Search

Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are detected and removed from the cell is poorly understood. Recent studies suggest that the peroxisomal matrix protein import machinery may serve double duty as a quality control machinery, where they are directly involved in activating pexophagy. Here, we explored whether any matrix import factors are required to prevent pexophagy, such that their loss designates peroxisomes for degradation. Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes. The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy. We also found that PEX13 protein level is downregulated to aid in the induction of pexophagy during amino acid starvation. Together, our study points to PEX13 as a novel pexophagy regulator that is modulated to maintain peroxisome homeostasis. Abbreviations: AAA ATPases: ATPases associated with diverse cellular activities; ABCD3: ATP binding cassette subfamily D member; 3ACOX1: acyl-CoA oxidase; 1ACTA1: actin alpha 1, skeletal muscle; ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; CAT: catalase; CQ: chloroquine; Dpf: days post fertilization: FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H2O2: hydrogen peroxide; HA – human influenza hemagglutinin; HBSS: Hanks’ Balanced Salt Solution; HCQ; hydroxychloroquine; KANL: lysine alanine asparagine leucine; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYC: MYC proto-oncogene, bHLH transcription factor; MZ: maternal and zygotic; NAC: N-acetyl cysteine; NBR1 – NBR1 autophagy cargo receptor; PBD: peroxisome biogenesis disorder; PBS: phosphate-buffered saline; PEX: peroxisomal biogenesis factor; PTS1: peroxisome targeting sequence 1; RFP: red fluorescent protein; ROS: reactive oxygen speciess; iRNA: short interfering RNA; SKL: serine lysine leucine; SLC25A17/PMP34: solute carrier family 25 member 17; Ub: ubiquitin; USP30: ubiquitin specific peptidase 30.

Selective autophagy is an essential mechanism to maintain organelle integrity and cellular homeostasis through the constant recycling of damaged or superfluous components. While distinct selective autophagy pathways mediate the degradation of diverse cellular substrates including organelles and pathogens, whether these distinct pathways can influence one another remains unknown. We address this question here using pexophagy, the autophagic degradation of peroxisomes, as a model. We demonstrate in cells that upregulated pexophagy exhausts selective autophagy and limits the degradation of both mitochondria and protein aggregates. We confirmed this finding in the pexophagy-mediated form of Zellweger Spectrum Disorder, a rare disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased aggrephagy reduces pexophagy using a model of Huntington’s Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increased substrate load.

Formation and fission of tubules from lysosomal organelles, such as autolysosomes, endolysosomes or phagolysosomes, are required for lysosome reformation. However, the mechanisms governing these processes in the different forms of lysosomal organelles are poorly understood. For instance, the role of phosphatidylinositol-4-phosphate (PI(4)P) is unclear as it was shown to promote the formation of tubules from phagolysosomes but was proposed to inhibit tubule formation on autolysosomes because the loss of PI4KIIIβ causes extensive lysosomal tubulations. Using super-resolution live-cell imaging, we show that Arf1-PI4KIIIβ positive vesicles are recruited to tubule fission sites from autolysosomes, endolysosomes and phagolysosomes. Moreover, we show that PI(4)P is required to form autolysosomal tubules and that increased lysosomal tubulation caused by loss of PI4KIIIβ represents impaired tubule fission. At the site of fission, we propose that Arf1-PI4KIIIβ positive vesicles mediate a PI(3)P signal on lysosomes in a process requiring the lipid transfer protein SEC14L2. Our findings indicate that Arf1-PI4KIIIβ positive vesicles and their regulation of PI(3)P are critical components of the lysosomal tubule fission machinery.

