bluuebunny/crossref_metadata_2025 huggingface dataset:
CORRELATION OF CLINICAL AND STRUCTURAL PROGRESSION WITH VISUAL ACUITY LOSS IN MACULAR TELANGIECTASIA TYPE 2
Authors: Peto Tunde , Heeren Tjebo F. C. , Clemons Traci E. , Sallo Ferenc B. , Leung Irene , Chew Emily Y. , Bird Alan C. ,   on behalf of the MacTel Study Group
Published: May 2017

Purpose:

To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity.

Methods:

An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization.

Results:

One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (−1.40 ± 0.14 letters, P < 0.001).

Conclusion:

Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.
Melding a High-Risk Patient for Continuous Flow Left Ventricular Assist Device into a Low-Risk Patient
Authors: Amione-Guerra Javier , Cruz-Solbes Ana S. , Gonzalez Bonilla Hilda , Estep Jerry D. , Guha Ashrith , Bhimaraj Arvind , Suarez Erik E. , Bruckner Brian A. , Torre-Amione Guillermo , Park Myung H. , Trachtenberg Barry H.
Published: May 2017

The model for end-stage liver disease (MELD) has been used as a predictor of mortality after left ventricular assist device (LVAD) placement. However, improvement or worsening of MELD and how those changes affect outcomes is unknown. We performed a retrospective analysis of 244 patients implanted with a continuous flow (CF) LVAD. Patients were dichotomized at admission into low- or high-risk categories using a cutoff of MELD ≥ 19, and they were reclassified at day of implant forming four groups: Group LL (low to low, remained low risk), LH (low to high, worsened to high risk), HH (high to high, remained high risk), and HL (high to low, improved to low risk). Patients who improved to a low risk (group HL) had the same 1 year survival as those that remained low risk (group LL; 80% vs. 77%; p = 0.6). However, patients who were initially classified as low risk and worsened to a high risk (group LH) had a survival that was worse than those that were consistently high risk (group HH; 55% vs. 10%; p = 0.01). Model for end-stage liver disease reclassification after adjusting for commonly attributed risk factors remained an independent predictor for mortality, including patients classified as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 and 2. In conclusion, our MELD score reclassification is an independent and powerful predictor of mortality in patients undergoing LVAD implantation.
Norepinephrine in septic shock: when and how much?
Authors: Hamzaoui Olfa , Scheeren Thomas W.L. , Teboul Jean-Louis
Published: May 2017

Purpose of review

Norepinephrine is the first-line agent recommended during resuscitation of septic shock to correct hypotension due to depressed vascular tone. Important clinical issues are the best timing to start norepinephrine, the optimal blood pressure target, and the best therapeutic options to face refractory hypotension when high doses of norepinephrine are required to reach the target.

Recent findings

Recent literature has reported benefits of early administration of norepinephrine because of the following reasons: profound and durable hypotension is an independent factor of increased mortality, early administration of norepinephrine increases cardiac output, improves microcirculation and avoids fluid overload. Recent data are in favor of targeting a mean arterial pressure of at least 65 mmHg and higher values in case of chronic hypertension. When hypotension is refractory to norepinephrine, it is recommended adding vasopressin, which is relatively deficient during sepsis and acts on other vascular receptors than α1-adernergic receptors. However, increasing the dose of norepinephrine further cannot be discouraged.

Early administration of norepinephrine is beneficial for septic shock patients to restore organ perfusion. The mean arterial pressure target should be individualized. Adding vasopressin is recommended in case of shock refractory to norepinephrine.
Pharmacotherapy options for pediatric diabetes
Authors: Marcovecchio Maria Loredana , Chiarelli Francesco
Published: May 2017

Purpose of review

Type 1 diabetes (T1D) and type 2 diabetes (T2D) are frequent conditions during childhood and adolescence. The present review offers an update on current available treatment strategies for T1D and T2D approved for use in children and adolescents.

