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Acute liver failure secondary to metastatic melanoma is exceedingly rare with the literature limited to case reports. The disease itself presents with vague symptoms making diagnosis difficult without a high clinical suspicion. Further to this, the prognosis of acute liver failure secondary to metastatic melanoma is dismal. We present the case of a 59-year-old male with a distant history of previously excised cutaneous melanoma who presented to our institution with abdominal pain and liver enzyme derangement suggestive of acute hepatitis. Due to progressive derangement in liver function and cross-sectional imaging suggestive of an infiltrative cause, a left axillary lymph node was biopsied which demonstrated metastatic melanoma. The patient subsequently deteriorated into acute liver failure and despite acute treatment of his underlying metastatic melanoma died 17 days post initial presentation. This case highlights an uncommon cause of acute liver failure as well as the poor prognosis associated with acute liver failure secondary to metastatic melanoma., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

Centrosomes are multi-protein organelles that function as microtubule (MT) organizing centers (MTOCs), ensuring spindle formation and chromosome segregation during cell division. 1 , 2 , 3 Centrosome structure includes core centrioles that recruit pericentriolar material (PCM) that anchors γ-tubulin to nucleate MTs. 1 , 2 In Drosophila melanogaster, PCM organization depends on proper regulation of proteins like Spd-2, which dynamically localizes to centrosomes and is required for PCM, γ-tubulin, and MTOC activity in brain neuroblast (NB) mitosis and male spermatocyte (SC) meiosis. 4 , 5 , 6 , 7 , 8 Some cells have distinct requirements for MTOC activity due to differences in characteristics like cell size 9 , 10 or whether they are mitotic or meiotic. 11 , 12 How centrosome proteins achieve cell-type-specific functional differences is poorly understood. Previous work identified alternative splicing 13 and binding partners 14 as contributors to cell-type-specific differences in centrosome function. Gene duplication, which can generate paralogs with specialized functions, 15 , 16 is also implicated in centrosome gene evolution, 17 including cell-type-specific centrosome genes. 18 , 19 To gain insight into cell-type-specific differences in centrosome protein function and regulation, we investigated a duplication of Spd-2 in Drosophila willistoni, which has Spd-2A (ancestral) and Spd-2B (derived). We find that Spd-2A functions in NB mitosis, whereas Spd-2B functions in SC meiosis. Ectopically expressed Spd-2B accumulates and functions in mitotic NBs, but ectopically expressed Spd-2A failed to accumulate in meiotic SCs, suggesting cell-type-specific differences in translation or protein stability. We mapped this failure to accumulate and function in meiosis to the C-terminal tail domain of Spd-2A, revealing a novel regulatory mechanism that can potentially achieve differences in PCM function across cell types., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

PromarkerD is a biomarker-based blood test that predicts kidney function decline in people with type 2 diabetes (T2D) who may otherwise be missed by current standard of care tests. This study examined the association between canagliflozin and change in PromarkerD score (Δ score) over a three-year period in T2D participants in the CANagliflozin cardioVascular Assessment Study (CANVAS). PromarkerD scores were measured at baseline and Year 3 in 2008 participants with preserved kidney function (baseline eGFR ≥60 mL/min/1.73 m 2 ). Generalized estimating equations were used to assess the effect of canagliflozin versus placebo on PromarkerD scores. At baseline, the participants (mean age 62 years, 32% females) had a median PromarkerD score of 3.9%, with 67% of participants categorized as low risk, 14% as moderate risk, and 19% as high risk for kidney function decline. After accounting for the known acute drop in eGFR following canagliflozin initiation, there was a significant treatment-by-time interaction ( p < 0.001), whereby participants on canagliflozin had decreased mean PromarkerD scores from baseline to Year 3 (Δ score: -1.0% [95% CI: -1.9%, -0.1%]; p = 0.039), while the scores of those on placebo increased over the three-year period (Δ score: 6.4% [4.9%, 7.8%]; p < 0.001). When stratified into PromarkerD risk categories, participants with high risk scores at baseline who were randomized to canagliflozin had significantly lower scores at Year 3 (Δ score: -5.6% [-8.6%, -2.5%]; p < 0.001), while those on placebo retained high scores (Δ score: 4.5% [0.3%, 8.8%]; p = 0.035). This post hoc analysis of data from CANVAS showed that canagliflozin significantly lowered PromarkerD risk scores, with the effect greatest in those T2D participants who were classified at study entry as at high risk of a subsequent decline in kidney function.