Background: Clostridioides difficile infection (CDI) can result in life-threatening illness requiring surgery. Surgical options for managing severe or fulminant, non-perforated C. difficile colitis include total abdominal colectomy with end ileostomy or creation of a diverting loop ileostomy with antegrade vancomycin lavage. Methods: The Surgical Infection Society's Therapeutics and Guidelines Committee convened to develop guidelines for summarizing the current SIS recommendations for total abdominal colectomy versus diverting loop ileostomy with antegrade lavage for severe or fulminant, non-perforated C. difficile colitis. PubMed, Embase, and the Cochrane database were searched for pertinent studies. Severe infection was defined as laboratory diagnosis of C. difficile infection with leukocytosis (white blood cell count of ≥15,000 cells/mL) or elevated creatinine (serum creatinine level >1.5 mg/dL). Fulminant infection was defined as laboratory diagnosis of C. difficile infection with hypotension or shock, ileus, or megacolon. Perforation was defined as complete disruption of the colon wall. Total abdominal colectomy was defined as resection of the ascending, transverse, descending, and sigmoid colon with end ileostomy. For the purpose of the guideline, the terms subtotal colectomy, total abdominal colectomy, and rectal-sparing total colectomy were used interchangeably. Diverting loop ileostomy with antegrade enema was defined as creation of both a diverting loop ileostomy with intra-operative colonic lavage and post-operative antegrade vancomycin unless otherwise specified. Evaluation of the published evidence was performed using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. Using a process of iterative consensus, all committee members voted to accept or reject each recommendation. Results: We recommend that total abdominal colectomy be the procedure of choice for definitive therapy of severe or fulminant, non-perforated C. difficile colitis. In select patients, colon preservation using diverting loop ileostomy with intra-colonic vancomycin may be associated with higher rates of ostomy reversal and restoration of gastrointestinal continuity but may lead to development of recurrent C. difficile colitis. Conclusions: This guideline summarizes the current Surgical Infection Society recommendations regarding use of total abdominal colectomy versus diverting loop ileostomy with antegrade lavage for adults with severe or fulminant, non-perforated C. difficile infection.

Animal models have been utilized to understand the pathogenesis of Zellweger spectrum disorders (ZSDs); however, the link between clinical manifestations and molecular pathways has not yet been clearly established. We generated peroxin 5 homozygous mutant zebrafish (pex5−/−) to gain insight into the molecular pathogenesis of peroxisome dysfunction. pex5−/− display hallmarks of ZSD in humans and die within one month after birth. Fasting rapidly depletes lipids and glycogen in pex5−/− livers and expedites their mortality. Mechanistically, deregulated mitochondria and mechanistic target of rapamycin (mTOR) signaling act together to induce metabolic alterations that deplete hepatic nutrients and accumulate damaged mitochondria. Accordingly, chemical interventions blocking either the mitochondrial function or mTOR complex 1 (mTORC1) or a combination of both improve the metabolic imbalance shown in the fasted pex5−/− livers and extend the survival of animals. In addition, the suppression of oxidative stress by N-acetyl L-cysteine (NAC) treatment rescued the apoptotic cell death and early mortality observed in pex5−/−. Furthermore, an autophagy activator effectively ameliorated the early mortality of fasted pex5−/−. These results suggest that fasting may be detrimental to patients with peroxisome dysfunction, and that modulating the mitochondria, mTORC1, autophagy activities, or oxidative stress may provide a therapeutic option to alleviate the symptoms of peroxisomal diseases associated with metabolic dysfunction.