Recent findings

Insulin remains the main and essential therapeutic strategy in youth with T1D. A second generation of insulin analogues is being evaluated and could help in improving glycemic control. Over the last decades advances in technology have allowed the implementation of insulin pump therapy and continuous glucose monitoring, and are now leading the way towards the development of an artificial pancreas or closed loop system.

Treatment of T2D is based on lifestyle interventions and metformin as the first-line drug to be used. Little evidence is available for other oral hypoglycemic drugs, currently used in adults.

Although much progress has been made in the field of diabetes management, there are still several unmet goals. One of the main issues is to develop a system allowing more physiological insulin coverage. For both T1D and T2D, there is a strong need of new drugs to be used alone or in combination, mainly in patients struggling to achieve good glycemic control.
Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma—New Therapeutic Targets
Authors: Mitteldorf Christina , Berisha Arbeneshe , Pfaltz Monique C. , Broekaert Sigrid M.C. , Schön Michael P. , Kerl Katrin , Kempf Werner
Published: May 2017

Programmed death ligand 1 (PD-L1) is expressed by 20% to 57% of systemic diffuse large B cell lymphomas (DLBCLs). PD-L1 expression in primary cutaneous DLBCL (pcDLBCL) has not been studied so far. Sixteen paraffin-embedded tissue samples of pcDLBCL (13 leg type [LT], 3 others [OT]) were investigated for PD-1, PD-L1, and CD33 expression and the cellular composition of the tumor microenvironment, focusing on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. Membrane-bound PD-L1 expression by the tumor cells was observed in all samples, albeit to a variable extent (19.9%). As expected, most DLBCL-LT (10 cases) were classified as activated B cell like type, with a higher PD-L1 score (21.9%) compared with that of the germinal center B cell like type (7.7%). The surrounding infiltrate consisted predominately of CD163(+) M2 rather than CD68(+) macrophages (CD68:CD163=1:4 to 6). Moreover, a considerable proportion of CD33(+) MDSCs with PD-L1 coexpression was admixed. Tumor cells expressed CD33 to variable degrees (2% to 60%). The number of MDSCs or M2 macrophages did not correlate with pcDLBCL subtypes LT or OT. T cells were only a minor component of the tumor microenvironment. We propose that PD-L1(+) tumor cells and PD-L1(+) MDSCs shield the tumor against PD-1(+) tumor-infiltrating lymphocytes, consequently leading to inhibition and diminution of tumor-infiltrating lymphocytes. Moreover, we found a polarization to M2 macrophages, which may contribute to the poor prognosis of DLBCL patients. Thus, targeting of tumor cells and MDSCs using anti-PD-1/anti-PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat this aggressive form of cutaneous B-cell lymphoma.
H3F3A (Histone 3.3) G34W Immunohistochemistry
Authors: Amary Fernanda , Berisha Fitim , Ye Hongtao , Gupta Manu , Gutteridge Alice , Baumhoer Daniel , Gibbons Rebecca , Tirabosco Roberto , O’Donnell Paul , Flanagan Adrienne M.
Published: May 2017

Giant cell tumor of bone (GCTB) is a locally aggressive subarticular tumor. Having recently reported that H3.3 G34W mutations are characteristic of this tumor type, we have now investigated the sensitivity and specificity of the anti-histone H3.3 G34W rabbit monoclonal antibody in a wide variety of tumors including histologic mimics of GCTB to assess its value as a diagnostic marker. We also determined the incidence of H3.3 G34 mutations in primary malignant bone tumors as assessed by genotype and H3.3 G34W immunostaining. A total of 3163 tumors were tested. Totally, 213/235 GCTB (90.6%) showed nuclear H3.3 p.G34W immunoreactivity. This was not the case for the rare variants, p.G34L, M, and V, which occurred most commonly in the small bones of the hands, patella, and the axial skeleton. If these sites were excluded from the analysis, H3.3 G34W expression was found in 97.8% of GCTB. Malignant bone tumors initially classified as osteosarcomas were the only other lesions (n=11) that showed G34W expression. Notably an additional 2 previously reported osteosarcomas with a p.G34R mutation were not immunoreactive for the antibody. A total of 11/13 of these malignant H3.3-mutant tumors exhibited an osteoclast-rich component: when imaging was available all but one presented at a subarticular site. We propose that subarticular primary malignant bone sarcoma with H3.3 mutations represent true malignant GCTB, even in the absence of a benign GCTB component.
Myopericytomatosis
Authors: Hung Yin P. , Fletcher Christopher D.M.
Published: May 2017

