Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis.

Aspergillus fumigatus is the causative agent of invasive aspergillosis, an infection with mortality rates of up to 50%. The glucan-rich cell wall of A. fumigatus is a protective structure that is absent from human cells and is a potential target for antifungal treatments.

Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity.

MYCBP2 is a ubiquitin (Ub) E3 ligase (E3) that is essential for neurodevelopment and regulates axon maintenance. MYCBP2 transfers Ub to nonlysine substrates via a newly discovered RING-Cys-Relay (RCR) mechanism, where Ub is relayed from an upstream cysteine to a downstream substrate esterification site. The molecular bases for E2-E3 Ub transfer and Ub relay are unknown.

Age-Related Compensatory Reconfiguration of PFC Connections during Episodic Memory Retrieval.

During demanding cognitive tasks, older adults (OAs) frequently show greater prefrontal cortex (PFC) activity than younger adults (YAs). This age-related increase in PFC activity is often associated with enhanced cognitive performance, suggesting functional compensation. However, the brain is a complex network of interconnected regions, and it is unclear how network connectivity of PFC regions differs for OAs versus YAs.

Targeting a critical step in fungal hexosamine biosynthesis.

is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs.

Specialist nurse initiated interventions in breast cancer care: A systematic review of randomised controlled trials.

Aims And Objectives: To evaluate the effectiveness of specialist nurse interventions in the care of women with breast cancer.

Background: Nurses perform a crucial role in physical and psychosocial support of women with breast cancer. However, only few reviews have explored and discussed the roles and interventions carried out by specialised nurses in breast cancer care.

Age-related differences in recognition in associative memory.

Aging is often accompanied by associative memory changes, although their precise nature remains unclear. This study examines how recognition of item position in the context of associative memory differs between younger and older adults. Participants studied word pairs (A-B, C-D) and were later tested with intact (A-B), reversed (D-C), recombined (A-D), and recombined and reversed (B-C) pairs.

Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity.

Ubiquitination is initiated by transfer of ubiquitin (Ub) from a ubiquitin-activating enzyme (E1) to a ubiquitin-conjugating enzyme (E2), producing a covalently linked intermediate (E2-Ub) . Ubiquitin ligases (E3s) of the 'really interesting new gene' (RING) class recruit E2-Ub via their RING domain and then mediate direct transfer of ubiquitin to substrates . By contrast, 'homologous to E6-AP carboxy terminus' (HECT) E3 ligases undergo a catalytic cysteine-dependent transthiolation reaction with E2-Ub, forming a covalent E3-Ub intermediate.

Quality of Life among Cancer Patients.

Introduction: Cancer is a leading cause of death. People living with cancer experience a variety of symptoms. Quality of life (QOL) is a major concern of patients with terminal cancer.

A Randomized controlled trial to evaluate the impact of a Nurse Navigator Programme on outcomes of people with breast cancer: study protocol.

Aim: To evaluate the effectiveness of a Nurse Navigator Programme on anxiety, psychological distress and quality of life in people with breast cancer.

Background: Breast cancer is the most frequently detected malignancy and a major cause of cancer death among women around the world. The lengthy course of illness from initial diagnosis to treatment and subsequent follow-up causes deterioration in physical, psychological and social status among patients.

Chemical ubiquitination for decrypting a cellular code.

The modification of proteins with ubiquitin (Ub) is an important regulator of eukaryotic biology and deleterious perturbation of this process is widely linked to the onset of various diseases. The regulatory capacity of the Ub signal is high and, in part, arises from the capability of Ub to be enzymatically polymerised to form polyubiquitin (polyUb) chains of eight different linkage types. These distinct polyUb topologies can then be site-specifically conjugated to substrate proteins to elicit a number of cellular outcomes.

Genetically Directed Production of Recombinant, Isosteric and Nonhydrolysable Ubiquitin Conjugates.

We describe the genetically directed incorporation of aminooxy functionality into recombinant proteins by using a mutant Methanosarcina barkeri pyrrolysyl-tRNA synthetase/tRNACUA pair. This allows the general production of nonhydrolysable ubiquitin conjugates of recombinant origin by bioorthogonal oxime ligation. This was exemplified by the preparation of nonhydrolysable versions of diubiquitin, polymeric ubiquitin chains and ubiquitylated SUMO.

Probes of ubiquitin E3 ligases enable systematic dissection of parkin activation.

E3 ligases represent an important class of enzymes, yet there are currently no chemical probes for profiling their activity. We develop a new class of activity-based probe by re-engineering a ubiquitin-charged E2 conjugating enzyme and demonstrate the utility of these probes by profiling the transthiolation activity of the RING-in-between-RING (RBR) E3 ligase parkin in vitro and in cellular extracts. Our study provides valuable insight into the roles, and cellular hierarchy, of distinct phosphorylation events in parkin activation.

Symptoms experienced by cancer patients and barriers to symptom management.

Background: People living with cancer experience wide variety of symptoms. If symptoms are not managed well, it may hamper an individual's ability to continue his or her activities of daily life. Treatment of symptoms relieves suffering and improves the rate of recovery as well as the quality of life.