Background Several case reports suggest that penetrating thoracic cage fractures are an important cause for hemopericardium and cardiac tamponade following blunt trauma. However, the prevalence of this mechanism of injury is not fully known, and considering this association may provide a better understanding of the utility of cardiac component of the FAST (Focused Assessment with Sonography for Trauma). Objective To determine the association of thoracic cage fractures and pericardial effusion in patients with blunt trauma. Methods We performed a retrospective, multicenter cohort study using the Trauma Quality Improvement Program (TQIP) database (2015–2017) of adults ≥18 years of age whose mechanism of injury was either a fall or motor vehicle accident. Thoracic cage fractures were defined as any rib or sternum fracture. The primary outcome was the presence of pericardial effusion. Confounding variables were accounted for using multivariable logistic regression. Results We included 1,673,704 patients in the study; 226,896 (14%) patients had at least one thoracic cage fracture. A pericardial effusion was present in 4923 (0.3%) patients. When a thoracic cage fracture was present, the odds of having a pericardial effusion was significantly higher (adjusted Odds Ratio [aOR] 6.5 [95% CI: 6.1–7.0]). Patients with left and right-sided rib fractures had similar odds of a pericardial effusion (aOR 1.2 [95% CI 1.04–1.4]). Sternal fractures carried the highest odds of having a pericardial effusion (aOR 11.1 [9.9–12.3]). Conclusion Thoracic cage fractures secondary to blunt trauma represent a significant independent risk factor for the development of a pericardial effusion. Our findings lend support for the mechanism of bony injuries causing penetrating cardiac trauma. Given these findings, and the fact that many thoracic cage fractures are detected after the initial evaluation, we support maintaining the cardiac view in the FAST examination for all blunt trauma patients.

Magnetism in topological materials creates phases exhibiting quantized transport phenomena with potential technological applications. The emergence of such phases relies on strong interaction between localized spins and the topological bands, and the consequent formation of an exchange gap. However, this remains experimentally unquantified in intrinsic magnetic topological materials. Here, this interaction is quantified in MnBi

In this study, we hypothesized that deregulation in the maintenance of the pool of coenzyme A (CoA) may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Specific deletion of Acot12 (Acot12−/−), the major acyl-CoA thioesterase, induced the accumulation of acetyl-CoA and resulted in the stimulation of de novo lipogenesis (DNL) and cholesterol biosynthesis in the liver. KEGG pathway analysis suggested PPARα signaling as the most significantly enriched pathway in Acot12−/− livers. Surprisingly, the exposure of Acot12−/− hepatocytes to fenofibrate significantly increased the accumulation of acetyl-CoA and resulted in the stimulation of cholesterol biosynthesis and DNL. Interaction analysis, including proximity-dependent biotin identification (BioID) analysis, suggested that ACOT12 may directly interact with vacuolar protein sorting-associated protein 33A (VPS33A) and play a role in vesicle-mediated cholesterol trafficking and the process of lysosomal degradation of cholesterol in hepatocytes. In summary, in this study, we found that ACOT12 deficiency is responsible for the pathogenesis of NAFLD through the accumulation of acetyl-CoA and the stimulation of DNL and cholesterol via activation of PPARα and inhibition of cholesterol trafficking., Non-alcoholic fatty liver disease: Boosting regulatory enzyme a potential treatment A deficiency in levels of a key enzyme disturbs lipid metabolism in the liver and triggers non-alcoholic fatty liver disease (NAFLD). NAFLD is a common chronic condition in which fat builds up in the liver, heightening the risk of serious health problems. However, the exact mechanisms behind NAFLD are unclear. In experiments on mice, Eun-Jung Jin at Wongwang University in Iksan, South Korea, and co-workers found that deficiencies of an enzyme called ACOT12 can induce NAFLD regardless of dietary intake. The team generated mice without the Acot12 gene, which boosted the biosynthesis of lipid and accumulation of cholesterol in liver cells. Further examination showed that ACOT12 may directly interact with a protein that prompts cholesterol trafficking and degradation. Loss of ACOT12 activated a signaling pathway that inhibited this process. Their findings may inform NAFLD therapies.

Background The incidence of underlying malignancy in appendicitis ranges between 0.5% and 1.7%. We sought to identify the subset of patients with appendicitis who are at increased risk of appendiceal malignancy. Methods Using the Eastern Association for the Surgery of Trauma Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous database, we included all patients from 28 centers undergoing immediate, delayed, or interval appendectomy between 2017 and 2018. Univariate then multivariable analyses were performed to compare patients with and without malignancy and to identify independent demographic, clinical, laboratory, and/or radiological predictors of malignancy. Akaike information criteria for regression models were used to evaluate goodness of fit. Results A total of 3,293 patients were included. The median age was 38 (27–53) years, and 46.5% were female patients. On pathology, 48 (1.5%) had an underlying malignancy (adenocarcinoma [60.4%], neuroendocrine [37.5%], and lymphoma [2.1%]). Patients with malignancy were older (56 [34.5–67] vs 37 [27–52] years, P 40 years with an appendiceal diameter >10 mm on computed tomography was 2.95% compared with 0.97% in patients ≤40 years old with appendiceal diameter ≤10 mm. The corresponding risk ratio for that population was 3.03 (95% confidence interval: 1.24–7.42; P = .02). Conclusion The combination of age >40 and an appendiceal diameter >10 mm is associated with a greater than 3-fold increased risk of malignancy in patients presenting with appendicitis.

Quality control of peroxisomes is essential for cellular homeostasis. However, the mechanism underlying pexophagy is largely unknown. In this study, we identified HSPA9 as a novel pexophagy regulator. Downregulation of HSPA9 increased macroautophagy/autophagy but decreased the number of peroxisomes in vitro and in vivo. The loss of peroxisomes by HSPA9 depletion was attenuated in SQSTM1-deficient cells. In HSPA9-deficient cells, the level of peroxisomal reactive oxygen species (ROS) increased, while inhibition of ROS blocked pexophagy in HeLa and SH-SY5Y cells. Importantly, reconstitution of HSPA9 mutants found in Parkinson disease failed to rescue the loss of peroxisomes, whereas reconstitution with wild type inhibited pexophagy in HSPA9-depleted cells. Knockdown of Hsc70-5 decreased peroxisomes in Drosophila, and the HSPA9 mutants failed to rescue the loss of peroxisomes in Hsc70-5-depleted flies. Taken together, our findings suggest that the loss of HSPA9 enhances peroxisomal degradation by pexophagy.

Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections. Together, the World Society of Emergency Surgery, the Global Alliance for Infections in Surgery, the Surgical Infection Society-Europe, The World Surgical Infection Society, and the American Association for the Surgery of Trauma have jointly completed an international multi-society document to promote global standards of care in SSTIs guiding clinicians by describing reasonable approaches to the management of SSTIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting evidence was shared by an international task force with different clinical backgrounds.

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

International audience; Macroautophagy is a highly conserved eukaryotic cellular pathway involving the engulfment of macromolecules, organelles, and invading microbes by a double-membrane compartment and subsequent lysosomal degradation. The mechanisms that regulate macroautophagy, and the interaction of its components with other cellular pathways, have remained unclear. Here, we performed proximity-dependent biotin identification (BioID) on 39 core human macroautophagy proteins, identifying over 700 unique high confidence proximity interactors with new putative connections between macroautophagic and essential cellular processes. Of note, we identify members of the OSBPL (oxysterol binding protein like) family as Atg8-family protein interactors. We subsequently conducted comprehensive screens of the OSBPL family for LC3B-binding and roles in xenophagy and aggrephagy. OSBPL7 and OSBPL11 emerged as novel lipid transfer proteins required for macroautophagy of selective cargo. Altogether, our proximity interaction map provides a valuable resource for the study of autophagy and highlights the critical role of membrane contact site proteins in the pathway.

International audience; Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy.Abbreviations: ATG9A: autophagy related 9A; Baf A1: bafilomycin A1; BioID: proximity-dependent biotin identification; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CCZ1: CCZ1 homolog, vacuolar protein trafficking and biogenesis associated; DQ-BSA: dye quenched-bovine serum albumin; FYCO1: FYVE and coiled-coil domain autophagy adaptor 1; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; KO: knockout; LRPPRC: leucine rich pentatricopeptide repeat containing; MG132: carbobenzoxy-Leu-Leu-leucinal; MON1: MON1 homolog, secretory trafficking associated; mtDNA: mitochondrial DNA; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; RMC1: regulator of MON1-CCZ1; TBC1D15: TBC1 domain family member 15; TBC1D17: TBC1 domain family member 17; TOMM20: translocase of outer mitochondrial membrane 20; WDR91: WD repeat domain 91; WT: wild type.

The 6th Open European peroxisome meeting (OEPM) was held on the 26th and 27th of October (2018) in Groningen, the Netherlands. OEPM is a biannual meeting organized by a European peroxisome research group. Previous meetings were held in Leuven, BE (2006), Lunteren, NL (2010), Dijon, FR (2012), Neuss, GER (2014) and Vienna, AU (2016). Over 120 participants were registered from 14 European countries, as well as Israel, Canada, the USA and South Korea. A large number of European research groups participated, including established and younger groups, showing that peroxisome research is blooming in Europe. This will further expand with the EU Marie Curie Innovative training network PERICO (PERoxisome Interactions and COmmunication; http://www.itn-PERICO.eu; coordinated by Ida van der Klei), which recently started and aims to train the next generation of peroxisome researchers.

The regulation of organelle abundance is crucial for cellular health and function. In this study, Riccio et al. show that the mitochondrial deubiquitinase USP30 localizes to peroxisomes, where it regulates PEX2-dependent pexophagy potential and demonstrates its potential as a therapeutic target for the treatment of Zellweger’s spectrum disorders., The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role of the deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes are highly dynamic, changing in abundance in response to metabolic stress. In our recent study identifying the role of USP30 in mitophagy, we observed USP30 to be localized to punctate structures resembling peroxisomes. We report here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes. We find that overexpressing USP30 prevents pexophagy during amino acid starvation, and its depletion results in pexophagy induction under basal conditions. We demonstrate that USP30 prevents pexophagy by counteracting the action of the peroxisomal E3 ubiquitin ligase PEX2. Finally, we show that USP30 can rescue the peroxisome loss observed in some disease-causing peroxisome mutations, pointing to a potential therapeutic target.

With our Spring 2021 volume, Studies in Applied Linguistics & TESOL (SALT) celebrates its twentieth anniversary. The journal was founded in 2001, originally called Working Papers in TESOL and Applied Linguistics. In the late 1990s, a young faculty member ZhaoHong Han joined the TESOL and Applied Linguistics Program at Teachers College. Inspired by a journal published by the University of Hawaii called Working Papers in ESL Studies -- one that evolved over time into a very influential outlet, Dr. Han wanted to create synergy among doctoral students across the three tracks of SLA, assessment and language use, offering them authentic editorial experience as well as a platform to publish their work-in-progress. The web journal was subsequently founded to be a place of incubation, a venue where students and scholars could experiment with ongoing ideas for their research and receive feedback from multiple perspectives. The journal grew to garner an international reputation over the years and changed its name to SALT in 2019.

On April 8, 2021, we had the great pleasure of speaking over Zoom with Professor ZhaoHong Han, the founding editor of SALT, which was originally called Working Papers in TESOL and Applied Linguistics. In celebration of the journal’s 20thanniversary, we discussed the motivation and vision behind establishing a web journal, future directions, essential qualities of an outstanding original research article, and advice for early career scholars and graduate students who are starting out to get their work published in journals.

The emergence of magnetism in quantum materials creates a platform to realize spin-based applications in spintronics, magnetic memory, and quantum information science. A key to unlocking new functionalities in these materials is the discovery of tunable coupling between spins and other microscopic degrees of freedom. We present evidence for interlayer magnetophononic coupling in the layered magnetic topological insulator MnBi2Te4. Employing magneto-Raman spectroscopy, we observe anomalies in phonon scattering intensities across magnetic field-driven phase transitions, despite the absence of discernible static structural changes. This behavior is a consequence of a magnetophononic wave-mixing process that allows for the excitation of zone-boundary phonons that are otherwise ‘forbidden’ by momentum conservation. Our microscopic model based on density functional theory calculations reveals that this phenomenon can be attributed to phonons modulating the interlayer exchange coupling. Moreover, signatures of magnetophononic coupling are also observed in the time domain through the ultrafast excitation and detection of coherent phonons across magnetic transitions. In light of the intimate connection between magnetism and topology in MnBi2Te4, the magnetophononic coupling represents an important step towards coherent on-demand manipulation of magnetic topological phases.

