Treatment and prevention of malaria in pregnancy: opportunities and challenges

Control of malaria in pregnancy through prevention or treatment may save lives of mothers and babies. Selection of drugs for treatment of infected pregnant women, or for prevention in exposed populations is problematic owing to resistance to established drugs and lack of pregnancy-specific safety and pharmacological data for new drugs. Encouragingly, a number of new drugs and combinations of drugs hold promise for effective treatment, but adequate data on their safety in pregnancy is currently lacking. Our principal challenges are to decide which drugs to develop for use in malaria treatment and prevention in pregnancy and to develop mechanisms to rapidly and comprehensively evaluate their safety. Prevention of pregnancy malaria by vaccination may also become possible, but targets must be closely defined, and strategies developed to test candidates against meaningful end points.     

Whole-blastocyst culture followed by laser drilling technology enhances the efficiency of inner cell mass isolation and embryonic stem cell derivation from good- and poor-quality mouse embryos: new insights for derivation of human embryonic stem cell lines

The optimization of human embryonic stem (hES) cell line derivation methods is challenging because many worldwide laboratories have neither access to spare human embryos nor ethical approval for using supernumerary human embryos for hES cell derivation purposes. Additionally, studies performed directly on human embryos imply a waste of precious human biological material. In this study, we developed a new strategy based on the combination of whole-blastocyst culture followed by laser drilling destruction of the trophoectoderm for improving the efficiency of inner cell mass (ICM) isolation and ES cell derivation using murine embryos. Embryos were divided into good- and poor-quality embryos. We demonstrate that the efficiency of both ICM isolation and ES cell derivation using this strategy is significantly superior to whole-blastocyst culture or laser drilling technology itself. Regardless of the ICM isolation method, the ES cell establishment depends on a feeder cell growth surface. Importantly, this combined methodology can be successfully applied to poor-quality blastocysts that otherwise would not be suitable for laser drilling itself nor immunosurgery in an attempt to derive ES cell lines due to the inability to distinguish the ICM. The ES cell lines derived by this combined method were characterized and shown to maintain a typical morphology, undifferentiated phenotype, and in vitro and in vivo three germ layer differentiation potential. Finally, all ES cell lines established using either technology acquired an aneuploid karyotype after extended culture periods, suggesting that the method used for ES cell derivation does not seem to influence the karyotype of the ES cells after extended culture. This methodology may open up new avenues for further improvements for the derivation of hES cells, the majority of which are derived from frozen, poor-quality human embryos.     

Bayesian Models of Mentalizing

Surprisingly effortless is the human capacity known as “mentalizing”, i.e., the ability to explain and predict the behavior of others by attributing to them independent mental states, such as beliefs, desires, emotions or intentions. This capacity is, among other factors, dependent on the correct anticipation of the dynamics of facially expressed emotions based on our beliefs and experience. Important information about the neural processes involved in mentalizing can be derived from dynamic recordings of neural activity such as the EEG. We here exemplify how the so-called Bayesian probabilistic models can help us to model the neural dynamic involved in the perception of clips that evolve from neutral to emotionally laden faces. Contrasting with conventional models, in Bayesian models, probabilities can be used to dynamically update beliefs based on new incoming information. Our results show that a reproducible model of the neural dynamic involved in the appraisal of facial expression can be derived from the grand mean ERP over five subjects. One of the two models used to predict the individual subject dynamic yield correct estimates for four of the five subjects analyzed. These results encourage the future use of Bayesian formalism to build more detailed models able to describe the single trial dynamic.     

Diagnostic implications of soluble triggering receptor expressed on myeloid cells-1 in patients with acute respiratory distress syndrome and abdominal diseases: a preliminary observational study

Introduction  

Patients admitted to the intensive care unit (ICU) because of acute or decompensated chronic abdominal disease and acute respiratory failure need to have the potential infection diagnosed as well as its site (pulmonary or abdominal). For this purpose, we measured soluble triggering receptor expression on myeloid cells-1 (sTREM-1) in alveolar and peritoneal fluid.     

ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1

Amyloid β (Aβ) peptides, the primary constituents of senile plaques and a hallmark in Alzheimer's disease pathology, are generated through the sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. The early endosome is thought to represent a major compartment for APP processing; however, the mechanisms of how BACE1 encounters APP are largely unknown. In contrast to APP internalization, which is clathrin-dependent, we demonstrate that BACE1 is sorted to early endosomes via a route controlled by the small GTPase ADP ribosylation factor 6 (ARF6). Altering ARF6 levels or its activity affects endosomal sorting of BACE1, and consequently results in altered APP processing and Aβ production. Furthermore, sorting of newly internalized BACE1 from ARF6-positive towards RAB GTPase 5 (RAB5)-positive early endosomes depends on its carboxyterminal short acidic cluster-dileucine motif. This ARF6-mediated sorting of BACE1 is confined to the somatodendritic compartment of polarized neurons in agreement with Aβ peptides being primarily secreted from here. These results demonstrate a spatial separation between APP and BACE1 during surface-to-endosome transport, suggesting subcellular trafficking as a regulatory mechanism for this proteolytic processing step. It thereby provides a novel avenue to interfere with Aβ production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP.