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Quorum sensing (QS) is a bacterial communication mechanism in which secreted signaling molecules impact population function and gene expression. QS-like phenomena have been reported in eukaryotes with largely unknown contributing molecules, functions, and mechanisms. We identify Qsp1, a secreted peptide, as a central signaling molecule that regulates virulence in the fungal pathogen Cryptococcus neoformans. QSP1 is a direct target of three transcription factors required for virulence, and qsp1Δ mutants exhibit attenuated infection, slowed tissue accumulation, and greater control by primary macrophages. Qsp1 mediates autoregulatory signaling that modulates secreted protease activity and promotes cell wall function at high cell densities. Peptide production requires release from a secreted precursor, proQsp1, by a cell-associated protease, Pqp1. Qsp1 sensing requires an oligopeptide transporter, Opt1, and remarkably, cytoplasmic expression of mature Qsp1 complements multiple phenotypes of qsp1Δ. Thus, C. neoformans produces an autoregulatory peptide that matures extracellularly but functions intracellularly to regulate virulence.

Abstract Background An effective referral system is essential for a high-quality health system that provides safe surgical care while optimizing patient outcomes and ensuring efficiency. The role of referral systems in countries with under-resourced health systems is poorly understood. The aim of this study was to examine the rates, preventability, reasons and patterns of outward referrals of surgical patients across three levels of the healthcare system in Northern Tanzania. Methods Referrals from surgical and obstetric wards were assessed at 20 health facilities in five rural regions prospectively over 3 months. Trained physician data collectors used data collection forms to capture referral details daily from hospital referral letters and through discussions with clinicians and nurses. Referrals were deemed preventable if the presenting condition was one that should be managed at the referring facility level per the national surgical, obstetric and anaesthesia plan but was referred. Results Seven hundred forty-three total outward referrals were recorded during the study period. The referral rate was highest at regional hospitals (2.9%), followed by district hospitals (1.9%) and health centers (1.5%). About 35% of all referrals were preventable, with the highest rate from regional hospitals (70%). The most common reasons for referrals were staff-related (76%), followed by equipment (55%) and drugs or supplies (21%). Patient preference accounted for 1% of referrals. Three quarters of referrals (77%) were to the zonal hospital, followed by the regional hospitals (17%) and district hospitals (12%). The most common reason for referral to zonal (84%) and regional level (66%) hospitals was need for specialist care while the most common reason for referral to district level hospitals was non-functional imaging diagnostic equipment (28%). Conclusions Improving the referral system in Tanzania, in order to improve quality and efficiency of patient care, will require significant investments in human resources and equipment to meet the recommended standards at each level of care. Specifically, improving access to specialists at regional referral and district hospitals is likely to reduce the number of preventable referrals to higher level hospitals, thereby reducing overcrowding at higher-level hospitals and improving the efficiency of the health system.

The crinipelloid genera Crinipellis and Moniliophthora (Agaricales, Marasmiaceae) are characterized by basidiomes that produce long, dextrinoid, hair-like elements on the pileus surface. Historically, most species are believed to be saprotrophic or, rarely, parasitic on plant hosts. The primary morphological diagnostic characters that separate Crinipellis and Moniliophthora are pliant vs. stiff (Crinipellis) stipes and a tendency toward production of reddish pigments (ranging from violet to orange) in the basidiome in Moniliophthora. Additionally, most species of Moniliophthora appear to have a biotrophic habit, while those of Crinipellis are predominantly saprotrophic. Recently, several new neotropical collections prompted a morphological and phylogenetic analysis of this group. Herein, we propose a new species and two new combinations: Moniliophthora mayarum sp. nov., described from Belize, is characterized by its larger pileus and narrower basidiospores relative to other related species; Moniliophthora ticoi comb. nov. (= Crinipellis ticoi) is recollected and redescribed from biotrophic collections from northern Argentina; and M. brasiliensis comb. nov. (= Crinipellis brasiliensis), a parasite of Heteropterys acutifolia. The addition of these three parasitic species into Moniliophthora support a hypothesis of a primarily biotrophic/parasitic habit within this genus.