The emergence of magnetism in quantum materials creates a platform to realize spin-based applications in spintronics, magnetic memory, and quantum information science. A key to unlocking new functionalities in these materials is the discovery of tunable coupling between spins and other microscopic degrees of freedom. We present evidence for interlayer magnetophononic coupling in the layered magnetic topological insulator MnBi

Background Severe cardiac injury caused by penetrating rib or sternal fractures after blunt chest trauma is a rare clinical entity that has been described in only a few case reports over the last half-century. As a result, questions have arisen about the utility of the cardiac component in the Focused Assessment with Sonography in Trauma (cFAST) examination in evaluating blunt trauma patients. Case Report We present a series of 3 patients who sustained blunt trauma and were discovered on cFAST examination to have developed pericardial tamponade from overlying rib or sternal fractures in the emergency departments of two academic level I trauma hospitals in the United States. Why Should an Emergency Physician Be Aware of This? These cases highlight the need for emergency and trauma physicians to be aware of blunt-induced, penetrating trauma to the heart and mediastinum, and for future trauma care guidelines to consider the importance of the cFAST examination.

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in hospitals worldwide. The cornerstones of effective treatment of IAIs include early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using a critical care environment, combined with an optimal surgical approach. Together, the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST) have jointly completed an international multi-society document in order to facilitate clinical management of patients with IAIs worldwide building evidence-based clinical pathways for the most common IAIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting information was shared by an international task force from 46 countries with different clinical backgrounds. The aim of the document is to promote global standards of care in IAIs providing guidance to clinicians by describing reasonable approaches to the management of IAIs.

Engineering lysosomal enzymes to bind the diphtheria toxin receptor with high affinity increases uptake into cells and tissues., Enzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The inefficient uptake of recombinant enzymes via the mannose-6-phosphate receptor, however, prohibits the broad utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that chimeric TPP1 binds with high affinity to target cells and is efficiently delivered into lysosomes. Further, we show superior uptake of chimeric TPP1 over TPP1 alone in brain tissue following intracerebroventricular injection in mice lacking TPP1, demonstrating the potential of this strategy for enhancing lysosomal storage disease therapy.

Brown-Séquard syndrome (BSS) presents as an ipsilateral loss of motor function, proprioception and vibratory sensation accompanied by contralateral pain and temperature loss two to three levels below the level of the injury. It is one of the syndromes associated with incomplete transection of the spinal cord. Classic BSS is rare as most patients present with mixed neurological deficits related to damage of the spinal cord and surrounding structures. BSS remains prevalent in areas with high trauma burden, where assaults with sharp weapons are common. We present the case of a man aged 38 years who sustained a stab injury to the left back. BSS was diagnosed. He underwent removal of the weapon in the operating room and had an uneventful recovery to near baseline functional level after a course of rehabilitation. Despite being a rare aetiology, BSS continues to be an excellent reminder to trauma providers of the anatomy and physiology of neuroanatomical tracts.

Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide (TRP-NAM) pathway and subsequently NAD+ dependent metabolism regulator sirtuin1 (SIRT1). We report that severe malnutrition in weanling mice, induced by feeding a low protein diet, leads to an impaired TRP-NAM pathway and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAM pathway improves hepatic mitochondrial and overall metabolic function which is dependent on SIRT1. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAM pathway can partially improve liver metabolic function in severe malnutrition and could lead to the development of new interventions for children with severe malnutrition.

