bluuebunny/crossref_metadata_2025 huggingface dataset:
Is There a Point to Performing a Penile Duplex Ultrasound?
Authors: Morgado Afonso , Diniz Paulo , Silva Carlos Martins
Published: August 2019

Introduction

Specialized diagnostic evaluation of erectile dysfunction (ED) may require an intracavernous injection test (IIT) or penile duplex ultrasound (PDU).

Aim

Our primary objective was to compare the prognostic value of IIT and PDU for treatment efficacy and patient satisfaction with first-line sildenafil citrate.

Methods

After 200 patients were screened, a total of 77 patients with ED had a standardized PDU by a blinded third party, and peak systolic velocity (PSV), end diastolic flow (EDF), and resistive index (RI) in timely intervals were recorded. The erection hardness score (EHS) was used to score erection rigidity during the test and was also noted. Patients also completed a briefed International Index of Erectile Function (IIEF-5) questionnaire and were started on open-label 100 mg sildenafil citrate at baseline. The IIEF-5 and erectile dysfunction inventory of treatment satisfaction (EDITS) questionnaires were repeated and completed at 6 months’ follow-up. Improvement, cure, and satisfaction were defined as an increase of 4 points in IIEF-5 with an IIEF-5 score higher than 21 points and EDITS score higher than 50, respectively. Receiver operating characteristic curves were drawn and the area under the curve (AUC) was calculated and compared.

Main Outcome Measure

EHS did not have a different or larger AUC than PSV, EDF, and RI for improvement, cure, and satisfaction with sildenafil citrate.

Results

The patient’s mean age was 58.76 ± 10.27 years and almost half of the patients had moderate ED according to the IIEF-5 (42.8%). Improvement, cure, and satisfaction were high among participants (77.9%, 64.9%, and 67.5%, respectively). The erection rigidity EHS also showed an excellent-to-good ability to predict improvement, cure, and patient satisfaction (AUC = 0.921, 0.873, and 0.898, respectively) with sildenafil citrate.

Clinical Implications

There is no point in performing more than an IIT when a specialized diagnostic evaluation is required for diagnostic or medico-legal reasons because PDU is time-consuming and requires both hardware and ultrasound skills with no added prognostic value.

Strengths and Limitations

This is the first prospective study to directly compare IIT with PDU, and validated disease-specific questionnaires were used to assess both clinical efficacy and satisfaction. Moreover, the PDU was performed by a blinded third party. However, this was a single-center study and the population included was small.

Conclusion

PDU parameters add no prognostic value to determining erection rigidity during a standard IIT. Erection rigidity during IIT, as assessed with the EHS, suffices as a prognostic tool.
Working smarter, not harder: objective-dependent management of an invasive thistle, Carduus nutans
Authors: Zhang Rui , Shea Katriona
Published: August 2019

Many invasive species managers state that their objective is to “control” an invader. However, the appropriate choice of a management option requires a more explicit statement of management objectives, in terms of both the relevant time horizon and spatial scale. Using data from a 2-yr mowing experiment, we show that the most effective management strategy for controlling an invasive thistle depends fundamentally on the management goals. We integrate field data from a two-cohort experiment with modeling to assess 14 mowing treatments (differing in intensity, frequency, and timing, and thus also in their required logistical effort) based on their effectiveness in (1) reducing population density of the existing cohort, (2) decreasing projected long-term population growth, and (3) limiting projected population spread of an invasive thistle, musk thistle (Carduus nutansL.). The treatment with high intensity and a single late mow caused the largest reduction in plant survival (and density of existing adult plants); the treatment with high intensity and an early mow in addition to a late mow was most effective at reducing population growth rate and population spread. Against expectation and conventional wisdom, the most frequent mowing treatment did not provide the most effective management outcome for any stated objective. This study highlights the necessity of clearly defined management aims; the term “control” is too vague to be truly useful. The results also provide important insights for the management of this invasive species.
THE ANGRY IŠTAR OF ETURKALAMMA: BM 32482+ AND THE CONSERVATION OF CULTIC TRADITIONS IN THE LATE BABYLONIAN PERIOD
Authors: Da Riva Rocio
Published: August 2019

BM 32482 + is a Late Babylonian tablet with descriptions of rites and ceremonies held in the Eturkalamma temple of Bēlet-Bābili (Ištar of Babylon). The text refers to prayers and recitations to appease the goddess. Cult personnel from her temple (išippupriest) are also mentioned, as is music, anigûtuperformed by anadītupriestess, a ritual involving asakkikuddītu,a cultic commentary, omens involving birds, and astrological observations. Despite the fragmentary condition of the tablet, it seems that the performance of thenigûtuwas in one way or another related to the preservation of the temple rituals, which would otherwise have been forgotten.
The association between gut microbiota composition and BMI in Chinese male college students, as analysed by next-generation sequencing
Authors: Lv Yanrong , Qin Xiangxiang , Jia Huaijie , Chen Sirui , Sun Weiwei , Wang Xiaoxia
Published: August 2019

