The clearance of mitochondria by autophagy, mitophagy, is important for cell and organism health 1, and known to be regulated by ubiquitin. During Drosophila intestine development, cells undergo a ...dramatic reduction in cell size and clearance of mitochondria that depends on autophagy, the E1 ubiquitin-activating enzyme Uba1, and ubiquitin 2. Here we screen a collection of putative ubiquitin-binding domain-encoding genes for cell size reduction and autophagy phenotypes. We identify the endosomal sorting complex required for transport (ESCRT) components TSG101 and Vps36, as well as the novel gene Vps13D. Vps13D is an essential gene that is necessary for autophagy, mitochondrial size, and mitochondrial clearance in Drosophila. Interestingly, a similar mitochondrial phenotype is observed in VPS13D mutant human cells. The ubiquitin-associated (UBA) domain of Vps13D binds K63 ubiquitin chains, and mutants lacking the UBA domain have defects in mitochondrial size and clearance and exhibit semi-lethality, highlighting the importance of Vps13D ubiquitin binding in both mitochondrial health and development. VPS13D mutant cells possess phosphorylated DRP1 and mitochondrial fission factor (MFF) as well as DRP1 association with mitochondria, suggesting that VPS13D functions downstream of these known regulators of mitochondrial fission. In addition, the large Vps13D mitochondrial and cell size phenotypes are suppressed by decreased mitochondrial fusion gene function. Thus, these results provide a previously unknown link between ubiquitin, mitochondrial size regulation, and autophagy.
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•Vps13D is required for viability, autophagy, and mitochondrial clearance•Drosophila and human VPS13D mutants possess a defect in mitochondrial size•The Vps13D UBA domain binds K63 ubiquitin chains and influences mitochondrial size•The large Vps13D mitochondrial phenotype is suppressed by inhibition of fusion
Autophagy and mitochondrial clearance are important for cell health. Anding et al. identify Vps13D as a gene that is required for autophagy, mitochondrial size, and clearance in Drosophila, and human cells lacking VPS13D function have a similar mitochondrial size defect. Vps13D provides a unique link between mitochondrial size and autophagy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In hair cells, although mechanotransduction channels have been localized to tips of shorter stereocilia of the mechanically sensitive hair bundle, little is known about how force is transmitted to ...the channel. Here, we use a biophysical model of the membrane-channel complex to analyze the nature of the gating spring compliance and channel arrangement. We use a triangulated surface model and Monte Carlo simulation to compute the deformation of the membrane under the action of tip link force. We show that depending on the gating spring stiffness, the compliant component of the gating spring arises from either the membrane alone or a combination of the membrane and a tether that connects the channel to the actin cytoskeleton. If a bundle is characterized by relatively soft gating springs, such as those of the bullfrog sacculus, the need for membrane reinforcement by channel tethering then depends on membrane parameters. With stiffer gating springs, such as those from rat outer hair cells, the channel must be tethered for all biophysically realistic parameters of the membrane. We compute the membrane forces (resultants), which depend on membrane tension, bending modulus, and curvature, and show that they can determine the fate of the channel.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An introduction is presented in which the editor discusses articles in the issue on topics including focuses on contexts, policies, practices, and challenges for successes related to an emerging ...vision for eco social work; and considered that eco social work are inclusive of structural social work
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK, VSZLJ
•A review is presented on the use of chromatography for separations in metabolomics.•The supports/formats and stationary phases used in metabolomics were examined.•Applications based on liquid, gas, ...and supercritical fluid chromatography were discussed.•The combination of chromatography with mass spectrometry vs NMR was considered.•Areas of potential future work in chromatography for metabolomics were identified.