Background: Appendectomy for acute appendicitis is the most common procedure performed emergently by general surgeons in the United States. The current management of acute appendicitis is increasingly controversial as non-operative management gains favor as a primary therapy. Appendiceal neoplasms are found rarely and often as an incidental finding in the setting of appendectomy for acute appendicitis. Criteria and screening for appendiceal neoplasms are not standardized among surgical societies.Methods: We reviewed electronic medical records for a nine-year period (2010-2018) of patients who underwent appendectomy in two municipal hospitals in The Bronx, New York City. The authors also examined patients undergoing appendectomy during the same time interval through a query of the National Surgical Quality Improvement Program (NSQIP) database. Results: We found a 1.7% incidence of appendiceal neoplasms locally and a 0.53% incidence of appendiceal tumors in available national population sample. Both groups demonstrated an increased incidence of appendiceal carcinoma by age. This finding was most pronounced after the age of 40 in both local and national populations. In our study, the incidence of appendiceal tumors increased with each decade interval up to the age of 80, and peaked at 2.1% in patients between 70 and 79 years.Conclusions: We submit that the management of acute appendicitis involves a consideration of appendiceal neoplasm in patients over the age of 40. This should be considered in the management of older patients with acute appendicitis before a decision to embark on non-operative therapy. If this is undertaken, interval appendectomy or further cancer screening and surveillance should be performed.

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not impair tumor growth, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. Here, we show that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Furthermore, HA facilitates proliferation in nutrient-starved wild-type PDA. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

Lysosomal storage diseases are a group of over 70 inherited genetic diseases caused by a defect or deficiency in a lysosomal protein. Enzyme replacement therapy, in which a functional copy of the defective enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases; however, the inefficient uptake of recombinant enzymes into cells and tissuesviathe low-affinity mannose-6-phosphate receptor prohibits broader utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endo-lysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that the targeted TPP1 chimera binds with high affinity to target cells and is delivered into lysosomes with much greater efficiency than TPP1 alone. Further, we demonstrate efficient and durable uptake of the chimerain vivofollowing intracerebroventricular injection in mice lacking TPP1. Targeting the highly efficient diphtheria toxin internalization pathway represents a novel approach for improving the efficacy and utility of enzyme replacement therapy for treating lysosomal storage diseases.

A 66-year-old man presented with upper back cellulitis and imaging findings consistent with a necrotising soft tissue infection. He was started on broad-spectrum intravenous antibiotics and was taken to the operating room for immediate surgical debridement. On postoperative day 5, the culture was noted to be growing Gemella morbillorum, an exceedingly rare cause of necrotising soft tissue infections in immunocompetent hosts. His condition improved, and he was transitioned to oral antibiotics and discharged home.

Membrane-bound organelles in eukaryotic cells form an interactive network to coordinate and facilitate cellular functions. The formation of close contacts, termed “membrane contact sites” (MCSs), represents an intriguing strategy for organelle interaction and coordinated interplay. Emerging research is rapidly revealing new details of MCSs. They represent ubiquitous and diverse structures, which are important for many aspects of cell physiology and homeostasis. Here, we provide a comprehensive overview of the physiological relevance of organelle contacts. We focus on mitochondria, peroxisomes, the Golgi complex and the plasma membrane, and discuss the most recent findings on their interactions with other subcellular organelles and their multiple functions, including membrane contacts with the ER, lipid droplets and the endosomal/lysosomal compartment., Graphical abstract Unlabelled Image, Highlights • Membrane contact sites (MCSs) physically and functionally link organelles. • MCSs are ubiquitous, diverse and dynamic. • Mitochondria, ER, peroxisomes, Golgi and plasma membrane all form numerous MCSs. • MCSs facilitate intracellular signalling, lipid and metabolite transfer. • MCSs are important for organelle dynamics, division and inheritance.