Duodenal varices (DVs) are ectopic gastrointestinal varices (ECVs) associated with portal hypertension (PH). We present the case of an 82-year-old woman who presented with symptomatic anemia secondary to DV hemorrhage diagnosed on oesophagogastroduodenoscopy. This lesion was treated with endoscopic adrenaline injection and clip application. The patient re-presented on multiple occasions with bleeding recurrence localized to the duodenum, which was managed with intramuscular octreotide and oral beta-blockade resulting in sustained remission of bleeding. This case highlights a rare cause of upper gastrointestinal hemorrhage and highlights the value of somatostatin analogues for conservative treatment of DVs., (© 2022 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.

Microcephaly is a failure to develop proper brain size and neuron number. Mutations in diverse genes are linked to microcephaly, including several with DNA damage repair (DDR) functions; however, it is not well understood how these DDR gene mutations limit brain size. One such gene is TRAIP, which has multiple functions in DDR. We characterized the Drosophila TRAIP homolog nopo, hereafter traip, and found that traip mutants (traip-) have a brain-specific defect in the mushroom body (MB). traip- MBs were smaller and contained fewer neurons, but no neurodegeneration, consistent with human primary microcephaly. Reduced neuron numbers in traip- were explained by premature loss of MB neuroblasts (MB-NBs), in part via caspase-dependent cell death. Many traip- MB-NBs had prominent chromosome bridges in anaphase, along with polyploidy, aneuploidy or micronuclei. Traip localization during mitosis is sufficient for MB development, suggesting that Traip can repair chromosome bridges during mitosis if necessary. Our results suggest that proper brain size is ensured by the recently described role for TRAIP in unloading stalled replication forks in mitosis, which suppresses DNA bridges and premature neural stem cell loss to promote proper neuron number., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies globally; however, a survival paradox has been observed unique to this malignancy. The aim of this study was to review survival outcomes of patients diagnosed with stage II and stage III rectal cancer, to determine whether a survival paradox is present in our centre and assess for patient-related factors that can explain the observed paradox or were predictors of prognosis., Methods: A retrospective review of data collected from 2006 to 2018 of patients diagnosed with rectal cancer in three separate centres was conducted. Percentages pertaining to patient and tumour characteristics, presentation, management and subsequent recurrence were reported. Preoperative and postoperative factors associated with survival were determined using univariable and multivariable logistic regression analysis., Results: Stage IIB/C patients had significantly higher carcinoembryonic antigen (CEA) levels compared to stage IIA and stage IIIA patients (P < 0.001). Stage IIB/C patients had significantly larger primary rectal tumour and were more symptomatic (i.e. rectal bleeding, altered bowel habits and obstruction) at the time of diagnosis (P = 0.007). Preoperative CEA was an independent prognostic factor for cancer-specific survival in patients diagnosed with stage IIB/C and stage IIIA disease (P = 0.008) on multivariable analysis. Overall survival was greatest in stage IIIA disease, which was significantly greater than stage IIB/C disease., Conclusion: This study confirms the existence of a survival paradox in patients diagnosed with CRC in an Australian tertiary centre and adds further weight to the revision of the TNM staging to provide more emphasis on the T stage., (© 2021 Royal Australasian College of Surgeons.)

Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid)., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interests relevant to this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The true incidence of unsuspected choledocholithiasis found during laparoscopic cholecystectomy (LC) is unknown. Untreated 'silent' stones may be associated with significant long-term risks. The aim of this study was to establish the incidence of unsuspected common bile duct stones (CBDS) and to determine the management and associated risk factors for unsuspected CBDS., Methods: Retrospective review of a large consecutive series of patients from Australia who underwent LC in a tertiary referral setting. Percentages of unsuspected CBDS, management and complications were reported. Pre-operative and intra-operative factors associated with unsuspected CBDS were determined using multivariable logistic regression analysis., Results: From a total of 1998 patients who underwent LC, 747 (37.4%) patients with no pre-operative suspicious factors were the subject of this study. CBDS were detected in 24 (3.2%) patients and all were managed either laparoscopically or endoscopically. Risk factors independently associated with unsuspected CBDS included patients >55 years of age (odds ratio 2.93, P = 0.038) and a large cystic duct size (odds ratio = 3.13, P < 0.001) on multivariable analysis., Conclusion: The incidence of patients with unsuspected CBDS on intra-operative cholangiography is low. Complete clearance of these stones can be achieved using a combination of laparoscopic and endoscopic methods., (© 2020 Royal Australasian College of Surgeons.)