Altered gut microbial ecology contributes to the development of metabolic diseases including obesity. However, studies based on different populations have generated conflicting results due to diet, environment, methodologies, etc. The aim of our study was to explore the association between gut microbiota and BMI in Chinese college students. The 16S next-generation sequencing (NGS) was used to test the gut microbiota of nine lean, nine overweight/obesity and ten normal-weight male college students. The differences in gut microbiota distribution among three groups were compared, and the relationship between the richness, diversity, composition of gut microbiota and BMI were analysed. The predominant phyla Bacteroidetes and Firmicutes were further confirmed by real-time PCR. Metagenomic biomarker discovery was conducted by linear discriminant analysis (LDA) effect size (LEfSe). NGS revealed that gut microbiota composition was different among three groups, but there was no difference in the abundance ratio of Firmicutes:Bacteroidetes. Several bacterial taxa were in linear relationship with BMI (positive relationship: uncultured bacterium (Bacteroides genus); negative relationship: Porphyromonadaceae, Acidaminococcaceae, Rikenellaceae, Desulfovibrionaceae, Blautia, Anaerotruncus, Parabacteroides, Alistipes). Moreover, gut microbiota diversity decreased with the increase in BMI. And LEfSe analysis indicated that Blautia, Anaerotruncus and its uncultured species were significantly enriched in the lean group (LDA score ≥ 3), Parasuterella and its uncultured species were significantly enriched in the overweight/obese groups (LDA score ≥ 3). In general, gut microbiota composition and microbial diversity were associated with BMI in Chinese male college students. Our results might enrich the understanding between gut microbiota and obesity.
High dietary vitamin C intake reduces glucocorticoid-induced immunosuppression and measures of oxidative stress in vitamin C-deficient senescence marker protein 30 knockout mice
Authors: Uchio Ryusei , Hirose Yoshitaka , Murosaki Shinji , Ishigami Akihito
Published: August 2019

Vitamin C (VC) is a vital micronutrient for humans and some other mammals and also has antioxidant activity. Stress-induced elevation of glucocorticoid production is well known to cause immunosuppression. The present study evaluated the effect of high VC intake on glucocorticoid-induced immune changes in mice. Senescence marker protein 30 knockout mice with genetic VC deficiency were fed a diet containing the recommended VC content (20 mg/kg per d; 0·02 %VC group) or a high VC content (200 mg/kg per d; 0·2 %VC group) for 2 months, then dexamethasone was given by intraperitoneal injection. After administration of dexamethasone, the plasma ascorbic acid concentration decreased significantly in the 0·02 %VC group and was unchanged in wild-type C57BL/6 mice on a VC-deficient diet (wild-type group), while it was significantly higher in the 0·2 %VC group compared with the other two groups. In the 0·02 %VC and wild-type groups, dexamethasone caused a significant decrease in the cluster of differentiation (CD)4+and CD8+T cells among splenocytes as well as a significant decrease in IL-2, IL-12p40 and interferon-γ protein production by splenocytes and a significant decrease in T-cell proliferation among splenocytes. In the 0·2 %VC group, these dexamethasone-induced immunosuppression improved when compared with the other two groups. In addition, reduction in the intracellular levels of ascorbic acid, superoxide dismutase and glutathione in splenocytes by dexamethasone as well as elevation in thiobarbituric acid-reactive substances were significantly suppressed in the 0·2 %VC group. These findings suggest that high dietary VC intake reduces glucocorticoid-induced T-cell dysfunction by maintaining intracellular antioxidant activity.
From Across the Water: Nusakambangan and the Making of a Notorious Prison Island
Authors: Stutje Klaas
Published: August 2019

This article examines the social and spatial embedding of the Indonesian prison island of Nusakambangan within the colonial society of the Dutch East Indies. It challenges the conception of the colonial prison site as an unquestioned symbol of discipline and control in the hands of the authorities, doing so by studying the various images, reputations, and stigmas of the island that circulated in the colony. Its reputation was established and disseminated by journalists, politicians, and other “informed outsiders”, who paid short authorized visits to the island, and their conclusions and evaluations determined, to a large extent, the effectiveness of Nusakambangan as a deterrent and as a symbol of colonial discipline and control.
Stories from people living with frailty
Authors: Lloyd Anna , Haraldsdottir Erna , Kendall Marilyn , Murray Scott A. , McCormack Brendan
Published: August 2019

We describe the findings of a qualitative longitudinal interview study of a group of initially community-dwelling frail older people, and their informal and formal carers. We used a narrative approach to explore the role that narrative may have for people living with frailty. This has been less explored comparative to the experiences of those living with chronic illness. The frail older people told stories of their experiences that revealed three distinct shapes or typologies. These were eitherstable,unbalancingoroverwhelmed, and related to how the person managed to adapt to increasing challenges and losses, and to reintegrate their sense of self into a cohesive narrative. Each is illustrated by an individual case story. Frailty is described as both biographically anticipated yet potentially biographically disruptive as older people may struggle to make sense of their circumstances without a clear single causative factor. Findings are discussed in relation to biographical disruption and reconstruction in chronic illness and the rhetoric around ‘successful ageing’. We conclude by drawing attention to the complex individual and social factors that contribute to the experience of living with frailty in later life.
Intranuclear characteristics of pig oocytes stained with brilliant cresyl blue and nucleologenesis of resulting embryos
Authors: Murin Matej , Strejcek Frantisek , Bartkova Alexandra , Morovic Martin , Benc Michal , Prochazka Radek , Lucas-Hahn Andrea , Pendovski Lazo , Laurincik Jozef
Published: August 2019