Background and ObjectivesPatients taking opioids are at risk of developing dependence and possibly abuse. Given the role of the mesolimbic dopamine system in opioid reward, blocking dopamine D2 receptors should limit the abuse liability of opioid analgesics. This pilot study evaluates the analgesic efficacy of oxycodone combined with an atypical antipsychotic (dopamine D2 receptor antagonist).MethodsA randomized, double-blind, within-subjects, controlled trial in healthy volunteers was conducted at UT Health SA Pain Clinic. Fifteen volunteers with previous medical exposure to opioids were enrolled. Risperidone (2 mg) or ziprasidone (80 mg) in combination with oxycodone (5, 10, 15 mg) was administered. Pain intensity using the cold pressor test, Current Opioid Misuse Measure (COMM), Addiction Research Center Inventory (ARCI, opioid subscale), Drug likability with drug effects questionnaire (DEQ) were assessed.ResultsOxycodone produced dose dependent increases in thermal analgesia on the cold pressor test that was significant at 10 and 15 mg (t = 3.087, P = 0.017). The combination did not significantly alter thermal analgesia. There was no significant effect of the combination on the ARCI or the POMS.Discussion and ConclusionThe combination of an atypical antipsychotic with oxycodone does not alter analgesic response or increase the incidence of adverse effects when compared to oxycodone alone. Such information is critical for the development of drug combinations for the treatment of pain and provide the foundation for future studies of abuse potential in drug users.Scientific SignificanceThis intervention in chronic pain patients is unique because it utilizes FDA approved drugs in combination to reduce abuse liability. The first step, and aim of this study, is to confirm the drug combination does not interfere with analgesic efficacy. The next step is to examine the combination in recreational drug users to assess the potential to block the euphoric effects of oxycodone. Ultimately, if this combination is effective, this approach could be beneficial in management of chronic pain.

Abstract Fungi that bind leaf litter into mats and produce white‐rot via degradation of lignin and other aromatic compounds influence forest nutrient cycling and soil fertility. Extent of white‐rot litter mats formed by basidiomycete fungi in Puerto Rico decreased in response to disturbances—a simulated hurricane treatment executed by canopy trimming and debris addition in 2014, a drought in 2015, a treefall, and two hurricanes 10 days apart in September 2017. Percent fungal litter mat cover ranged from 0.4% after Hurricanes Irma and Maria to a high of 53% in forest with undisturbed canopy prior to the 2017 hurricanes, with means mostly between 10% and 45% of fungal litter mat cover in undisturbed forest. Drought decreased litter mat cover in both treatments, except in one control plot dominated by a drought‐resistant fungus, Marasmius crinis‐equi. Percent fungal litter mat cover sharply declined after hurricanes, a treefall, and a simulated hurricane treatment. Solar radiation was significantly inversely correlated with relative humidity (RH) and percent litter mat cover within each of the four climatic seasons. Solar radiation was also directly correlated with prior month litterfall, while RH was moderately correlated with throughfall, rain, and litter wetness. However, rainfall was inversely correlated with litter mat cover, possibly due to erosion or saturation during high rainfall events. Canopy opening reduced leaf fall and litter mat cover but these variables were not correlated except in winter. The main factor inhibiting basidiomycete fungi that bind leaf litter into mats was likely lower litter moisture associated with drought and increased solar radiation from canopy opening but secondary compounds in green litterfall may have contributed. Although higher litterfall likely increases fungal mat cover under closed canopy, changes in environmental factors apparently had a stronger inhibitory effect following canopy disturbances. Drought tolerance of some basidiomycete fungal litter mat species provided some resilience to drought.

