Reconsidering the selectivity of bulk autophagy: cargo hitchhiking specifies cargo for degradation.

Bulk macroautophagy/autophagy, typically induced by starvation, is generally thought to non-selectively isolate cytosolic components for degradation. However, a detailed analysis of bulk autophagy cargo has not been conducted. We recently employed mass spectrometry to analyze the contents of isolated autophagic bodies.

Building on the successes of patient-focused drug development: a call for new policies to maintain momentum.

Since its commencement as part of the Food and Drug Administration's (FDA) Prescription Drug User Fee Act (PDUFA) V in 2012, patient-focused drug development (PFDD) has become an integral part of the drug development paradigm. FDA encourages the development and use of Patient-Experience Data (PED) as it provides important information on the patients' needs and perspectives and inform regulatory decision-making. While the FDA is required to fill out a table which includes a list of various types of Patient Experience Data (PED) and if such data was reviewed by FDA as part of a drug application, there is still a need to understand how FDA uses PED in its regulatory decision-making.

Biomolecular condensates mediate bending and scission of endosome membranes.

Multivesicular bodies are key endosomal compartments implicated in cellular quality control through their degradation of membrane-bound cargo proteins. The ATP-consuming ESCRT protein machinery mediates the capture and engulfment of membrane-bound cargo proteins through invagination and scission of multivesicular-body membranes to form intraluminal vesicles. Here we report that the plant ESCRT component FREE1 forms liquid-like condensates that associate with membranes to drive intraluminal vesicle formation.

Resistance Management for Cancer: Lessons from Farmers.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response.

Receptor-mediated cargo hitchhiking on bulk autophagy.

While the molecular mechanism of autophagy is well studied, the cargoes delivered by autophagy remain incompletely characterized. To examine the selectivity of autophagy cargo, we conducted proteomics on isolated yeast autophagic bodies, which are intermediate structures in the autophagy process. We identify a protein, Hab1, that is highly preferentially delivered to vacuoles.

A 4H-SiC CMOS Oscillator-Based Temperature Sensor Operating from 298 K up to 573 K.

In this paper, we propose a temperature sensor based on a 4H-SiC CMOS oscillator circuit and that is able to operate in the temperature range between 298 K and 573 K. The circuit is developed on Fraunhofer IISB's 2 μm 4H-SiC CMOS technology and is designed for a bias voltage of 20 V and an oscillation frequency of 90 kHz at room temperature. The possibility to relate the absolute temperature with the oscillation frequency is due to the temperature dependency of the threshold voltage and of the channel mobility of the transistors.

The mechanism of Atg15-mediated membrane disruption in autophagy.

Autophagy is a lysosomal/vacuolar delivery system that degrades cytoplasmic material. During autophagy, autophagosomes deliver cellular components to the vacuole, resulting in the release of a cargo-containing autophagic body (AB) into the vacuole. AB membranes must be disrupted for degradation of cargo to occur.

Integrated 64 pixel UV image sensor and readout in a silicon carbide CMOS technology.

This work demonstrates the first on-chip UV optoelectronic integration in 4H-SiC CMOS, which includes an image sensor with 64 active pixels and a total of 1263 transistors on a 100 mm chip. The reported image sensor offers serial digital, analog, and 2-bit ADC outputs and operates at 0.39 Hz with a maximum power consumption of 60 μW, which are significant improvements over previous reports.

Phase separation in evaporating all-aqueous sessile drops.

The phase transition and phase distribution in an all-aqueous sessile drop containing polyethylene glycol (PEG) and dextran is studied. Evaporation of water triggers the formation of dextran-rich droplets close to the contact line of the drop that subsequently migrate towards the drop center. The likely reason for the droplet migration is Marangoni convection due to stresses at the interface between the dextran-rich droplets and the surrounding liquid.

Comparative incidence of early and late bloodstream and respiratory tract co-infection in patients admitted to ICU with COVID-19 pneumonia versus Influenza A or B pneumonia versus no viral pneumonia: wales multicentre ICU cohort study.

Objective: The aim is to characterise early and late respiratory and bloodstream co-infection in patients admitted to intensive care units (ICUs) with SARS-CoV-2-related acute hypoxemic respiratory failure (AHRF) needing respiratory support in seven ICUs within Wales, during the first wave of the COVID-19 pandemic. We compare the rate of positivity of different secondary pathogens and their antimicrobial sensitivity in three different patient groups: patients admitted to ICU with COVID-19 pneumonia, Influenza A or B pneumonia, and patients without viral pneumonia.

Design: Multicentre, retrospective, observational cohort study with rapid microbiology data from Public Health Wales, sharing of clinical and demographic data from seven participating ICUs.

Wetting of phase-separated droplets on plant vacuole membranes leads to a competition between tonoplast budding and nanotube formation.

Seeds of dicotyledonous plants store proteins in dedicated membrane-bounded organelles called protein storage vacuoles (PSVs). Formed during seed development through morphological and functional reconfiguration of lytic vacuoles in embryos [M. Feeney , 177, 241-254 (2018)], PSVs undergo division during the later stages of seed maturation.

Intracellular wetting mediates contacts between liquid compartments and membrane-bound organelles.

Protein-rich droplets, such as stress granules, P-bodies, and the nucleolus, perform diverse and specialized cellular functions. Recent evidence has shown the droplets, which are also known as biomolecular condensates or membrane-less compartments, form by phase separation. Many droplets also contact membrane-bound organelles, thereby functioning in development, intracellular degradation, and organization.