Background: Pancreatic cancer is associated with a dismal prognosis, with ductal adenocarcinoma being the most common form of primary neoplasm diagnosed. Clear cell carcinoma is usually associated with kidney, ovarian or bladder malignancy but rarely associated with pancreatic malignancy. According to the WHO classification, primary clear cell adenocarcinoma of the pancreas is a rare "miscellaneous" carcinoma, and to date few cases have been reported in the literature., Case: A 63-year old female who presented to a metropolitan hospital in Australia with abdominal pain suggestive of pancreatitis. Abdominal computed tomography subsequently demonstrated a necrotic mass in the neck of the pancreas with hepatic metastasis. Subsequent histopathological and immunohistochemical analysis was consistent with pancreatic clear cell adenocarcinoma. The patient was discharged to home to commence on dose reduced nab-paclitaxel and gemcitabine., Conclusion: This case reports a rare variant of pancreatic malignancy and contributes further evidence to the body of literature highlighting clear cell adenocarcinoma as a histological subtype of pancreatic neoplasm, albeit rare in nature., (© 2020 Wiley Periodicals LLC.)

Non-small cell lung cancer (NSCLC) is characterised by diffuse metastases, with common sites being the brain, liver, bones, and adrenal glands. Small bowel metastasis from NSCLC is a rare phenomenon, particularly in patients with an adenocarcinoma histology. We report the case of a 56-year-old lung adenocarcinoma patient with a duodenal metastasis diagnosed on FDG/PET-CT and confirmed on duodenal biopsy. Although initially asymptomatic, he subsequently presented with obstructive jaundice secondary to rapid local disease progression at the duodenal metastasis, requiring endoscopic intervention for biliary drainage. He was commenced on single agent pembrolizumab, with disease response on subsequent follow-up. This case highlights a rare case of gastrointestinal metastasis from NSCLC requiring endoscopic intervention due to rapid progression of the disease at the site of metastasis., Competing Interests: The authors disclose no conflicts of interest associated with the production of the submitted manuscript., (Copyright © 2020 by S. Karger AG, Basel.)

Euglycemic ketoacidosis is a recognised side effect secondary to sodium-glucose cotransporter 2 inhibitor use in the treatment of type 2 diabetes mellitus; however, there is scarce evidence to suggest whether preexisting comorbid conditions contribute to the development of this potentially life-threatening complication. We describe a case of euglycemic ketoacidosis in a patient with type 2 diabetes mellitus in the context of empagliflozin use after a recent diagnosis of metastatic lung adenocarcinoma. The diagnosis was complicated by a pulmonary embolism and hospital-acquired pneumonia, and was subsequently established after an anion-gap metabolic acidosis was identified on arterial blood gas and serum ketone measurement. The patient required admission to the intensive care unit for fluid resuscitation and regular intravenous insulin to ensure resolution of acidosis and maintenance of normoglycaemia. The patient was discharged to home for outpatient single-agent pembrolizumab for treatment of his lung adenocarcinoma. This article highlights the importance or awareness of oral hypoglycaemic medications and their side effects, along with providing further evidence for the potential contribution of malignancy to the development of euglycemic ketoacidosis in a patient with type 2 diabetes mellitus., Competing Interests: The authors declare no conflicts of interest in the publication of this manuscript., (Copyright © 2020 Robert Sean O'Neill et al.)

