized condition, 21 pyrrolo[1,2-]quinazolines, as well as an imidazo[1,2-]quinazoline and 4 pyrrolo[2,1-]isoquinolines, were obtained in moderate to good yields.