Ignaz Semmelweis, a Hungarian physician often labeled the “Savior of Women,” pioneered the use of antiseptic techniques to decrease puerperal fever. Although his seminal 1861 publication,
The ...Etiology, Concept and Prophylaxis of Childbed Fever
, was poorly received at the time, it is now the foundation for contemporary preventative obstetric practices, including routine hand washing. Despite this progress, maternal infection remains one of the top causes of maternal death worldwide and is currently ranked third behind hypertension and hemorrhage. The World Health Organization (WHO) has reported that as of 2017, approximately 810 women died each day from preventable causes related to . . .
Assessing the global threat from Zika virus Lessler, Justin; Chaisson, Lelia H.; Kucirka, Lauren M. ...
Science (American Association for the Advancement of Science),
08/2016, Volume:
353, Issue:
6300
Journal Article
Peer reviewed
Open access
First discovered in 1947, Zika virus (ZIKV) infection remained a little-known tropical disease until 2015, when its apparent association with a considerable increase in the incidence of microcephaly ...in Brazil raised alarms worldwide. There is limited information on the key factors that determine the extent of the global threat from ZIKV infection and resulting complications. Here, we review what is known about the epidemiology, natural history, and public health effects of ZIKV infection, the empirical basis for this knowledge, and the critical knowledge gaps that need to be filled.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent ...degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously “undruggable” targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK–CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The number of patients with cancer who are age 65 years or older (hereinafter "older") is increasing dramatically. One obvious aspect of cancer care for this group is that they are experiencing ...age-related changes in multiple organ systems, including the brain, which complicates decisions about systemic therapy and assessments of survivorship outcomes. There is a consistent body of evidence from studies that use neuropsychological testing and neuroimaging that supports the existence of impairment following systemic therapy in selected cognitive domains among some older patients with cancer. Impairment in one or more cognitive domains could have important effects in the daily lives of older patients. However, an imperfect understanding of the precise biologic mechanisms underlying cognitive impairment after systemic treatment precludes development of validated methods for predicting which older patients are at risk. From what is known, risks may include lifestyle factors such as smoking, genetic predisposition, and specific comorbidities such as diabetes and cardiovascular disease. Risk also interacts with physiologic and cognitive reserve, because even at the same chronological age and with the same number of illnesses, older patients vary from having high reserve (ie, biologically younger than their age) to being frail (biologically older than their age). Surveillance for the presence of cognitive impairment is also an important component of long-term survivorship care with older patients. Increasing the workforce of cancer care providers who have geriatrics training or who are working within multidisciplinary teams that have this type of expertise would be one avenue toward integrating assessment of the cognitive effects of cancer systemic therapy into routine clinical practice.
Purpose
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that occurs during REM sleep, characterized by REM sleep without atonia (RSWA) and dream enactment behavior (DEB). RBD ...is associated with several diseases and medications but most notably is a prodromal feature of synucleinopathies, including Parkinson’s disease (PD). This article reviews RBD, its treatments, and implications for PD therapeutics.
Recent Findings
Recent research recognizes RBD as a prodromal marker of PD, resulting in expansion of basic science and clinical investigations of RBD. Current basic science research investigates the pathophysiology of RBD and explores animal models to allow therapeutic development. Clinical research has focused on natural history observation, as well as potential RBD treatments and their impact on sleep and phenoconversion to neurodegenerative disease.
Summary
RBD serves as a fresh access point to develop both neuroprotective and symptomatic therapies in PD. These types of investigations are novel and will benefit from the more established basic science infrastructure to develop new interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Coronavirus disease 19 (COVID‐19) has recently emerged as a major threat to human health. Infections range from asymptomatic to severe (increased respiratory rate, hypoxia, significant lung ...involvement on imaging) or critical (multi‐organ failure or dysfunction or respiratory failure requiring mechanical ventilation or high‐flow nasal cannula). Current evidence suggests that pregnancy women are at increased risk of severe disease, specifically the need for hospitalization, ICU admission, and mechanical ventilation, and the already complex management of infection with an emerging pathogen may be further complicated by pregnancy. The goal of this review is to provide an overview of what is known about the clinical course of COVID‐19 in pregnancy, drawing on (a) experience with other coronaviruses such as SARS and MERS, (b) knowledge of immunologic and physiologic changes in pregnancy and how these might impact infection with SARS‐CoV‐2, and (c) the current literature reporting outcomes in pregnant women with SARS‐CoV‐2. We also briefly summarize considerations in management of severe COVID‐19 in pregnancy.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
During the final stages of Drosophila melanogaster oogenesis fifteen nurse cells, sister cells to the oocyte, degenerate as part of normal development. This process involves at least two cell death ...mechanisms, caspase-dependent cell death and autophagy, as indicated by apoptosis and autophagy markers. In addition, mutations affecting either caspases or autophagy partially reduce nurse cell removal, leaving behind end-stage egg chambers with persisting nurse cell nuclei. To determine whether apoptosis and autophagy work in parallel to degrade and remove these cells as is the case with salivary glands during pupariation, we generated mutants doubly affecting caspases and autophagy. We found no significant increase in either the number of late stage egg chambers containing persisting nuclei or in the number of persisting nuclei per egg chamber in the double mutants compared to single mutants. These findings suggest that there is another cell death mechanism functioning in the ovary to remove all nurse cell remnants from late stage egg chambers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
The last step of cell death is cell clearance, a process critical for tissue homeostasis. For efficient cell clearance to occur, phagocytes and dead cells need to reciprocally signal to each ...other. One important phenomenon that is under-investigated, however, is that phagocytes not only engulf corpses but contribute to cell death progression. The aims of this study were to determine how the phagocytic receptor Draper non-autonomously induces cell death, using the Drosophila ovary as a model system. We found that Draper, expressed in epithelial follicle cells, requires its intracellular signaling domain to kill the adjacent nurse cell population. Kinases Src42A, Shark and JNK (Bsk) were required for Draper-induced nurse cell death. Signs of nurse cell death occurred prior to apparent engulfment and required the caspase Dcp-1, indicating that it uses a similar apoptotic pathway to starvation-induced cell death. These findings indicate that active signaling by Draper is required to kill nurse cells via the caspase Dcp-1, providing novel insights into mechanisms of phagoptosis driven by non-professional phagocytes.
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