Brilliant cresyl blue (BCB) vital labelling is a powerful method for analyzing the quality of porcine cumulus–oocyte complexes. Our aim was to investigate the correlation between the selection of porcine oocytes using BCB labelling and selected intranuclear characteristics of porcine oocytes and parthenotes. Moreover, BCB labelling was correlated with the diameter of the oocyte and the developmental potential of the parthenotes. The following methods were used: BCB labelling, measurement of the diameter of the oocyte, parthenogenetic activation, immunocytochemistry, transmission electron microscopy, enucleation and relative protein concentration (RPC) analysis. We determined that the diameter of the oocytes in the BCB-positive (BCB+) group was significantly larger than in the BCB-negative (BCB−) group. Immediately after oocyte selection according to BCB labelling, we found significant difference in chromatin configuration between the analyzed groups. BCB+ oocytes were significantly better at maturation than BCB− oocytes. BCB+ embryos were significantly more competent at cleaving and in their ability to reach the blastocyst stage than BCB− embryos. Ultrastructural analyses showed that the formation of active nucleoli in the BCB+ group started at the 8-cell stage. Conversely, most BCB− embryos at the 8-cell and 16-cell stages were fragmented. No statistically significant difference in RPC in nucleolus precursor bodies (NPBs) between BCB+ and BCB− oocytes was found. We can conclude that BCB labelling could be suitable for assessing the quality of porcine oocytes. Moreover, the evaluation of RPC indicates that the quantitative content of proteins in NPB is already established in growing oocytes.
Sperm characterization of the Amazonian freshwater cururu stingrayPotamotrygon wallacei(Potamotryogonidae): basic knowledge for reproduction and conservation plans
Authors: Morales-Gamba Ruben Dario , Caldas Jôsie Schwartz , Godoy Leandro , Marcon Jaydione Luiz
Published: August 2019

This study aimed to describe the morphology and sperm quality of free-living adult males of cururu stingrayPotamotrygon wallacei, endemic from the Rio Negro basin, Brazilian Amazon. The sperm was collectedin locofrom the seminal vesicle region and fixed in buffered saline formaldehyde solution for further evaluation of morphometry, sperm plasma membrane integrity and sperm concentration. The spermatozoa presented a total length of 138.25 ± 1.82 μm with a helical shape and a long head. A high percentage of cells with intact membrane (98 ± 2%) and normal spermatozoa (92 ± 1%) were observed. The cell concentration was 0.34 ± 0.05 × 1010spermatozoa/ml of semen. These observations are unprecedented for potamotrygonid species and will serve as a basis for future management and conservation strategies.
Comparison of iodine status pre- and post-mandatory iodine fortification of bread in South Australia: a population study using newborn thyroid-stimulating hormone concentration as a marker
Authors: Wassie Molla Mesele , Yelland Lisa N , Smithers Lisa G , Ranieri Enzo , Zhou Shao Jia
Published: August 2019

Objective:

The present study aimed to evaluate the effect of mandatory iodine fortification of bread on the iodine status of South Australian populations using newborn thyroid-stimulating hormone (TSH) concentration as a marker.

Design:

The study used an interrupted time-series design.

Setting:

TSH data collected between 2005 and 2016 (n 211 033) were extracted from the routine newborn screening programme in South Australia for analysis. Iodine deficiency is indicated when more than 3 % of newborns have TSH > 5 mIU/l.

Participants:

Newborns were classified into three groups: the pre-fortification group (those born before October 2009); the transition group (born between October 2009 and June 2010); and the post-fortification group (born after June 2010).

Results:

The percentage of newborns with TSH > 5 mIU/l was 5·1, 6·2 and 4·6 % in the pre-fortification, transition and post-fortification groups, respectively. Based on a segmented regression model, newborns in the post-fortification period had a 10 % lower risk of having TSH > 5 mIU/l than newborns in the pre-fortification group (incidence rate ratio (IRR) = 0·90; 95 % CI 0·87, 0·94), while newborns in the transitional period had a 22 % higher risk of having TSH > 5 mIU/l compared with newborns in the pre-fortification period (IRR = 1·22; 95 % CI 1·13, 1·31).