Renal clinical chemistry only detects kidney dysfunction after considerable damage has occurred and is imperfect in predicting long term outcomes. Consequently, more sensitive markers of early damage and better predictors of progression are being urgently sought, to better support clinical decisions and support shorter clinical trials. Transglutaminase 2 (TG2) is strongly implicated in the fibrotic remodeling that drives chronic kidney disease (CKD). We hypothesized that urinary TG2 and its ε-(γ-glutamyl)-lysine crosslink product could be useful biomarkers of kidney fibrosis and progression. Animal models: a rat 4-month 5/6th subtotal nephrectomy model of CKD and a rat 8-month streptozotocin model of diabetic kidney disease had 24-hour collection of urine, made using a metabolic cage, at regular periods throughout disease development. Patients: Urine samples from patients with CKD (n = 290) and healthy volunteers (n = 33) were collected prospectively, and progression tracked for 3 years. An estimated glomerular filtration rate (eGFR) loss of 2-5 mL/min/year was considered progressive, with rapid progression defined as > 5 mL/min/year. Assays: TG2 was measured in human and rat urine samples by enzyme-linked immunosorbent assay (ELISA) and ε-(γ-glutamyl)-lysine by exhaustive proteolytic digestion and amino acid analysis. Urinary TG2 and ε-(γ-glutamyl)-lysine increased with the development of fibrosis in both animal model systems. Urinary TG2 was 41-fold higher in patients with CKD than HVs, with levels elevated 17-fold by CKD stage 2. The urinary TG2:creatinine ratio (UTCR) was 9 ng/mmol in HV compared with 114 ng/mmol in non-progressive CKD, 1244 ng/mmol in progressive CKD and 1898 ng/mmol in rapidly progressive CKD. Both urinary TG2 and ε-(γ-glutamyl)-lysine were significantly associated with speed of progression in univariate logistic regression models. In a multivariate model adjusted for urinary TG2, ε-(γ-glutamyl)-lysine, age, sex, urinary albumin:creatinine ratio (UACR), urinary protein:creatinine ratio (UPCR), and CKD stage, only TG2 remained statistically significant. Receiver operating characteristic (ROC) curve analysis determined an 86.4% accuracy of prediction of progression for UTCR compared with 73.5% for UACR. Urinary TG2 and ε-(γ-glutamyl)-lysine are increased in CKD. In this pilot investigation, UTCR was a better predictor of progression in patients with CKD than UACR. Larger studies are now warranted to fully evaluate UTCR value in predicting patient outcomes.

Objectives. In patients with prostate cancer (PC) receiving prostate-specific membrane antigen- (PSMA-) targeted radioligand therapy (RLT), higher baseline standardized uptake values (SUVs) are linked to improved outcome. Thus, readers deciding on RLT must have certainty on the repeatability of PSMA uptake metrics. As such, we aimed to evaluate the test-retest repeatability of lesion uptake in a large cohort of patients imaged with 18F-DCFPyL. Methods. In this prospective, IRB-approved trial (NCT03793543), 21 patients with history of histologically proven PC underwent two 18F-DCFPyL PET/CTs within 7 days (mean 3.7, range 1 to 7 days). Lesions in the bone, lymph nodes (LN), and other organs were manually segmented on both scans, and uptake parameters were assessed (maximum (SUVmax) and mean (SUVmean) SUVs), PSMA-tumor volume (PSMA-TV), and total lesion PSMA (TL-PSMA, defined as PSMA−TV×SUVmean)). Repeatability was determined using Pearson’s correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. Results. In total, 230 pairs of lesions (177 bone, 38 LN, and 15 other) were delineated, demonstrating a wide range of SUVmax (1.5–80.5) and SUVmean (1.4–24.8). Including all sites of suspected disease, SUVs had a strong interscan correlation (R2≥0.99), with high repeatability for SUVmean and SUVmax (wCOV, 7.3% and 12.1%, respectively). High SUVs showed significantly improved wCOV relative to lower SUVs (P

In this paper, we argue that a particular set of issues mars traditional assessment practices. They may be difficult for educators to design and implement; only provide discrete snapshots of performance rather than nuanced views of learning; be unadapted to the particular knowledge, skills, and backgrounds of participants; be tailored to the culture of schooling rather than the cultures schooling is designed to prepare students to enter; and assess skills that humans routinely use computers to perform. We review extant artificial intelligence approaches that–at least partially–address these issues and critically discuss whether these approaches present additional challenges for assessment practice.

Quality control is very important aspect in Building Information Modelling (BIM) workflows. Whatever stage of the lifecycle it is important to get and to follow building indicators. The BIM it is very data consuming field and analysis of these data require advance numerical tools from image processing to big data analysis. Artificial intelligent (AI) and machine learning (ML) had proven their efficiency to deal with automate processes and extract useful sources of data in different industries. In addition to the indicators tracking, AI and ML can make a good prediction about when and where to provide maintenance and/or quality control. In this article, a review of the AI and ML application in BIM will be presented. Further suggestions and challenges will be also discussed. The aim is to provide knowledge on the needs nowadays into building and landscaping domain, and to give a wide understanding on how those technics would impact industries and future studies.