Background: Pancreatic cancer (PC) is a leading cause of cancer related mortality worldwide, with poor survival due to late diagnosis. Currently, biomarkers have limited use in early diagnosis of PC. Macrophage inhibitory cytokine-1 or growth differentiation factor-15 (MIC-1/GDF15) has been implicated as a potential serum biomarker in PC and other malignancies., Aim: To determine the role of MIC-1/GDF15 in detecting pre-malignant pancreatic lesions and neoplastic tumours in an asymptomatic high-risk cohort part of Australian Pancreatic Cancer Screening Program., Methods: A feasibility prospective single centre cohort study was performed. Participants recruited for yearly surveillance with endoscopic ultrasound (EUS) had serial fasting blood samples collected before EUS for MIC-1/GDF15, C-reactive protein and carbohydrate antigen 19-9. Patients were stratified into five groups based on EUS findings: Normal; pancreatic cysts, branch-duct intraductal papillary mucinous neoplasm; diffuse non-specific abnormalities; and neoplastic tumours. MIC-1/GDF15 serum levels were quantified using ELISA. Participants in whom EUS demonstrated abnormalities but not malignancy were closely followed up with magnetic resonance imaging (MRI) or computed tomography., Results: One hundred twenty participants were prospectively recruited from 2011-2018. Forty-seven participants (39.2%) had an abnormal EUS and five participants (4.2%) were diagnosed with neoplastic tumours, three by EUS (two pancreatic and one liver) and two by MRI/computed tomography (breast cancer, bladder cancer), which were performed for follow up of abnormal EUS. Baseline serum MIC-1/GDF15 was a significant predictor of neoplastic tumours on receiver operator characteristic curve analysis [area under curve (AUC) = 0.814, P = 0.023]. Baseline serum MIC-1/GDF15 had moderate predictive capacity for branch-duct intraductal papillary mucinous neoplasm (AUC = 0.644) and neoplastic tumours noted on EUS (AUC = 0.793), however this was not significant ( P = 0.188 and 0.081 respectively). Serial serum MIC-1/GDF15 did not demonstrate a significant percentage change between a normal and abnormal EUS ( P = 0.213). Median baseline MIC-1/GDF15 was greater in those with neoplastic tumours (Median = 1039.6, interquartile range = 727.0-1977.7) compared to those diagnosed with a benign lesion (Median = 570.1, interquartile range = 460.7-865.2) on EUS and MRI ( P = 0.012)., Conclusion: In this pilot study MIC-1/GDF15 has predictive capacity for neoplastic tumours in asymptomatic individuals with a genetic predisposition for PC. Further imagining may be warranted in patients with abnormal EUS and raised serum MIC-1/GDF15. Larger multicentric prospective studies are required to further define the role of MIC-1/GDF15 as a serological biomarker in pre-malignant pancreatic lesions and neoplastic tumours., Competing Interests: Conflict-of-interest statement: The authors declare no competing interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

We describe the case of a 90-year-old female who presented with signs of a strangulated inguinal hernia. Further history revealed a paired biliary-pancreatic stent insertion three years prior for ascending cholangitis and a long-standing asymptomatic right inguinal hernia. Biochemistry revealed a slightly elevated C-reactive protein level of 65 mmol/L, but was otherwise unremarkable. Abdominal CT demonstrated two plastic biliary stents within an incarcerated right inguinal hernia. At the time of surgery, a 3-mm perforation due to the stents was identified in the small bowel within the hernia. The stents were retrieved via an enterotomy that was subsequently repaired with full-thickness interrupted sutures. A tissue-suture repair of the inguinal hernia was performed due to significant contamination of enteric contents in the operative field. The patient had an unremarkable recovery and was discharged four days after her operation. This is a very rare acute presentation of stent migration with only a handful of such reported cases in the literature. With the rising number of endoscopic biliary stenting procedures, these complications are likely to increase, and clinicians need to be aware of this possibility in patients with pre-existing hernias., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Tsang et al.)

Screening for pancreatic cancer (PC) in high-risk groups aimed to detect early cancers is currently done only in the research setting, and data on psychological outcomes of screening in these populations is scarce. To determine the psychological impact of a national Australian pancreatic screening program, a prospective study was conducted using validated psychological measures: impact of events scale (IES), psychological consequences questionnaire (PCQ) and the cancer worry scale. Measures were administered at baseline, 1-month and at 1-year post-enrolment and correlations with abnormal endoscopic ultrasound (EUS) results were calculated. Over a 6-year period, 102 participants were recruited to the screening program. Thirty-nine patients (38.2%) had an abnormal endoscopic ultrasound, and two patients (2.0%) were diagnosed with PC and two with other malignancies. Those with a personal history of cancer or a positive BRCA2 mutation demonstrated significantly increased worry about developing other types of cancer at baseline (p < 0.01). Irrespective of EUS result, there was a significant decrease of total IES score at 1 year (Z = - 2.0, p = 0.041). In patients with abnormal EUS results, there was a decrease in the total IES score at 1 year (Z = - 2.5, p = 0.011). In participants deemed to be most distressed at baseline based on their negative PCQ score, there was a significant decrease of the total PCQ (Z = - 3.2, p = 0.001), emotional (Z = - 3.0, p = 0.001), social (Z = 3.0, p = 0.001) and physical (Z = - 2.8, p = 0.002) subscale at 1-year post-intervention. This study provides evidence of the long-term psychological benefits of PC screening in high-risk patients. There was no negative impact of screening in the short-term and the positive benefits appeared at 1-year post-intervention irrespective of screening result.

