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Abstract Background Saksenaea species (spp.) are uncommon causes of mucormycosis but are emerging pathogens mostly associated with trauma and soil contamination often in immunocompetent hosts. Due to lack of sporulation in the laboratory, diagnosis and susceptibility testing is difficult so optimal treatment regimens are unknown. Case presentation A 67 year-old man from the Northern Territory in Australia, with a history of eosinophilic granulomatosis with polyangiitis, developed disseminated Saksenaea infection after initially presenting with symptoms consistent with bacterial pyelonephritis. Despite a delay in diagnosis; with aggressive surgical management and dual therapy with amphotericin B and posaconazole, he survived. Conclusions We describe an unusual case of disseminated infection with a favourable outcome to date.

The Gonghe Basin on the Qinghai-Tibet Plateau has a cold, arid climate and has suffered severe land degradation. Climate change as well as anthropogenic activities including overgrazing have resulted in widespread blowout development and the formation of some of Earth’s largest blowouts. The blowouts are part of an aeolian dominated landscape that passes from deflation zone to grass covered plain, and then through blowouts of increasing size and complexity to transverse barchanoid dunes that are migrating into the valley of the Yellow River. A combination of structure-from-motion (SfM) optical drone mapping, ground-penetrating radar (GPR) and soil pits are used to investigate blowout scour hollows and depositional lobes. Comparisons of the volumes of sediment removed from the scour hollows with the volumes of sediment deposited within adjacent lobes varies between sites. The lobe volume is invariably less than the volume of the scour hollow. This can, in part, be attributed to aeolian reworking of the lobe, distributing sand further downwind and uplifting of dust. However, much of the difference in volumes between the scour and lobe can be attributed to the measurement technique, particularly where GPR was employed to calculate lobe volumes. The wavelength of the GPR limits its ability to resolve thin layers of sand resulting in an underestimate of the deposited sand at the margins of a lobe where the sand thickness is equal to, or less than, the wavelength of the GPR. For thin sand layers, beneath the resolution of the GPR, soil pits suggest a closer match between the volume of sand eroded from the scour and the volume of the lobe, albeit with large measurement uncertainty. We put forth two hypotheses to explain the spatio-temporal evolution of the blowout dune field. The downwind increase in blowout dune size could either reflect a downwind propagation of aeolian instability; or it could result from an upwind propagation of the instability, which started at the highest points in the landscape and has subsequently migrated in a northwesterly direction, towards lower elevations. Recent optically stimulated luminescence dating appear to support the latter hypothesis.

Novel psychoactive substances (NPS) threaten public health and safety while also straining the limited resources of forensic laboratories. To efficiently allocate the finite resources available, we propose a new strategy for prioritizing NPS with abuse liability testing using a preclinical behavioral procedure in rats known as intracranial self-stimulation (ICSS). To validate this assay, the recently-scheduled synthetic cathinone α-PHP was compared to cocaine, a mechanistically similar drug of abuse, as a positive control and saline as a negative control. Male Sprague-Dawley rats (n=6) were implanted with electrodes targeting the medial forebrain bundle and trained to respond by lever-press for electrical brain stimulation. The rats were tested with doses of 0.32, 1.0, and 3.2 mg/kg α-PHP as well as 10 mg/kg of cocaine and saline administered by intraperitoneal injection. Neither saline nor 0.32 mg/kg α-PHP altered ICSS response rates compared to baseline levels of responding; however, doses of 1.0 and 3.2 mg/kg α-PHP and 10 mg/kg cocaine facilitated ICSS responding. This ICSS profile suggests that α-PHP has high abuse potential, with a rapid onset of effects and a long duration of action, and supports the decision to schedule this compound. This study demonstrates the ability of ICSS to distinguish between compounds of low and high potential for abuse. A strategy is proposed here to screen NPS using ICSS and classify emerging drugs into four priority categories for further analysis.