Chitosan, a deacetylated form of chitin, is required for the virulence of Cryptococcus neoformans. There are three chitin deacetylase genes (CDA) that are essential for chitosan production, and deletion of all three genes results in the absence of chitosan, loss of virulence, and induction of a protective host response when used as a vaccine. Cda1 plays a major role in deacetylating chitin during pulmonary infection of CBA/J mice. Inoculation with the cda1Δ strain did not lead to a lethal infection. However, the infection was not cleared. The persistence of the fungus in the host suggests that chitin is still being deacetylated by Cda2 and/or Cda3. To test this hypothesis, we subjected strains deleted of two CDA genes to fungal virulence in CBA/J, C57BL/6 and BALB/c and found that cda1Δcda2Δ was avirulent in all mouse lines, as evidenced by its complete clearance. Consistent with the major role of Cda1 in CBA/J, we found that cda2Δcda3Δ was as virulent as its wild-type progenitor KN99. On the other hand, cda1Δcda3Δ displayed virulence comparable to that of cda1Δ. The virulence of each mutant correlates with the amount of chitosan produced when grown under host-mimicking culture conditions. In addition, the avirulence of cda1Δcda2Δ was followed by the induction of a protective immune response in C57BL/6 and CBA/J mice, when a live or heat-killed form of the mutant was used as a vaccine respectively. Taken together, these data imply that, in C. neoformans, coordinated activity of both Cda1 and Cda2 is essential for mediating fungal virulence.

Pregnancy complications can have long-term negative effects on the health of the affected mothers and their children. In this review, we highlight the underlying inflammatory etiologies of common pregnancy complications and discuss how aberrant inflammation may lead to the acquisition of innate immune memory. The latter can be described as a functional epigenetic reprogramming of innate immune cells following an initial exposure to an inflammatory stimulus, ultimately resulting in an altered response following re-exposure to a similar inflammatory stimulus. We propose that aberrant maternal inflammation associated with complications of pregnancy increases the cross-generational risk of developing noncommunicable diseases (i.e., pregnancy complications, cardiovascular disease, and metabolic disease) through a process mediated by innate immune memory. Elucidating a role for innate immune memory in the cross-generational health consequences of pregnancy complications may lead to the development of novel strategies aimed at reducing the long-term risk of disease.

Background The relationship between asthma and coronavirus disease 2019 (COVID-19) risk is not clear and may be influenced by level of airway obstruction, asthma medication and known COVID-19 risk factors. We aimed to investigate COVID-19 risk in people with asthma. Methods We used UK Biobank data from all participants tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n=107 412; 17 979 test positive). Questions at baseline defined ever asthma and asthma medications. Baseline forced expiratory volume in 1 s (FEV1) was categorised into quartiles. Logistic regression modelled relationships between asthma, and asthma categories (age at onset, medications, FEV1 quartiles), and risk of SARS-CoV-2 positive test. We investigated modification by sex, ethnic group, smoking and body mass index. Results There was a reduced risk of a positive test associated with early-onset asthma (

Summary: GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as two weeks post-mitosis. The underlying mechanisms are largely unclear. Here, we analyze GABAergic inputs in newborn hippocampal granule cells mediated by soma-targeting parvalbumin and dendrite-targeting somatostatin interneurons. Surprisingly, both interneuron subtypes activate α5-subunit-containing GABAA receptors (α5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, parvalbumin interneurons mediate linear GABAergic synaptic currents lacking α5-subunits, while somatostatin interneurons continue to target nonlinear α5-GABAARs. Computational modeling shows that the voltage-dependent amplification of α5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potential.

Background and objective Different lung function trajectories through life can lead to COPD in adulthood. This study investigated whether circulating levels of biomarkers can differentiate those with accelerated (AD) from normal decline (ND) trajectories. Methods The Tasmanian Longitudinal Health Study (TAHS) is a general population study that measured spirometry and followed up participants from ages 7 to 53 years. Based on their forced expiratory volume in 1 s (FEV1) trajectories from age 7 to 53 years, this analysis included those with COPD at age 53 years (60 with AD and 94 with ND) and controls (n=720) defined as never-smokers with an average FEV1 trajectory. Circulating levels of selected biomarkers determined at 53 and 45 years of age were compared between trajectories. Results Results showed that CC16 levels (an anti-inflammatory protein) were lower and C-reactive protein (CRP) (a pro-inflammatory marker) higher in the AD than in the ND trajectory. Higher CC16 levels were associated with a decreased risk of belonging to the AD trajectory (OR=0.79 (0.63–0.98) per unit increase) relative to ND trajectory. Higher CRP levels were associated with an increased risk of belonging to the AD trajectory (OR=1.07, 95% CI: 1.00–1.13, per unit increase). Levels of CC16 (area under the curve (AUC)=0.69, 95% CI: 0.56–0.81, p=0.002), CRP (AUC=0.63, 95% CI: 0.53–0.72, p=0.01) and the combination of both (AUC=0.72, 95% CI: 0.60–0.83, p

