VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System

The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently ('specialised') or non-covalently ('cargo' effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a 'core' T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the machinery with differential effector specificity and efficiency of target cell delivery

Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning

A Case Report of a Pheochromocytoma Presenting With Neurological Manifestations

Case Report A 51 year-old Caucasian female with a past medical history of hypertension, coronary artery disease and cerebrovascular accident presented to the emergency room with acute onsetdysarthria and right-sided hemiparesis. The patient reported that she noticed these symptoms when she woke that morning,but had resolved by the time she reached the emergency room,an hour later. She denied experiencing palpitations, headache,chest pain or shortness of breath

A 52-year-old Female with Ramsay Hunt Syndrome

Case Report A 52 year-old female with a history of poorly controlled type IIdiabetes and a recent admission of right-sided pre-septal orbitalcellulitis presented with a facial rash and severe ear and eye painfor three days. The patient noted sudden right-sided vision lossand associated right-sided face, ear and eye pain three days prior toadmission. The pain was a 9/10 and was worsening since its onset.Upon questioning she also noted decreased taste sensation. Shedenied tinnitus, vertigo, hearing loss, nausea, vomiting, or fevers

Sarcoidosis Cannot Be Reliably Distinguished from Other Causes of Hepatic Granulomas in a Liver Biopsy Alone

Context: Hepatic granulomas occur in a variety of circumstances. Sarcoidosis is a common cause with the liver following lymph nodes and the lung in frequency of involvement. The present study aimed to determine where granulomatous hepatisis caused by sarcoidosis can be distinguished in a liver biopsy from other etiologies

From the Editors

As the Jefferson Forum embarks on its 11th issue a number of additions have beeninstituted. First, we are proud to announce new faculty collaborators with Dr. StevenHerrine, Dr. Danielle Duffy, Dr. Daniel Frisch, Dr. Anjali Avadhani, Dr. JosephDesimone and Dr. Edward Ruby. Our faculty has helped us with creating a new section of outstanding articles thatwe introduce in this issue. The “Best Of” designation allows us to highlight articlesthat were chosen by peer and faculty review as the best example of academic worksubmitted in each field of medicine. We hope that this addition will inspire moreresidents and faculty to get involved with the journal

Breeding durations as estimators of adult sex ratios and population size

Adult sex ratios (ASRs) and population size are two of the most fundamental parameters in population biology, as they are the main determinants of genetic and demographic viability, and vulnerability of a population to stochastic events. Underpinning the application of population viability analysis for predicting the extinction risk of populations is the need to accurately estimate parameters that determine the viability of populations (i.e. the ASR and population size). Here we demonstrate that a lack of temporal information can confound estimation of both parameters. Using acoustic telemetry, we compared differences in breeding durations of both sexes for a giant Australian cuttlefish Sepia apama breeding aggregation to the strongly male-biased operational sex ratio (4:1), in order to estimate the population ASR. The ratio of breeding durations between sexes was equal to the operational sex ratio, suggesting that the ASR is not strongly male-biased, but balanced. Furthermore, the short residence times of individuals at the breeding aggregation suggests that previous density-based abundance estimates have significantly underestimated population size. With the current wide application of population viability analysis for predicting the extinction risk of populations, tools to improve the accuracy of such predictions are vital. Here we provide a new approach to estimating the fundamental ASR parameter, and call for temporal considerations when estimating population size.Nicholas Leslie Payne, Bronwyn May Gillanders and Jayson Semmen