Sex differences in human locomotion are of interest in a broad variety of interdisciplinary applications. Although kinematic sex differences have been studied for many years, the underlying reasons behind several noted differences, such as pelvis and torso range of motion, are still not well understood. Walking speed and body size in particular represent confounding influences that hinder our ability to determine causal factors. The purpose of this study was to investigate sex differences in whole body gait kinematics across a range of controlled, non-dimensional walking and running speeds. We hypothesized that as task demand (i.e. gait speed) increased, the influences of modifiable factors would decrease, leading to a kinematic motion pattern convergence between sexes. Motion capture data from forty-eight healthy young adults (24 M, 24 F) wearing controlled footwear was captured at three walking and three running Froude speeds. Spatiotemporal metrics, center of mass displacement, and joint/segment ranges of motion were compared between sexes using 2x6 mixed-model ANOVAs. Three dimensional time-series waveforms were also used to describe the time-varying behavior of select joint angles. When controlling for size, sex differences in spatiotemporal metrics and center of mass displacement disappeared. However, contrary to our hypothesis, sagittal plane ankle, frontal plane pelvis, and transverse plane pelvis and torso range of motion all displayed sex differences that persisted or increased with gait speed. Overall, most spatiotemporal sex differences appear to be related to size and self-selection of gait speeds, while in contrast, sex differences in joint motion may be more inherent and ubiquitous than previously thought. Discussion on potential causal factors is presented.

Abstract Radiation therapy is a source of tumor antigen release that has the potential to serve as an endogenous tumor vaccination event. In preclinical models radiation therapy synergizes with checkpoint inhibitors to cure tumors via CD8 T cell responses. To evaluate the immune response initiated by radiation therapy, we used a range of approaches to block the pre-existing immune response artifact initiated by tumor implantation. We demonstrate that blocking immune responses at tumor implantation blocks development of a tumor-resident antigen specific T cell population and prevents tumor cure by radiation therapy combined with checkpoint immunotherapy. These data demonstrate that this treatment combination relies on a pre-existing immune response to cure tumors, and may not be a solution for patients without pre-existing immunity.

Summary: Histone H3 lysine 79 (H3K79) methylation is enriched on actively transcribed genes, and its misregulation is a hallmark of leukemia. Methylation of H3K79, which resides on the structured disk face of the nucleosome, is mediated by the Dot1L methyltransferase. Dot1L activity is part of a trans-histone crosstalk pathway, requiring prior histone H2B ubiquitylation of lysine 120 (H2BK120ub) for optimal activity. However, the molecular details describing both how Dot1L binds to the nucleosome and why Dot1L is activated by H2BK120 ubiquitylation are unknown. Here, we present the cryoelectron microscopy (cryo-EM) structure of Dot1L bound to a nucleosome reconstituted with site-specifically ubiquitylated H2BK120. The structure reveals that Dot1L engages the nucleosome acidic patch using a variant arginine anchor and occupies a conformation poised for methylation. In this conformation, Dot1L and ubiquitin interact directly through complementary hydrophobic surfaces. This study establishes a path to better understand Dot1L function in normal and leukemia cells. : Dot1L is a histone H3K79-specific methyltransferase that is critical to the pathogenesis of leukemia. Here, Anderson et al. report the cryo-EM structure of Dot1L in complex with a ubiquitylated nucleosome, providing molecular details of how Dot1L binds its nucleosome substrate and is activated by ubiquitin. Keywords: chromatin, structural biology, single particle, cryo-EM, histone methyltransferase, nucleosome, Dot1L, ubiquitin

Introduction: Among adult emergency department (ED) patients, we sought to examine how estimates of substance use prevalence and the need for interventions can differ, based on the type of screening and assessment strategies employed. Methods: We estimated the prevalence of substance use and the need for interventions using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in a secondary analysis of data from two cross-sectional studies using random samples of English- or Spanish-speaking 18-64-year-old ED patients. In addition, the test performance characteristics of three simplified screening strategies consisting of selected questions from the ASSIST (lifetime use, past three-month use, and past three-month frequency of use) to identify patients in need of a possible intervention were compared against using the full ASSIST. Results: Of 6,432 adult ED patients, the median age was 37 years-old, 56.6% were female, and 61.6% were white. Estimated substance use prevalence among this population differed by how it was measured (lifetime use, past three-month use, past three-month frequency of use, or need for interventions). As compared to using the full ASSIST, the predictive value and accuracy to identify patients in need of any intervention was best for a simplified strategy asking about past three-month substance use. A strategy asking about daily/near-daily use was better in identifying patients needing intensive interventions. However, some patients needing interventions were missed when using these simplified strategies. Conclusion: Substance use prevalence estimates and identification of ED patients needing interventions differ by screening strategies used. EDs should carefully select strategies to identify patients in need of substance use interventions.