The removal of damaged or superfluous organelles from the cytosol by selective autophagy is required to maintain organelle function, quality control and overall cellular homeostasis. Precisely how substrate selectivity is achieved, and how individual substrates are degraded during selective autophagy in response to both extracellular and intracellular cues is not well understood. The aim of this review is to highlight pexophagy, the autophagic degradation of peroxisomes, as a model for selective autophagy. Peroxisomes are dynamic organelles whose abundance is rapidly modulated in response to metabolic demands. Peroxisomes are routinely turned over by pexophagy for organelle quality control yet can also be degraded by pexophagy in response to external stimuli such as amino acid starvation or hypoxia. This review discusses the molecular machinery and regulatory mechanisms governing substrate selectivity during both quality-control pexophagy and pexophagy in response to external stimuli, in yeast and mammalian systems. We draw lessons from pexophagy to infer how the cell may coordinate the degradation of individual substrates by selective autophagy across different cellular cues.

The mechanistic target of rapamycin (mTOR) controls metabolic pathways in response to nutrients. Recently, we have shown that mTOR complex 2 (mTORC2) modulates the hexosamine biosynthetic pathway (HBP) by promoting the expression of the key enzyme of the HBP, glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1). Here, we found that GFAT1 Ser-243 phosphorylation is also modulated in an mTORC2-dependent manner. In response to glutamine limitation, active mTORC2 prolongs the duration of Ser-243 phosphorylation, albeit at lower amplitude. Blocking glycolysis using 2-deoxyglucose robustly enhances Ser-243 phosphorylation, correlating with heightened mTORC2 activation, increased AMPK activity, and O-GlcNAcylation. However, when 2-deoxyglucose is combined with glutamine deprivation, GFAT1 Ser-243 phosphorylation and mTORC2 activation remain elevated, whereas AMPK activation and O-GlcNAcylation diminish. Phosphorylation at Ser-243 promotes GFAT1 expression and production of GFAT1-generated metabolites including ample production of the HBP end-product, UDP-GlcNAc, despite nutrient starvation. Hence, we propose that the mTORC2-mediated increase in GFAT1 Ser-243 phosphorylation promotes flux through the HBP to maintain production of UDP-GlcNAc when nutrients are limiting. Our findings provide insights on how the HBP is reprogrammed via mTORC2 in nutrient-addicted cancer cells.

Septins are a conserved family of GTPases that associate with numerous components of the cytoskeleton and the inner leaflet of the plasma membrane. These proteins are involved in many biological processes, including cell division and membrane trafficking, and serving as a scaffolding component of the cytoskeleton used to recruit other proteins and form diffusion barriers to maintain the composition of membrane domains. In order to carry out their cellular functions, septins undergo interactions via their NC or G interfaces to form heteromeric rod-like structures that can polymerize into filaments and associate laterally into bundles. While electron microscopy studies of affinity-tagged and purified Saccharomyces cerevisiae septin complexes have provided evidence for this periodic organization and in-registry lateral bundling in vitro, the in-vivo arrangement of stress fiber-associated septin bundles in mammalian cells remains poorly characterized. We report here on a direct stochastic optical reconstruction microscopy and photoactivated localization microscopy study of the 2D spatial distribution of septins in mammalian cells. From simulated and experimental results, we show the effects of labeling method, labeling efficiency, and fluorescent emitter photophysics on image reconstruction and interpretation. Our experimental results are consistent with septin organization by polymerization of hetero-octamers and an approximate 30-35 nm periodicity between subsequent units of SEPT2-SEPT2 or SEPT9-SEPT9.

Glycogen synthase kinase 3β (GSK3β) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3β function is controlled through its nuclear localization. Here, using ARPE-19 and MDA-MB-231 human cell lines, we found that inhibition of mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3β from the cytosol to the nucleus and to a GSK3β-dependent reduction of the levels of both c-Myc and Snail. mTORC1 is known to be controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance, and we observed here that AMPK activation or amino acid deprivation promotes GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through a perturbation of RAS oncogene family member 7 (Rab7) resulted in loss of GSK3β from lysosomes and in enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-Myc levels. These findings indicate that the nuclear localization and function of GSK3β is suppressed by mTORC1 and suggest a link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling cellular biomass production.