Conclusions:

Using TSH as a marker, South Australia would be classified as mild iodine deficiency post-fortification in contrast to iodine sufficiency using median urinary iodine concentration as a population marker. Re-evaluation of the current TSH criteria to define iodine status in populations is warranted in this context.
Kant on the Role of Religion for Moral Progress
Authors: Buddeberg Eva
Published: August 2019

This article examines Kant’s understanding of moral progress, especially in his Religion where he argues that religion and, more importantly, the foundation of an ethical community are necessary to promote moral progress. However, it is less the identification of any factual moral progress but rather the idea of moral progress as an action guiding principle that Kant identifies as central. The conclusion shows how Kant’s insights are in accordance with the argument that we should not look for comprehensive moral progress in history but adhere to the idea of possible future moral progress.
Effect of community members' willingness to disclose a mental disorder on their psychiatric symptom scores: analysis of data from two randomised controlled trials of mental health first aid training
Authors: Jorm A. F. , Mackinnon A. J. , Hart L. M. , Reavley N. J. , Morgan A. J.
Published: August 2019

Aims

The prevalence of common mental disorders has not declined in high-income countries despite substantial increases in service provision. A possible reason for this lack of improvement is that greater willingness to disclose mental disorders might have led to increased reporting of psychiatric symptoms, thus masking reductions in prevalence. This masking hypothesis was tested using data from two trials of interventions that increased willingness to disclose and that also measured symptoms. Both interventions involved Mental Health First Aid (MHFA) training, which is known to reduce stigma, including unwillingness to disclose a mental health problem.

Methods

A cross-lagged panel analysis was carried out on data from two large Australian randomised controlled trials of MHFA training. The first trial involved 1643 high school students in Year 10 (mean age 15.87 years), who were randomised to receive either teen MHFA training or physical first aid training as the control. The second trial involved 608 Australia public servants who were randomised to receive either eLearning MHFA, blended eLearning MHFA or eLearning physical first aid as the control. In both trials, willingness to disclose a mental disorder as described in vignettes and psychiatric symptoms (K6 scale) were measured pre-training, post-training and at 12-month follow-up.

Results

Both trials found that MHFA training increased willingness to disclose. However, a cross-lagged panel analysis showed no effect of this change on psychiatric symptom scores.

Conclusions

Greater willingness to disclose did not affect psychiatric symptom scores. Because the trials increased willingness to disclose through a randomly assigned intervention, they provide a strong causal test of the masking hypothesis. It is therefore unlikely that changes in willingness to disclose are masking reductions in prevalence in the population.
Studying the Societal Dimensions of Atmospheric Carbon Removal
Authors: Mahowald Natalie , Zelikova Jane , Kling Catherine
Published: August 2019

Workshop on Human/Societal Dimensions of a New Carbon Economy with Carbon180; Washington, D.C., 13 February 2019
Climate Change Pressures Land and Food Resources, Report Warns
Authors: Showstack Randy
Published: August 2019

There is a window of time to act now before threats increase further and solutions become less effective, a new report from the Intergovernmental Panel on Climate Change states.
Impact of Hydrological Conditions on the Biogeochemical Dynamics of Suspended Particulate Organic Matter in the Upper Mixed Layer of the Southern East China Sea
Authors: Liu Qianqian , Kandasamy Selvaraj , Wang Huawei , Wang Lin , Lin Baozhi , Gao Aiguo , Chen Chen‐Tung Arthur
Published: August 2019

We investigate suspended particles collected from the upper mixed layer in the inner shelf of the southern East China Sea during autumn 2013 for carbon and nitrogen (POC and PN) contents and their isotope compositions (δ13C and δ15N) along with hydrographic parameters to understand the sources and dynamics of particulate organic matter (POM) in the study area. Results indicated that the extensive hydrological processes affect the biogeochemical composition of suspended POM, as revealed by the horizontally mixing POM and the spatial variation of δ15N and molar C/N ratio. Low C/N (2.4–6.5) and a weak correlation between POC and in situ chlorophyll fluorescence suggested that POM is dominated by the recently formed and well‐preserved planktonic OM. By fitting the linear correlation between δ13C and POC data with a photosynthetic fractionation model, we further disentangled dynamic controls of phytoplankton production and species diversity on δ13C variability (−24.3 to −21.3‰), emphasizing the constant effect of productivity‐derived POC on δ13C (0.02‰ per μg/L). The δ15N variability (2.3–7.4‰) is largely controlled by the mixing of isotopically different nitrogen sources, in which the importance of biological nitrogen fixation is unfolded based on the small δ15N and the negative correlation between δ15N of POM and seawater temperature. This implies that Kuroshio‐induced biological N fixation plays an important role in supporting the marine production in the East China Sea. These hydrologically driven δ13C and δ15N changes of marine productivity‐derived POM suggest that internal biophysical dynamics rather than terrestrial versus marine OM mixing largely control the C and N compositional variability in the shelf seas.
Local and Remote Forcing of Denitrification in the Northeast Pacific for the Last 2,000 Years
Authors: Wang Yi , Hendy Ingrid L. , Thunell Robert
Published: August 2019