Introduction: Adult intussusception (AI) is both a challenging and rare diagnosis, with predisposing factors including malignancy, surgery and infection to name a few. Transient jejunal intussusception is a subset of AI which is usually diagnosed radiologically, with diagnostic laparoscopy utilised to determine whether a malignant cause is identifiable and subsequently treatable., Presenting Case: We present the case of a previously healthy 36-year-old male diagnosed with transient jejunal intussusception on computed tomography after presenting with abdominal pain. Blood tests on admission were normal apart from polycythaemia. His only significant history was that of chronic anabolic steroid use. He had a subsequent normal gastroscopy and colonoscopy with diagnostic laparoscopy demonstrating thickening of the small bowel. Histopathological analysis of the intraoperative specimen was normal. The patient improved and was discharged with no further complications., Conclusion: This case highlights the potential association between anabolic steroid use resulting in polycythaemia, and AI or transient jejunal intussusception, along with further validating a conservative approach in the management of AI in patients deemed to be low risk of malignancy on pre-operative evaluation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Niemann-Pick Disease (NPD) type B is a rare autosomal recessive disease characterised by hepatosplenomegaly and pulmonary disease, highlighted by preserved volumes and diminished diffusion capacity of the lung for carbon monoxide (DLCO) on pulmonary function tests (PFTs). There is no current accepted treatment for the disease. We present a case of a successful bilateral lung transplant in a patient with a DLCO of 14%, and significant pulmonary changes attributable to NPD type B on computed tomography (CT) chest, and both microscopic and macroscopic assessment of the lung explant. To the author's knowledge this is only the third case of lung transplantation in a patient with NPD type B and is one of two current living patients post lung transplantation for NPD type B., Case Report: A 64-year-old male patient underwent bilateral lung transplantation for NPD type B. Preoperative PFTs demonstrated preserved volumes with significantly decreased DLCO, with imaging showing a diffuse reticular interstitial pattern, typical of chronic fibrotic lung disease. The patient suffered from primary graft dysfunction type 3 in the postoperative period as well as rejection managed with methylprednisolone and intravenous immunoglobulin. The patient improved steadily and was discharged 80 days post-transplantation., Conclusions: This case is only the third reported case of lung transplantation in a patient with NPD type B and the second case of a patient with NPD type B currently living post-transplantation, being at postoperative day (POD) 267 at the time of manuscript drafting. It demonstrates that lung transplantation, although hazardous, is a viable strategy for treatment in patients with NPD type B who have significant pulmonary involvement.

Aim: All Irish children with ulcerative colitis (UC) attend the National Centre for Paediatric Gastroenterology at Our Lady's Children's Hospital, Crumlin. The aim of this study was to determine the outcomes of children with acute severe ulcerative colitis (ASC) and the impact of infliximab on these outcomes following its introduction for this indication in 2011., Methods: A retrospective chart review of all patients admitted with ASC between January 1, 2009 and December 31, 2015 was undertaken. Patients were identified from the departmental database cross-referenced with the hospital inpatient enquiry system. Inpatients with a paediatric ulcerative colitis activity index (PUCAI) of ≥65 were included. Data collected included baseline demographic and laboratory data, concomitant treatments, PUCAI scores on days 3 and 5, second-line treatments, surgery, and discharge outcomes. Infliximab dose, frequency, and available therapeutic drug monitoring results were recorded, along with clinical response outcomes (remission, primary, and secondary loss of response). The cohort was sub-analysed to determine if there was any era effect pre- and post-introduction of infliximab (2009-2010 and 2011-2015, respectively)., Results: Fifty-five patients (M:F = 1.4:1) were treated for acute severe colitis over the study period (8 in the pre-infliximab and 47 in the post-infliximab era) and 46/55 (86%) had steroid-refractory disease. Of these, 7/8 (88%) required colectomy in the pre-infliximab era, compared with 15/47 (36%) in the post-infliximab era. The remission rate with second-line infliximab was 61% at maximal follow-up. There were no identifiable factors that predicted likely success or failure of infliximab, including gender, CRP, day-3 and day-5 PUCAI scores. Of the 33 patients treated with infliximab, dose increase was required in 23/33 (70%); 21/33 (64%) received an accelerated dose schedule, and 9/33 (27%) eventually needed colectomy. Primary and secondary loss of response to infliximab was seen in one and nine patients, respectively., Conclusion: This is the first population-based study of the outcomes of severe UC in Irish children, and suggests a higher burden of steroid-refractory disease compared with previous international studies. While infliximab treatment has led to reduction in colectomy rates, a significant proportion of patients lose therapeutic effect.