Testing can do more than just determine what a student knows; it can aid the learning process, a phenomenon known as the testing effect. There is a growing trend for students to create and share self-assessment questions in their subject, as advocated by the contributing-student pedagogy (CSP). For subjects with large enrolments, this process can be facilitated by educational technology. PeerWise is an example of such technology. It is free, web-based software that allows students to author, share, answer, and provide feedback on multiple-choice quizzes in a collaborative and constructivist fashion. While it is popular, it is unclear to what degree it facilitates student learning. To evaluate its effectiveness, we introduced PeerWise into a second-year psychology subject. We measured the extent to which it increased scores in the final exam. We found that PeerWise did significantly increase exam scores, so was a useful learning aid.

Students have begun to show interest in adopting active and participatory roles that allow them to interact and work collaboratively with educators. One important aspect of students as partners is a process known as value co-creation. Value co-creation is the process of students' feedback, opinions, and other resources such as their intellectual capabilities and personalities, integrated alongside institutional resources, which can offer mutual value to both students and institutions. This paper presents the first conceptual model of value co-creation in higher education using a lens of co-creation cultivated through business and marketing literature. The model includes key components of value co-creation, co-production, and value-in-use as well as links to the anticipated benefits of value co-creation. The model can be used to inform and guide practice for the faculty and administration within higher education as well as to broaden the foundation of value co-creation literature.

Recent scholarly discussions about massive open online courses (MOOCs) highlight pedagogical and practical issues that separate MOOCs from other learning settings, especially how theories of learning translate to MOOC students' motivation, participation, and performance. What is missing from these discussions is the purpose of the MOOC. We report a comparative study of two MOOCs that differ in educational purpose, but are similar in design. Our sample consisted of 983 students in a professional development MOOC, and 648 students in a MOOC focused on general interest. We first report differences between the two MOOCs, in terms of student demographics, achievement motivation, and participation. For each MOOC, we ran a two-stage regression analysis to determine the extent to which motivation variables (stage 1) and participation variables (stage 2) predicted performance. Patterns in demographic background and motivation differed in ways that were consistent with the MOOCs' purposes. Motivation and participation predicted performance, but this relationship differed between the two MOOCs and reflected the patterns of participation. Professional development motivation contributed to final grade in the professional development MOOC, but not the general interest MOOC. The findings have implications for how MOOC designers think about their target audience, and for students who aim for high final grades.

People with a mental illness experience a disproportionate burden of chronic disease morbidity and mortality; contributed to by a higher prevalence of health risk behaviours that increase the risk of chronic disease development. Amongst this population there is little understanding of multiple risk behaviour co-occurrence and client interest in improving multiple such risks. A cross-sectional survey was undertaken with a random selection of 557 clients of 12 community mental health services in Australia. Participants reported their engagement in health risk behaviours (tobacco smoking, harmful alcohol consumption, inadequate fruit and/or vegetable consumption, and inadequate physical activity), and those deemed ‘at risk’ reported whether they were seriously considering improving their risk behaviours. Almost all participants engaged in at least one risk behaviour (96.1%), with 78.4% of participants engaging in two or more risk behaviours. Of those with two risks, the most frequently paired behaviours were inadequate fruit and vegetable consumption and inadequate physical activity (39.7%); of those with three risks the most common combination was inadequate fruit and vegetable consumption, tobacco smoking and harmful alcohol consumption (42.5%). Of those at risk for all behaviours, 68.4% were interested in improving multiple behaviours, and 14% were interested in improving all; with these participants being most frequently interested in changing smoking, nutrition, and physical activity (19.3%), followed by all risk behaviours (14.0%). The findings strengthen the evidence that people with a mental illness are interested in improving their health risk behaviours and indicate a need to address the multiple health risks in this population group.