Chromatography is a robust and reliable separation method that can use various stationary phases to separate complex mixtures commonly seen in metabolomics. This review examines the types of chromatography and stationary phases that have been used in targeted or untargeted metabolomics with methods such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. General considerations for sample pretreatment and separations in metabolomics are considered, along with the various supports and separation formats for chromatography that have been used in such work. The types of liquid chromatography (LC) that have been most extensively used in metabolomics will be examined, such as reversed-phase liquid chromatography and hydrophilic liquid interaction chromatography. In addition, other forms of LC that have been used in more limited applications for metabolomics (e.g., ion-exchange, size-exclusion, and affinity methods) will be discussed to illustrate how these techniques may be utilized for new and future research in this field. Multidimensional LC methods are also discussed, as well as the use of gas chromatography and supercritical fluid chromatography in metabolomics. In addition, the roles of chromatography in NMR- vs. MS-based metabolomics are considered. Applications are given within the field of metabolomics for each type of chromatography, along with potential advantages or limitations of these separation methods.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allegheny woodrats (Neotoma magister) are karst-specializing rodents that are rare or in conservation need in many states within their current range. Parasitism and habitat fragmentation have been ...suggested as primary reasons for declining populations. The presence, prevalence, and impact of ectoparasites, including fleas, ticks, and bots, is not fully understood rangewide. We collected Allegheny woodrat ectoparasites across 8 states in their range, identifying parasites via morphological and genetic means. Across contributions from 8 states, we discovered 2 woodrat-specific fleas parasitizing Allegheny woodrats: Orchopeas pennsylvanicus (all contributing states, n = 228) and Epitedia cavernicola (Indiana only, n = 9). The former was a new state record in New Jersey and Ohio. Woodrat specialists Ixodes woodi were morphologically identified as the dominant tick species (n = 38), and our contributions to genetic databases may ease confusion in future efforts. Three generalist species of ticks representing 8 individuals were identified as Dermacentor variabilis, Amblyomma americanum, and Ixodes scapularis. Only 2 bot fly species were recognized in Allegheny woodrats: 1 squirrel bot (Cuterebra emasculator) and 10 individuals of Cuterebra sp. not genetically conspecific to any known eastern U.S. rodent bot. The host specificity for fleas is not surprising, given that previous small-scale surveys and ticks primarily appear to be a mix of genus-specific (Ixodes woodi) and generalist species. There remains uncertainty with bots via morphological and genetic analyses. Our survey presents a wide-ranging baseline survey for Allegheny woodrats across their range, emphasizing the diversity (or specificity) of parasite groups for this species. An understanding of Allegheny woodrats and the health impact of ectoparasites is imperative because they face myriad challenges rangewide, especially considering the bot-driven demise of 1 woodrat in our study. Ectoparasites can have a marked impact on already-declining woodrat populations across their range and should not be overlooked in future surveys.
We reviewed invasive Nocardia infections in 3 noncontiguous geographic areas in the United States during 2011–2018. Among 268 patients with invasive nocardiosis, 48.2% were from Minnesota, 32.4% from ...Arizona, and 19.4% from Florida. Predominant species were N. nova complex in Minnesota (33.4%), N. cyriacigeorgica in Arizona (41.4%), and N. brasiliensis in Florida (17.3%). Transplant recipients accounted for 82/268 (30.6%) patients overall: 14 (10.9%) in Minnesota, 35 (40.2%) in Arizona, and 33 (63.5%) in Florida. Manifestations included isolated pulmonary nocardiosis among 73.2% of transplant and 84.4% of non–transplant patients and central nervous system involvement among 12.2% of transplant and 3.2% of non–transplant patients. N. farcinica (20.7%) and N. cyriacigeorgica (19.5%) were the most common isolates among transplant recipients and N. cyriacigeorgica (38.0%), N. nova complex (23.7%), and N. farcinica (16.1%) among non–transplant patients. Overall antimicrobial susceptibilities were similar across the 3 study sites.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell ...characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.
The emergence and spread of tick-borne arboviruses pose an increased challenge to human and animal health. In Europe this is demonstrated by the increasingly wide distribution of tick-borne ...encephalitis virus (TBEV, Flavivirus, Flaviviridae), which has recently been found in the United Kingdom (UK). However, much less is known about other tick-borne flaviviruses (TBFV), such as the closely related louping ill virus (LIV), an animal pathogen which is endemic to the UK and Ireland, but which has been detected in other parts of Europe including Scandinavia and Russia. The emergence and potential spatial overlap of these viruses necessitates improved understanding of LIV genomic diversity, geographic spread and evolutionary history. We sequenced a virus archive composed of 22 LIV isolates which had been sampled throughout the UK over a period of over 80 years. Combining this dataset with published virus sequences, we detected no sign of recombination and found low diversity and limited evidence for positive selection in the LIV genome. Phylogenetic analysis provided evidence of geographic clustering as well as long-distance movement, including movement events that appear recent. However, despite genomic data and an 80-year time span, we found that the data contained insufficient temporal signal to reliably estimate a molecular clock rate for LIV. Additional analyses revealed that this also applied to TBEV, albeit to a lesser extent, pointing to a general problem with phylogenetic dating for TBFV. The 22 LIV genomes generated during this study provide a more reliable LIV phylogeny, improving our knowledge of the evolution of tick-borne flaviviruses. Our inability to estimate a molecular clock rate for both LIV and TBEV suggests that temporal calibration of tick-borne flavivirus evolution should be interpreted with caution and highlight a unique aspect of these viruses which may be explained by their reliance on tick vectors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that ...Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities.
How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun-dependent manner. See related commentary by Amit and Maitra, p. 2240. This article is highlighted in the In This Issue feature, p. 2221.
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