Should I bend or should I grow: the mechanisms of droplet-mediated autophagosome formation.

Phase-separated droplets with liquid-like properties can be degraded by macroautophagy/autophagy, but the mechanism underlying this degradation is poorly understood. We have recently derived a physical model to investigate the interaction between autophagic membranes and such droplets, uncovering that intrinsic wetting interactions underlie droplet-membrane contacts. We found that the competition between droplet surface tension and the increasing tendency of growing membrane sheets to bend determines whether a droplet is completely engulfed or isolated in a piecemeal fashion, a process we term fluidophagy.

Wetting regulates autophagy of phase-separated compartments and the cytosol.

Compartmentalization of cellular material in droplet-like structures is a hallmark of liquid-liquid phase separation, but the mechanisms of droplet removal are poorly understood. Evidence suggests that droplets can be degraded by autophagy, a highly conserved degradation system in which membrane sheets bend to isolate portions of the cytoplasm within double-membrane autophagosomes. Here we examine how autophagosomes sequester droplets that contain the protein p62 (also known as SQSTM1) in living cells, and demonstrate that double-membrane, autophagosome-like vesicles form at the surface of protein-free droplets in vitro through partial wetting.

Leaving no one behind: using action research to promote male involvement in maternal and child health in Iringa region, Tanzania.

Introduction: Male involvement has been reported to improve maternal and child health (MCH) outcomes. However, most studies in low-income and middle-income countries have reported low participation of men in MCH-related programmes. While there is a growing interest in the involvement of men in MCH, little is known on how male involvement can be effectively promoted in settings where entrenched unequal gender roles, norms and relations constrain women from effectively inviting men to participate in MCH.

Agent-based modelling reveals strategies to reduce the fitness and metastatic potential of circulating tumour cell clusters.

Metastasis-the ability of cancer cells to disperse throughout the body and establish new tumours at distant locations-is responsible for most cancer-related deaths. Although both single and clusters of circulating tumour cells (CTCs) have been isolated from cancer patients, CTC clusters are generally associated with higher metastatic potential and worse prognosis. From an evolutionary perspective, being part of a cluster can provide cells with several benefits both in terms of survival (e.

Phase separation organizes the site of autophagosome formation.

Many biomolecules undergo liquid-liquid phase separation to form liquid-like condensates that mediate diverse cellular functions. Autophagy is able to degrade such condensates using autophagosomes-double-membrane structures that are synthesized de novo at the pre-autophagosomal structure (PAS) in yeast. Whereas Atg proteins that associate with the PAS have been characterized, the physicochemical and functional properties of the PAS remain unclear owing to its small size and fragility.

Kombucha: a novel model system for cooperation and conflict in a complex multi-species microbial ecosystem.

Kombucha, a fermented tea beverage with an acidic and effervescent taste, is composed of a multispecies microbial ecosystem with complex interactions that are characterized by both cooperation and conflict. In kombucha, a complex community of bacteria and yeast initiates the fermentation of a starter tea (usually black or green tea with sugar), producing a biofilm that covers the liquid over several weeks. This happens through several fermentative phases that are characterized by cooperation and competition among the microbes within the kombucha solution.

Identification of expression and function of the glucagon-like peptide-1 receptor in colonic smooth muscle.

The insulinotropic effects of the incretin hormone, glucagon-like peptide-1 (GLP-1) are mediated via GLP-1 receptors (GLP-1R) present on pancreatic β cells. GLP-1 causes a decrease in the motility of stomach and intestine which involves both central and peripheral nervous systems. The expression and function of GLP-1R in gastrointestinal smooth muscle, however, are not clear.

Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane.

TORC1 is a central regulator of cell growth in response to amino acids. The role of the evolutionarily conserved Gtr/Rag pathway in the regulation of TORC1 is well-established. Recent genetic studies suggest that an additional regulatory pathway, depending on the activity of Pib2, plays a role in TORC1 activation independently of the Gtr/Rag pathway.

Model-Systems to Understand the Biology and Clinical Significance of Circulating Tumor Cell Clusters.

The isolation of clusters of circulating tumor cells (CTCs) from cancer patients has recently challenged the accepted view that the initiation of secondary tumors during metastasis involves the dissemination of individual cancer cells. As such clusters appear to be more aggressive than single tumor cells, CTC clusters are now considered a main player in the metastatic process, and many studies are exploring their diagnostic, prognostic, and clinical significance. However, several technical challenges limit advances in this area.

Inverse scattering designs of dispersion-engineered planar waveguides.

We have introduced a semi-analytical IS technique suitable for multipole, rational function reflection coefficients, and used it for the design of dispersion-engineered planar waveguides. The technique is used to derive extensive dispersion maps, including higher dispersion coefficients, corresponding to three-, five- and seven-pole reflection coefficients. It is shown that common features of dispersion-engineered waveguides such as refractive-index trenches, rings and oscillations come naturally from this approach when the magnitude of leaky poles in increased.

Differential Behavior of Fibroblasts and Epithelial Cells on Structured Implant Abutment Materials: A Comparison of Materials and Surface Topographies.

Purpose: The aim of this study was to compare the proliferation and attachment behavior of fibroblasts and epithelial cells on differently structured abutment materials.

Materials And Methods: Three different surface topographies were prepared on zirconia and titanium alloy specimens and defined as follows: machined (as delivered without further surface modification), smooth (polished), and rough (sandblasted). Energy-dispersive X-ray spectroscopy, topographical analysis, and water contact angle measurements were used to analyze the surface properties.