Sedimentary δ15N (δ15Nsed) has been widely applied as a proxy for water column denitrification. When combined with additional productivity proxies, it provides insights into the driving forces behind long‐term changes in water column oxygenation. High‐resolution (~2 years) δ15Nsed and productivity proxy records (total organic carbon [TOC], Si/Ti, and Ca/Ti) from Santa Barbara Basin, California, were generated from a well‐dated Kasten core (SPR0901‐03KC). These records reveal the relationship between Southern California upwelling and oxygenation over the past 2,000 years. Inconsistencies between Si/Ti (coastal upwelling proxy) and TOC (total export productivity proxy) suggest wind curl upwelling influenced Southern California primary productivity, especially during intervals of weak coastal upwelling. Coherence between δ15Nsed, TOC, and drought indicators supports a local control of δ15Nsed by atmospheric circulation, as persistent northerly winds associated with an intensified North Pacific High pressure cell lead to enhanced coastal upwelling. In the northeast Pacific, δ15Nsed is used as a water mass tracer of denitrification signals transported north from the eastern tropical North Pacific (ETNP) via the California Undercurrent. A 1,200‐year δ15Nsed record from the Pescadero slope, Gulf of California, lies between denitrifying subsurface waters in the ETNP and Southern California. During the Medieval Climate Anomaly, coherence between Pescadero and Santa Barbara Basin δ15Nsed indicates connections between ETNP and Southern California on centennial timescales. Yet an out‐of‐phase relationship occurred when the Aleutian Low was anomalously strong during the Little Ice Age. We suggest intensified nutrient‐rich subarctic water advection might have transported high‐15N nitrate into Southern California when the California Undercurrent and ETNP denitrification weakened.
A Numerical Study of Lithospheric Deformation and Strain Partitioning Across the Longmen Shan Orogenic Belt, Eastern Tibetan Plateau
Authors: Sun Yujun , Li Hailong , Fan Taoyuan
Published: August 2019

The Longmen Shan orogenic belt is the landform boundary between the eastern Tibetan Plateau and the Sichuan Basin. However, there are significant differences in lithospheric deformation across its southern and northern segments. We established numerical models to investigate the effect of rheological heterogeneity on lithospheric deformation across the eastern plateau margin. The results show that the rheological heterogeneity of the Longmen Shan controls the type of lithospheric deformation and the strain partitioning. When the Longmen Shan is weak or narrow, high strain is predicted between the plateau and the Sichuan Basin along the Longmen Shan, which helps to explain the lack of a Cenozoic foreland basin along the southwestern part of the Sichuan Basin. However, when the upper crust of the Sichuan Basin is weak, the deformation should extend into the interior of the basin, such as the Longmen Shan‐Longquan Shan thrust system, which provides sedimentary space for the Cenozoic sediments. In contrast, when the Longmen Shan is strong or wide, the deformation is diffuse over a broad transition zone. The strain is mainly localized along the boundary between the Songpan‐Ganzi terrane and the Longmen Shan. This result can be used to understand the uplift of the Min Shan. Compared to the observations, the high strength of the Longmen Shan corresponds to the distribution of the Precambrian crystalline basement. The rheological heterogeneity of the Longmen Shan is from the result of the amalgamation of ancient continents, which illustrates the control of the ancient continental margin on recent tectonics.
Excess hepsin proteolytic activity limits oncogenic signaling and induces ER stress and autophagy in prostate cancer cells
Authors: Willbold Ramona , Wirth Katharina , Martini Thomas , Sültmann Holger , Bolenz Christian , Wittig Rainer
Published: August 2019

The serine protease hepsin is frequently overexpressed in human prostate cancer (PCa) and is associated with matrix degradation and PCa progression in mice. Curiously, low expression of hepsin is associated with poor survival in different cancer types, and transgenic overexpression of hepsin leads to loss of viability in various cancer cell lines. Here, by comparing isogenic transfectants of the PCa cell line PC-3 providing inducible overexpression of wild-type hepsin (HPN) vs. the protease-deficient mutant HPNS353A, we were able to attribute hepsin-mediated tumor-adverse effects to its excess proteolytic activity. A stem-like expression signature of surface markers and adhesion molecules, Notch intracellular domain release, and increased pericellular protease activity were associated with low expression levels of wild-type hepsin, but were partially lost in response to overexpression. Instead, overexpression of wild-type hepsin, but not of HPNS353A, induced relocalization of the protein to the cytoplasm, and increased autophagic flux in vitro as well as LC3B punctae frequency in tumor xenografts. Confocal microscopy revealed colocalization of wild-type hepsin with both LC3B punctae as well as with the autophagy cargo receptor p62/SQSTM1. Overexpression of wild type, but not protease-deficient hepsin induced expression and nuclear presence of CHOP, indicating activation of the unfolded protein response and ER-associated protein degradation (ERAD). Whereas inhibitors of ER stress and secretory protein trafficking slightly increased viability, combined inhibition of the ubiquitin-proteasome degradation pathway (by bortezomib) with either ER stress (by salubrinal) or autophagy (by bafilomycin A1) revealed a significant decrease of viability during overexpression of wild-type hepsin in PC-3 cells. Our results demonstrate that a precise control of Hepsin proteolytic activity is critical for PCa cell fate and suggest, that the interference with ERAD could be a promising therapeutic option, leading to induction of proteotoxicity in hepsin-overexpressing tumors.
In vivo Hox binding specificity revealed by systematic changes to a single cis regulatory module
Authors: Sánchez-Higueras Carlos , Rastogi Chaitanya , Voutev Roumen , Bussemaker Harmen J. , Mann Richard S. , Hombría James C.-G.
Published: August 2019