Myopericytoma is a benign tumor of concentrically distributed perivascular myoid cells. Its molecular basis and relationship with myofibroma/myofibromatosis and other pericytic tumors are not fully understood. In our consultation/surgical files of over 1000 myopericytic lesions, we identified 11 cases with diffuse dermal/subcutaneous involvement by microscopic myopericytomatous nodules, a phenomenon we have termed myopericytomatosis. Myopericytomatosis affected mostly adults (female:male=8:3; median age, 37 y; range, 9 to 63 y) in the lower extremities (foot/ankle, 5; calf, 3; knee, 1; thigh, 1; neck, 1) over months to 25 years, ranging from 1.5 to 11.0 (median, 6.0) cm in size. Histologically, myopericytomatosis displayed diffuse infiltration by innumerable discrete myopericytoma/myofibroma-like nodules of bland spindled-to-ovoid cells (smooth muscle actin positive), in a mainly perivascular distribution. No mitoses, atypia, or necrosis was noted. All patients were treated by surgical excision (1 patient also received adjuvant radiation), with margins focally positive in 5 of 6 known cases. Of the 6 cases with follow-up of 0.2 to 13.7 (median, 3.4) years, 1 recurred locally twice, while 5 cases showed no recurrence. Targeted next-generation DNA sequencing identified PDGFRB alterations in all cases of myopericytomatosis and conventional myopericytoma tested (5 cases each), including mutations in 4 cases of myopericytomatosis (N666K in 3; Y562-R565 deletion in 1 case) and 3 myopericytomas (Y562C, K653E, and splice acceptor deletion in 1 case each), as well as low-level PDGFRB amplification in 2 cases of myopericytomatosis and 4 myopericytomas. No BRAF, NOTCH, or GLI1 alterations were detected. In summary, myopericytomatosis is a rare, strikingly diffuse, but apparently benign variant of myopericytoma that typically involves superficial soft tissue in adults with innumerable discrete microscopic myopericytomatous nodules. The strongly activating PDGFRB mutation N666K is noted in myopericytomatosis, but not in conventional myopericytoma, suggesting that PDGFRB mutation status may account for their pathogenetic differences. As PDGFRB alterations are present in myopericytoma/myopericytomatosis and infantile myofibromatosis/myofibroma, these entities indeed lie within a histogenetic continuum. Identification of PDGFRB alterations suggests tyrosine kinase inhibition as a potential therapeutic strategy in myopericytic neoplasms if needed.
Multinodular and Vacuolating Neuronal Tumor
Authors: Cathcart Sahara J. , Klug Jeffrey R. , Helvey Jason T. , L. White Matthew , Gard Andrew P. , McComb Rodney D.
Published: May 2017