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence.

The abstract is a key element of a research article that can enhance the utility, discoverability and impact of the work presented. However, the quality and consistency of abstracts can vary, and the state of abstracts in the educational technology field has received little attention to date. In this editorial, we examine the purpose, structure and future of the abstract in educational technology research to provide advice on how to write a good and impactful abstract. A list of 14 elements derived from the literature was used to analyse the abstracts of the first 10 articles published in 2024 from each of the top 10 educational technology journals ranked by Google Scholar (n = 100). Elements such as background, aim, methods, results and implications were found to be present in most abstracts, although there is room for improvement in clarity in some cases. Other elements, including research questions, hypotheses and future directions, are not often incorporated, indicating these elements may not be necessary in this context. These findings can be used by authors to structure an impactful abstract and also highlight elements (e.g., theoretical framework, sample size and context) that should be included to improve discoverability of published work. [ABSTRACT FROM AUTHOR]

Abstract Background Trisectionectomy is a treatment option in extensive liver malignancy, including colorectal liver metastases (CRLM). However, the reported experience of this procedure is limited. Therefore, we present our experience with right hepatic trisectionectomy (RHT) for CRLM as an example and discuss the changing role of trisectionectomy in the context of modern treatment alternatives based on a literature review. Methods Between January 1993 and December 2014 all patients undergoing RHT at a single center in the UK for CRLM were included. Patient and tumor characteristics were reviewed and a multivariate analysis was done. Based on a literature review the role of trisectionectomy in the treatment of HPB malignancies was discussed. Results A total of 211 patients undergoing RHT were included. Overall perioperative morbidity was 40.3%. Overall 90‐day mortality was 7.6% but reduced to 2.8% over time. Multivariate analysis identified additional organ resection (P = .040) and blood transfusion (P = .028) as independent risk factors for morbidity. Multiple tumors, total hepatic vascular exclusion, and R1 resection were independent risk factors for significantly decreased disease‐free and disease‐specific survival. Further surgery for recurrence after RHT significantly prolonged survival compared with palliative chemotherapy only. Conclusion With the further development of surgical and multimodal treatment strategies in CRLM the indications for trisectionectomy are decreasing. Having being formerly associated with high rates of perioperative morbidity and mortality, this single‐center experience clearly shows that these concomitant risks decrease with experience, liberal use of portal vein embolization and improved patient selection. Trisectionectomy remains relevant in selected patients.

The lineage-specific receptor CSF1R controls macrophage development and homeostasis. Here the authors show that deletion of a conserved Csf1r enhancer (FIRE) selectively depletes brain microglia and resident macrophages in the epidermis, kidney, heart and peritoneum of otherwise healthy mice.

Region-specific increases in hippocampal activity have been reported in schizophrenia patients, yet there are little known about how these circuit levels changes modulate behavioral deficits. Here authors found that that over-expression of the a5 subunit of the GABAA receptor increased tonic GABA currents and normalized aberrant pyramidal cell activity in the ventral hippocampus which had distinct disease symptom outcomes depending on the pathway targeted

Advanced therapy medicinal products (ATMPs) require evaluation by the European Medicines Agency’s Committee for Advanced Therapies prior to being placed on the European market, subject to a Marketing Authorisation granted by the European Commission. In common with other medicinal products, various regulatory pathways are available for taking ATMPs through clinical trials to market authorisation, and the regulatory pathway taken will depend on a product’s characteristics and the target patient population. With the industry poised to deliver more late-stage clinical and commercial ATMPs for serious diseases with high unmet medical need (e.g., T cell immunotherapies for cancer), bringing medicines to patients through optimized regulatory strategies and expedited pathways is assuming greater importance. The European Medicines Agency’s priority medicines (PRIME) scheme was introduced in 2016 specifically to enable this, and eligibility has been granted to 19 ATMPs as of the fourth quarter (Q4) 2018. Furthermore, two chimeric antigen receptor (CAR) T cell therapies, Yescarta and Kymriah, have recently completed their journeys through the scheme to Marketing Authorisation. This review discusses how the regulatory pathway for any particular ATMP, with or without PRIME designation, is determined and navigated. Keywords: Marketing Authorisation, advanced therapy medicinal product, cell therapy, gene therapy, regulation, conditional approval, accelerated assessment, PRIME, RMAT designation, Sakigake designation