The cellular levels and activities of ribosomes directly regulate gene expression during numerous physiological processes. The mechanisms that globally repress translation are incompletely understood. Here, we use electron cryomicroscopy to analyze inactive ribosomes isolated from mammalian reticulocytes, the penultimate stage of red blood cell differentiation. We identify two types of ribosomes that are translationally repressed by protein interactions. The first comprises ribosomes sequestered with elongation factor 2 (eEF2) by SERPINE mRNA binding protein 1 (SERBP1) occupying the ribosomal mRNA entrance channel. The second type are translationally repressed by a novel ribosome-binding protein, interferon-related developmental regulator 2 (IFRD2), which spans the P and E sites and inserts a C-terminal helix into the mRNA exit channel to preclude translation. IFRD2 binds ribosomes with a tRNA occupying a noncanonical binding site, the ‘Z site’, on the ribosome. These structures provide functional insights into how ribosomal interactions may suppress translation to regulate gene expression.

[This corrects the article DOI: 10.1371/journal.pone.0187532.].

Human papilloma virus positive (HPV+) tumors represent a large proportion of anal, vulvar, vaginal, cervical and head and neck squamous carcinomas (HNSCC) and late stage invasive disease is thought to originate from a premalignant state. Cyclic dinucleotides that activate STimulator of INterferon Genes (STING) have been shown to cause rapid regression of a range of advanced tumors. We aimed to investigate STING ligands as a novel treatment for papilloma. We tested therapies in a spontaneous mouse model of papilloma of the face and anogenital region that histologically resembles human HPV-associated papilloma. We demonstrate that STING ligands cause rapid regression of papilloma, associated with T cell infiltration, and are significantly more effective than Imiquimod, a current immunotherapy for papilloma. In humans, we show that STING is expressed in the basal layer of normal skin and lost during keratinocyte differentiation. We found STING was expressed in all HPV-associated cervical and anal dysplasia and was strongly expressed in the cancer cells of HPV+ HNSCC but not in HPV-unrelated HNSCC. We found no strong association between STING expression and progressive disease in non-HPV oral dysplasia and oral pre-malignancies that are not HPV-related. These data demonstrate that STING is expressed in basal cells of the skin and is retained in HPV+ pre-malignancies and advanced cancers, but not in HPV-unrelated HNSCC. However, using a murine HNSCC model that does not express STING, we demonstrate that STING ligands are an effective therapy regardless of expression of STING by the cancer cells.

The teaching of reading has come to be regarded as one of the highest priority areas in modern education because schools have been failing to teach reading effectively to large numbers of students who progress to secondary school without having achieved a working competency in this basic skill. Much of the burden of reading instruction has fallen upon English teachers, many of whom are no better equipped to teach reading--particularly at the remedial level--than teachers of chemistry, home economics, or physical education. In this article, the author discusses what teachers can do to help students with reading difficulties. The author suggests that teachers should assume the responsibility for evaluating reading competency, diagnosing reading difficulties, prescribing study techniques to alleviate problems and ineffective procedures, and promoting enriched reading opportunities. In addition, the author also emphasizes the importance of devising alternate learning methods within content areas so that the non-reader or severely disabled reader can be exposed to the content of the course despite his disability.

The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstrate that the combination of immunotherapy and radiation results in improved therapeutic efficacy, and that the ideal timing of administration with radiation is dependent on the mechanism of action of the immunotherapy utilized.