Hox proteins belong to a family of transcription factors with similar DNA binding specificities that control animal differentiation along the antero-posterior body axis. Hox proteins are expressed in partially overlapping regions where each one is responsible for the formation of particular organs and structures through the regulation of specific direct downstream targets. Thus, explaining how each Hox protein can selectively control its direct targets from those of another Hox protein is fundamental to understand animal development. Here we analyse a cis regulatory module directly regulated by seven different Drosophila Hox proteins and uncover how different Hox class proteins differentially control its expression. We find that regulation by one or another Hox protein depends on the combination of three modes: Hox-cofactor dependent DNA-binding specificity; Hox-monomer binding sites; and interaction with positive and negative Hox-collaborator proteins. Additionally, we find that similar regulation can be achieved by Amphioxus orthologs, suggesting these three mechanisms are conserved from insects to chordates.
Genetic risk for autoimmunity is associated with distinct changes in the human gut microbiome
Authors: Russell Jordan T. , Roesch Luiz F. W. , Ördberg Malin , Ilonen Jorma , Atkinson Mark A. , Schatz Desmond A. , Triplett Eric W. , Ludvigsson Johnny
Published: August 2019

Susceptibility to many human autoimmune diseases is under strong genetic control by class II human leukocyte antigen (HLA) allele combinations. These genes remain by far the greatest risk factors in the development of type 1 diabetes and celiac disease. Despite this, little is known about HLA influences on the composition of the human gut microbiome, a potential source of environmental influence on disease. Here, using a general population cohort from the All Babies in Southeast Sweden study, we report that genetic risk for developing type 1 diabetes autoimmunity is associated with distinct changes in the gut microbiome. Both the core microbiome and beta diversity differ with HLA risk group and genotype. In addition, protective HLA haplotypes are associated with bacterial generaIntestinibacterandRomboutsia. Thus, general population cohorts are valuable in identifying potential environmental triggers or protective factors for autoimmune diseases that may otherwise be masked by strong genetic control.
The Hsp90 isoforms from S. cerevisiae differ in structure, function and client range
Authors: Girstmair Hannah , Tippel Franziska , Lopez Abraham , Tych Katarzyna , Stein Frank , Haberkant Per , Schmid Philipp Werner Norbert , Helm Dominic , Rief Matthias , Sattler Michael , Buchner Johannes
Published: August 2019

The molecular chaperone Hsp90 is an important regulator of proteostasis. It has remained unclear why S. cerevisiae possesses two Hsp90 isoforms, the constitutively expressed Hsc82 and the stress-inducible Hsp82. Here, we report distinct differences despite a sequence identity of 97%. Consistent with its function under stress conditions, Hsp82 is more stable and refolds more efficiently than Hsc82. The two isoforms also differ in their ATPases and conformational cycles. Hsc82 is more processive and populates closed states to a greater extent. Variations in the N-terminal ATP-binding domain modulate its dynamics and conformational cycle. Despite these differences, the client interactomes are largely identical, but isoform-specific interactors exist both under physiological and heat shock conditions. Taken together, changes mainly in the N-domain create a stress-specific, more resilient protein with a shifted activity profile. Thus, the precise tuning of the Hsp90 isoforms preserves the basic mechanism but adapts it to specific needs.
Ventral midbrain stimulation induces perceptual learning and cortical plasticity in primates
Authors: Arsenault John T. , Vanduffel Wim
Published: August 2019

Practice improves perception and enhances neural representations of trained visual stimuli, a phenomenon known as visual perceptual learning (VPL). While attention to task-relevant stimuli plays an important role in such learning, Pavlovian stimulus-reinforcer associations are sufficient to drive VPL, even subconsciously. It has been proposed that reinforcement facilitates perceptual learning through the activation of neuromodulatory centers, but this has not been directly confirmed in primates. Here, we paired task-irrelevant visual stimuli with microstimulation of a dopaminergic center, the ventral tegmental area (VTA), in macaques. Pairing VTA microstimulation with a task-irrelevant visual stimulus increased fMRI activity and improved classification of fMRI activity patterns selectively for the microstimulation-paired stimulus. Moreover, pairing VTA microstimulation with a task-irrelevant visual stimulus improved the subject’s capacity to discriminate that stimulus. This is the first causal demonstration of the role of neuromodulatory centers in VPL in primates.
The pause-initiation limit restricts transcription activation in human cells
Authors: Gressel Saskia , Schwalb Björn , Cramer Patrick
Published: August 2019

Eukaryotic gene transcription is often controlled at the level of RNA polymerase II (Pol II) pausing in the promoter-proximal region. Pausing Pol II limits the frequency of transcription initiation (‘pause-initiation limit’), predicting that the pause duration must be decreased for transcriptional activation. To test this prediction, we conduct a genome-wide kinetic analysis of the heat shock response in human cells. We show that the pause-initiation limit restricts transcriptional activation at most genes. Gene activation generally requires the activity of the P-TEFb kinase CDK9, which decreases the duration of Pol II pausing and thereby enables an increase in the productive initiation frequency. The transcription of enhancer elements is generally not pause limited and can be activated without CDK9 activity. Our results define the kinetics of Pol II transcriptional regulation in human cells at all gene classes during a natural transcription response.
Single-handed supramolecular double helix of homochiral bis(N-amidothiourea) supported by double crossed C−I···S halogen bonds
Authors: Yan Xiaosheng , Zou Kunshan , Cao Jinlian , Li Xiaorui , Zhao Zhixing , Li Zhao , Wu Anan , Liang Wanzhen , Mo Yirong , Jiang Yunbao
Published: August 2019