Multinodular and vacuolating neuronal tumor is a recently described seizure-associated entity with overlapping features of a malformative and neoplastic process. We report a case of multinodular and vacuolating neuronal tumor in a 29-year-old man with a history of recent headaches and complex partial seizures. Neuroimaging revealed a nonenhancing, T2 and T2 fluid-attenuated inversion recovery hyperintense multinodular lesion in the right temporal lobe. Lesional tissue demonstrated well-demarcated nodules of ganglioid cells with vacuolation of both the perikarya and the fibrillary neuropil-like background. The ganglioid cells showed weak cytoplasmic reactivity for synaptophysin and were nonreactive for neurofilament and chromogranin. CD34-positive stellate cells were present within the nodules. A 50-gene next-generation sequencing panel did not identify any somatic mutations in genomic DNA extracted from the tumor.
Lung Rest During Extracorporeal Membrane Oxygenation for Neonatal Respiratory Failure—Practice Variations and Outcomes
Authors: Alapati Deepthi , Aghai Zubair H. , Hossain Md Jobayer , Dirnberger Daniel R. , Ogino Mark T. , Shaffer Thomas H.
Published: May 2017

Objective:

Describe practice variations in ventilator strategies used for lung rest during extracorporeal membrane oxygenation for respiratory failure in neonates, and assess the potential impact of various lung rest strategies on the duration of extracorporeal membrane oxygenation and the duration of mechanical ventilation after decannulation.

Data Sources:

Retrospective cohort analysis from the Extracorporeal Life Support Organization registry database during the years 2008–2013.

Study Selection:

All extracorporeal membrane oxygenation runs for infants less than or equal to 30 days of life for pulmonary reasons were included.

Data Extraction:

Ventilator type and ventilator settings used for lung rest at 24 hours after extracorporeal membrane oxygenation initiation were obtained.

Data Synthesis:

A total of 3,040 cases met inclusion criteria. Conventional mechanical ventilation was used for lung rest in 88% of cases and high frequency ventilation was used in 12%. In the conventional mechanical ventilation group, 32% used positive end-expiratory pressure strategy of 4–6 cm H2O (low), 22% used 7–9 cm H2O (mid), and 43% used 10–12 cm H2O (high). High frequency ventilation was associated with an increased mean (sem) hours of extracorporeal membrane oxygenation (150.2 [0.05] vs 125 [0.02]; p < 0.001) and an increased mean (sem) hours of mechanical ventilation after decannulation (135 [0.09] vs 100.2 [0.03]; p = 0.002), compared with conventional mechanical ventilation among survivors. Within the conventional mechanical ventilation group, use of higher positive end-expiratory pressure was associated with a decreased mean (sem) hours of extracorporeal membrane oxygenation (high vs low: 136 [1.06] vs 156 [1.06], p = 0.001; mid vs low: 141 [1.06] vs 156 [1.06]; p = 0.04) but increased duration of mechanical ventilation after decannulation in the high positive end-expiratory pressure group compared with low positive end-expiratory pressure (p = 0.04) among survivors.

Conclusions:

Wide practice variation exists with regard to ventilator settings used for lung rest during neonatal respiratory extracorporeal membrane oxygenation. Use of high frequency ventilation when compared with conventional mechanical ventilation and use of low positive end-expiratory pressure strategy when compared with mid positive end-expiratory pressure and high positive end-expiratory pressure strategy is associated with longer duration of extracorporeal membrane oxygenation. Further research to provide evidence to drive optimization of pulmonary management during neonatal respiratory extracorporeal membrane oxygenation is warranted.
Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities
Authors: Hohl Tobias M.
Published: May 2017

Purpose of review

Invasive aspergillosis is a worldwide disease that primarily affects immune-compromised patients, agricultural workers with corneal abrasions, individuals with structural lung disease, and patients with primary immune deficiency. The critical function of the immune system is to prevent the germination of airborne conidia into tissue-invasive hyphae. This review covers recent advances that shape our understanding of anti-Aspergillus immunity at the molecular and cellular level.

Recent findings

Host defense against conidia and hyphae occurs via distinct molecular mechanisms that involve intracellular and extracellular killing pathways, as well as cooperation between different myeloid cell subsets. The strength and efficacy of the host response is shaped by the tissue microenvironment. In preclinical models of disease, host immune augmentation strategies have yielded benefits, yet translating these insights into therapeutic strategies in humans remains challenging.