An intimate link between centrosome function and neurogenesis is revealed by the identification of many genes with centrosome-associated functions that are mutated in microcephaly disorders. Consistent with the major role of the centrosome in mitosis, mutations in these centrosome-related microcephaly (CRM) genes are thought to affect neurogenesis by depleting the pool of neural progenitor cells, primarily through apoptosis as a consequence of mitotic failure or premature differentiation as a consequence of cell cycle delay and randomization of spindle orientation. However, as suggested by the wide range of microcephaly phenotypes and the multifunctional nature of many CRM proteins, this picture of CRM gene function is incomplete. Here, we explore several examples of CRM genes pointing to additional functions that contribute to microcephaly, including regulation of cell cycle signaling, actin cytoskeleton, and Hippo pathway proteins, as well as functions in postmitotic neurons and glia. As these examples are likely just the tip of the iceberg, further exploration of the roles of microcephaly-related genes are certain to reveal additional unforeseen functions important for neurodevelopment., (© 2018 O‘Neill et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

The septin family of hetero-oligomeric complex-forming proteins can be divided into subgroups, and subgroup members are interchangeable at specific positions in the septin complex. Drosophila melanogaster has five septin genes, including the two SEPT6 subgroup members Sep2 and Sep5 We previously found that Sep2 has a unique function in oogenesis, which is not performed by Sep5 Here, we find that Sep2 is uniquely required for follicle cell encapsulation of female germline cysts, and that Sep2 and Sep5 are redundant for follicle cell proliferation. The five D. melanogaster septins localize similarly in oogenesis, including as rings flanking the germline ring canals. Pnut fails to localize in Sep5; Sep2 double mutant follicle cells, indicating that septin complexes fail to form in the absence of both Sep2 and Sep5. We also find that mutations in septins enhance the mutant phenotype of bazooka, a key component in the establishment of cell polarity, suggesting a link between septin function and cell polarity. Overall, this work suggests that Sep5 has undergone partial loss of ancestral protein function, and demonstrates redundant and unique functions of septins., (Copyright © 2016 O'Neill and Clark.)

Septins are cytoskeletal proteins that form hetero-oligomeric complexes and function in many biological processes, including cytokinesis. Drosophila melanogaster has five septin genes. Sep5, which is the most recently evolved septin gene in Drosophila, is a retrogene copy of Sep2. Sep5 mutants appear wild type, whereas Sep2 mutant females are semisterile. Their ovaries have egg chambers containing abnormal numbers of nurse cells. The egg chamber phenotype is rescued to wild type by expressing a Sep2 cDNA, but it is only partially rescued by expressing a Sep5 cDNA, showing that these paralogs have diverged in function at the protein level. Sep2 Sep5 double mutants have an early pupal lethal phenotype and lack imaginal discs, suggesting that these genes have redundant functions during imaginal cell proliferation.

Retrogenes form a class of gene duplicate lacking the regulatory sequences found outside of the mRNA-coding regions of the parent gene. It is not clear how a retrogene's lack of parental regulatory sequences affects the evolution of the gene pair. To explore the evolution of parent genes and retrogenes, we investigated three such gene pairs in the family Drosophilidae; in Drosophila melanogaster, these gene pairs are CG8331 and CG4960, CG17734 and CG11825, and Sep2 and Sep5. We investigated the embryonic expression patterns of these gene pairs across multiple Drosophila species. Expression patterns of the parent genes and their single copy orthologs are relatively conserved across species, whether or not a species has a retrogene copy, although there is some variation in CG8331 and CG17734. In contrast, expression patterns of the retrogene orthologs have diversified. We used the genome sequences of 20 Drosophila species to investigate coding sequence evolution. The coding sequences of the three gene pairs appear to be evolving predominantly under negative selection; however, the parent genes and retrogenes show some distinct differences in amino acid sequence. Therefore, in general, retrogene expression patterns and coding sequences are distinct compared to their parents and, in some cases, retrogene expression patterns diversify.