The natural DNA double helix consists of two strands of nucleotides that are held together by multiple hydrogen bonds. Here we propose to build an artificial double helix from fragments of two strands connected by covalent linkages therein, but with halogen bonding as the driving force for self-assembling the fragments to the double helix. We succeed in building such a double helix in both solution and solid state, by using a bilateral N-(p-iodobenzoyl)alanine based amidothiourea which in its folded cis-form allows double and crossed C−I···S halogen bonds that lead to right- or left-handed double helix when the two alanine residues are of the same L,L- or D,D-configuration. The double helix forms in dilute CH3CN solution of the micromolar concentration level, e.g., 5.6 μM from 2D NOESY experiments and exhibits a high thermal stability in solution up to 75 °C, suggesting cooperative and thereby strong intermolecular double crossed halogen bonding that makes the double helix stable. This is supported by the observed homochiral self-sorting in solution.
MpsAB is important for Staphylococcus aureus virulence and growth at atmospheric CO2 levels
Authors: Fan Sook-Ha , Ebner Patrick , Reichert Sebastian , Hertlein Tobias , Zabel Susanne , Lankapalli Aditya Kumar , Nieselt Kay , Ohlsen Knut , Götz Friedrich
Published: August 2019

The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.
HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine
Authors: Miao Weili , Li Lin , Zhao Yonghui , Dai Xiaoxia , Chen Xuemei , Wang Yinsheng
Published: August 2019

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5′-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5′-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism.
Stable and bright formamidinium-based perovskite light-emitting diodes with high energy conversion efficiency
Authors: Miao Yanfeng , Ke You , Wang Nana , Zou Wei , Xu Mengmeng , Cao Yu , Sun Yan , Yang Rong , Wang Ying , Tong Yunfang , Xu Wenjie , Zhang Liangdong , Li Renzhi , Li Jing , He Haiping , Jin Yizheng , Gao Feng , Huang Wei , Wang Jianpu
Published: August 2019

Solution-processable perovskites show highly emissive and good charge transport, making them attractive for low-cost light-emitting diodes (LEDs) with high energy conversion efficiencies. Despite recent advances in device efficiency, the stability of perovskite LEDs is still a major obstacle. Here, we demonstrate stable and bright perovskite LEDs with high energy conversion efficiencies by optimizing formamidinium lead iodide films. Our LEDs show an energy conversion efficiency of 10.7%, and an external quantum efficiency of 14.2% without outcoupling enhancement through controlling the concentration of the precursor solutions. The device shows low efficiency droop, i.e. 8.3% energy conversion efficiency and 14.0% external quantum efficiency at a current density of 300 mA cm−2, making the device more efficient than state-of-the-art organic and quantum-dot LEDs at high current densities. Furthermore, the half-lifetime of device with benzylamine treatment is 23.7 hr under a current density of 100 mA cm−2, comparable to the lifetime of near-infrared organic LEDs.
Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling
Authors: Xu Zhi-Xiang , Tan Ji-Wei , Xu Haifei , Hill Cassandra J. , Ostrovskaya Olga , Martemyanov Kirill A. , Xu Baoji
Published: August 2019

Caspase-2 is the most evolutionarily conserved member in the caspase family of proteases and is constitutively expressed in most cell types including neurons; however, its physiological function remains largely unknown. Here we report that caspase-2 plays a critical role in synaptic plasticity and cognitive flexibility. We found that caspase-2 deficiency led to deficits in dendritic spine pruning, internalization of AMPA receptors and long-term depression. Our results indicate that caspase-2 degrades Rictor, a key mTOR complex 2 (mTORC2) component, to inhibit Akt activation, which leads to enhancement of the GSK3β activity and thereby long-term depression. Furthermore, we found that mice lacking caspase-2 displayed elevated levels of anxiety, impairment in reversal water maze learning, and little memory loss over time. These results not only uncover a caspase-2–mTORC2–Akt–GSK3β signaling pathway, but also suggest that caspase-2 is important for memory erasing and normal behaviors by regulating synaptic number and transmission.
Measuring the ionisation fraction in a jet from a massive protostar
Authors: Fedriani R. , Caratti o Garatti A. , Purser S. J. D. , Sanna A. , Tan J. C. , Garcia-Lopez R. , Ray T. P. , Coffey D. , Stecklum B. , Hoare M.
Published: August 2019