Orthogonal thiol functionalization at a single atomic center for profiling transthiolation activity of E1 activating enzymes.

Transthiolation is a fundamental biological reaction and is utilized by many enzymes involved in the conjugation of ubiquitin and ubiquitin-like proteins. However, tools that enable selective profiling of this activity are lacking. Transthiolation requires cysteine-cysteine juxtaposition; therefore a method that enables irreversible "stapling" of proximal thiols would facilitate the development of novel probes that could be used to profile this activity.

Jack in the box: inguinal endometriosis.

A 39-year-old woman with a left-sided inguinal swelling was referred to us with a diagnosis of inguinal hernia. On asking leading questions, the patient gave a typical history of cyclical pain and increased swelling during menstruation. Fine-needle aspiration biopsy revealed endometrial glands.

A phospha-oseltamivir-biotin conjugate as a strong and selective adhesive for the influenza virus.

We present the synthesis and application of a molecule containing both the powerful influenza neuraminidase (NA) inhibitor phospha-oseltamivir and d-biotin, connected via an undecaethylene glycol spacer. It inhibits influenza virus neuraminidase (from the H3N2 X31 virus) in the same range as oseltamivir, with a slow off-rate, and produces a stable NA-coated surface when loaded onto streptavidin-coated biosensors. Purified X31 virus binds to these loaded biosensors with an apparent dissociation constant in the low picomolar range and binding of antibodies to the immobilized virus could be readily detected.

Biotin-, fluorescein- and 'clickable' conjugates of phospha-oseltamivir as probes for the influenza virus which utilize selective binding to the neuraminidase.

The synthesis of conjugates of phospha-oseltamivir to the well established reporter groups fluorescein and biotin and an approach to multimeric inhibitors is described. We report powerful inhibition of the influenza neuraminidase by these probes and quantify fluorescence quenching during binding of the fluorescein conjugate through titration with the neuraminidase. Thus, we show that they could be useful tools to efficiently inhibit, detect and quantify the virus and the neuraminidase in biological systems.

Synthesis and inhibitory activity of sialic acid derivatives targeted at viral sialate-O-acetylesterases.

A series of sialosides modified at the 4- and 9-hydroxy group were synthesised and tested for inhibition of the viral haemagglutinin-esterase activity from various Orthomyxoviruses and Coronaviruses. While no inhibition of the sialate-4-O-acetylesterases from mouse hepatitis virus strain S or sialodacryoadenitis virus was found, a 9-O-methyl derivative displayed inhibitory activity against recombinant sialate-9-O-acetylesterase from influenza C virus.

Protein profile study of breast-tissue homogenates by HPLC-LIF.

Proteomics is a promising approach for molecular understanding of neoplastic processes including response to treatment. Widely used 2D-gel electrophoresis/Liquid chromatography coupled with mass spectrometry (LC-MS) are time consuming and not cost effective. We have developed a high-sensitivity (femto/subfemtomoles of protein/20 mul) High Performance Liquid Chromatography-Laser Induced Fluorescence HPLC-LIF instrument for studying protein profiles of biological samples.

Autofluorescence of breast tissues: evaluation of discriminating algorithms for diagnosis of normal, benign, and malignant conditions.

Objective: We evaluated different discriminating algorithms for classifying laser-induced fluorescence spectra of normal, benign, and malignant breast tissues that were obtained with 325-nm excitation.

Background Data: Mammography and histopathology are the conventional gold standard methods of screening and diagnosis of breast cancers, respectively. The former is prone to a high rate of false-positive results and poses the risk of repeated exposure to ionizing radiation, whereas the latter suffers from subjective interpretations of morphological features.

Biochemical correlation of Raman spectra of normal, benign and malignant breast tissues: a spectral deconvolution study.

The aim of this study was to understand and correlate spectral features and biochemical changes in normal, fibroadenoma and infiltrating ductal carcinoma of breast tissues using Raman spectra that were part of the spectroscopic models developed and evaluated by us earlier. Spectra were subjected to curve fitting and intensities plots of resultant curve resolved bands were computed. This study has revealed that fat (1301 and 1440 cm(-1)), collagen (1246, 1271, and 1671 cm(-1)) and DNA (1340 and 1480 cm(-1)) bands have strong presence in normal, benign and malignant breast tissues, respectively.

Raman spectroscopy of breast tissues.

Breast cancer is one of the leading female cancers. The major drawback of the gold standard of screening, mammography, is the high rate of false reports, aside from the risk from repeated exposure to harmful ionizing radiations. Histopathology, the gold standard of diagnosis, is time consuming and often prone to subjective interpretations.

Discrimination of normal and malignant mucosal tissues of the colon by Raman spectroscopy.

Objective: The objective of this study was to evaluate the applicability of the discrimination parameters Mahalanobis distance, spectral residuals, and limit tests, developed by this group to differentiate normal from malignant colon tissues.

Background Data: Colon cancers are diagnosed using fiberoptic endoscopic localization and a subsequent histopathological examination of biopsied tissue, which is highly dependent on the skill and experience of the investigator. There exists a risk of missing significant lesions, especially with carcinoma in situ lesions.