It is important to determine if massive stars form via disc accretion, like their low-mass counterparts. Theory and observation indicate that protostellar jets are a natural consequence of accretion discs and are likely to be crucial for removing angular momentum during the collapse. However, massive protostars are typically rarer, more distant and more dust enshrouded, making observational studies of their jets more challenging. A fundamental question is whether the degree of ionisation in jets is similar across the mass spectrum. Here we determine an ionisation fraction of ~5–12% in the jet from the massive protostar G35.20-0.74N, based on spatially coincident infrared and radio emission. This is similar to the values found in jets from lower-mass young stars, implying a unified mechanism of shock ionisation applies in jets across most of the protostellar mass spectrum, up to at least ~10 solar masses.
Transit amplifying cells coordinate mouse incisor mesenchymal stem cell activation
Authors: Walker Jemma Victoria , Zhuang Heng , Singer Donald , Illsley Charlotte Sara , Kok Wai Ling , Sivaraj Kishor K. , Gao Yan , Bolton Chloe , Liu Yuying , Zhao Mengyuan , Grayson Portia Rebecca Clare , Wang Shuang , Karbanová Jana , Lee Tim , Ardu Stefano , Lai Qingguo , Liu Jihui , Kassem Moustapha , Chen Shuo , Yang Kai , Bai Yuxing , Tredwin Christopher , Zambon Alexander C. , Corbeil Denis , Adams Ralf , Abdallah Basem M. , Hu Bing
Published: August 2019

Stem cells (SCs) receive inductive cues from the surrounding microenvironment and cells. Limited molecular evidence has connected tissue-specific mesenchymal stem cells (MSCs) with mesenchymal transit amplifying cells (MTACs). Using mouse incisor as the model, we discover a population of MSCs neibouring to the MTACs and epithelial SCs. WithNotchsignaling as the key regulator, we disclose molecular proof and lineage tracing evidence showing the distinct MSCs contribute to incisor MTACs and the other mesenchymal cell lineages. MTACs can feedback and regulate the homeostasis and activation of CL-MSCs through Delta-like 1 homolog (Dlk1), which balances MSCs-MTACs number and the lineage differentiation.Dlk1’s function on SCs priming and self-renewal depends on its biological forms and its gene expression is under dynamic epigenetic control. Our findings can be validated in clinical samples and applied to accelerate tooth wound healing, providing an intriguing insight of how to direct SCs towards tissue regeneration.
Extending Cardiac Functional Assessment with Respiratory-Resolved 3D Cine MRI
Authors: Liu Jing , Wang Yan , Wen Zhaoying , Feng Li , Lima Ana Paula Santos , Mahadevan Vaikom S. , Bolger Ann , Saloner David , Ordovas Karen
Published: August 2019

This study aimed to develop a cardiorespiratory-resolved 3D magnetic resonance imaging (5D MRI: x-y-z-cardiac-respiratory) approach based on 3D motion tracking for investigating the influence of respiration on cardiac ventricular function. A highly-accelerated 2.5-minute sparse MR protocol was developed for a continuous acquisition of cardiac images through multiple cardiac and respiratory cycles. The heart displacement along respiration was extracted using a 3D image deformation algorithm, and this information was used to cluster the acquired data into multiple respiratory phases. The proposed approach was tested in 15 healthy volunteers (7 females). Cardiac function parameters, including the end-systolic volume (ESV), end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF), were measured for the left and right ventricle in both end-expiration and end-inspiration. Although with the proposed 5D cardiac MRI, there were no significant differences (p > 0.05, t-test) between end-expiration and end-inspiration measurements of the cardiac function in volunteers, incremental respiratory motion parameters that were derived from 3D motion tracking, such as the depth, expiration and inspiration distribution, correlated (p < 0.05, correlation coefficient, Mann-Whitney) with those volume-based parameters of cardiac function and varied between genders. The obtained initial results suggested that this new approach allows evaluation of cardiac function during specific respiratory phases. Thus, it can enable investigation of effects related to respiratory variability and better assessment of cardiac function for studying respiratory and/or cardiac dysfunction.
Anthocyanins, delphinidin-3-O-glucoside and cyanidin-3-O-glucoside, inhibit immune checkpoints in human colorectal cancer cells in vitro and in silico
Authors: Mazewski Candice , Kim Morgan Sanha , Gonzalez de Mejia Elvira
Published: August 2019

The objective was to assess anti-progression and stimulatory immune response effects among anthocyanins (ANC) and their metabolites on human colorectal cancer cells in vitro and in silico. Pure phenolics including delphinidin-3-O-glucoside (D3G) and its metabolites, delphinidin (DC) and gallic acid (GA), were tested alone or in combination, on HCT-116 and HT-29 human colorectal cancer cells (100–600 µg/mL). HCT-116 and HT-29 50% inhibition concentrations (µg/mL) were 396 ± 23 and 329 ± 17 for D3G; 242 ± 16 and >600 for DC; and 154 ± 5 and 81 ± 5 for GA, respectively. Using molecular docking, cyanidin-3-O-glucoside (C3G) showed the highest potential to inhibit immune checkpoints: programmed cell death protein-1 (PD-1) (−6.8 kcal/mol) and programmed death-ligand-1 (PD-L1) (−9.6 kcal/mol). C3G, D3G, DC, GA, and D3G-rich extracts decreased PD-L1 protein expression in HCT-116 cells. C3G decreased PD-L1 fluorescence intensity by 39%. ANC decreased PD-1 expression in peripheral blood mononuclear cells in monoculture by 41% and 55%, and co-culture with HCT-116 and HT-29 cells by 39% and 26% (C3G) and 50% and 51% (D3G), respectively. D3G and C3G, abundant in plant foods, showed potential for binding with and inhibiting immune checkpoints, PD-1 and PD-L1, which can activate immune response in the tumor microenvironment and induce cancer cell death.