Although advances in early diagnostic strategies and in antifungal drugs have ameliorated clinical outcomes of invasive aspergillosis, further improvements depend on gaining deeper insight into and translating advances in anti-Aspergillus immunity.
Enterococcus faecalispromotes innate immune suppression and polymicrobial catheter-associated urinary tract infection
Authors: Tien Brenda Yin Qi , Sharon Goh Hwee Mian , Long Chong Kelvin Kian , Bhaduri-Tagore Soumili , Holec Sarah , Dress Regine , Ginhoux Florent , Ingersoll Molly A. , Williams Rohan B. H. , Kline Kimberly A.
Published: May 2017

Enterococcus faecalis, a member of the human gastrointestinal microbiota, is an opportunistic pathogen associated with hospital-acquired wound, bloodstream, and urinary tract infections.E. faecaliscan subvert or evade immune-mediated clearance, although the mechanisms are poorly understood. In this study, we examinedE. faecalis-mediated subversion of macrophage activation. We observed thatE. faecalisactively prevents NF-κB signaling in mouse RAW264.7 macrophages in the presence of Toll-like receptor agonists and during polymicrobial infection withEscherichia coli.E. faecalisandE. colico-infection in a mouse model of catheter-associated urinary tract infection (CAUTI) resulted in a suppressed macrophage transcriptional response in the bladder compared toE. coliinfection alone. Finally, we demonstrated that co-inoculation ofE. faecaliswithE. coliinto catheterized bladders significantly augmentedE. coliCAUTI. Taken together, these results support thatE. faecalissuppression of NF-κB-driven responses in macrophages promotes polymicrobial CAUTI pathogenesis.

Author Summary

Synergistic polymicrobial infections can contribute to both disease severity and persistence.Enterococcus faecalisandEscherichia coliare frequently co-isolated from polymicrobial urinary tract infections. Immunomodulation by co-infecting microbes can result in a more permissive environment for pathogens to establish infection. Presently, we do not yet understand how these microbes overcome host immunity to establish polymicrobial infections. To address this, we investigated how the immunosuppressive function ofE. faecaliscan contribute to acute infection. We defined thatE. faecalisis able to suppress macrophagesin vitro, despite the presence ofE. coli. We also demonstratedE. faecalis’ability to augmentE. colititersin vivoto establish kidney infection. Our findings raise the prospect thatE. faecaliscan alter host immunity to increase susceptibility to other uropathogens.
Active trachoma cases in the Solomon Islands have varied polymicrobial community structures but do not associate with individual non-chlamydial pathogens of the eye
Authors: Butcher Robert M R , Sokana Oliver , Jack Kelvin , Kalae Eric , Sui Leslie , Russell Charles , Houghton Joanna , Palmer Christine , Holland Martin J , Le Mesurier Richard T , Solomon Anthony W , Mabey David C W , Roberts Chrissy h.
Published: May 2017

Background

Several non-chlamydial microbial pathogens are associated with clinical signs of active trachoma in trachoma-endemic communities with a low prevalence of ocular Chlamydia trachomatis (Ct) infection. In the Solomon Islands, the prevalence of Ct among children is low despite the prevalence of active trachoma being moderate. We therefore set out to investigate whether active trachoma was associated with a common non-chlamydial infection or with a dominant polymicrobial community dysbiosis in the Solomon Islands.

Methods

We studied DNA from conjunctival swabs collected from 257 Solomon Islanders with active trachoma and matched controls. Droplet digital PCR was used to test for pathogens suspected to be able to induce follicular conjunctivitis. Polymicrobial community diversity and composition were studied by sequencing of hypervariable regions of the 16S ribosomal ribonucleic acid gene in a subset of 54 cases and 53 controls.

Results

Although Ct was associated with active trachoma, the number of infections was low (cases: 3.9%, controls: 0.4%). Estimated prevalence (cases, controls) of each non-chlamydial infection was as follows: S. aureus (1.9%, 1.9%), Adenoviridae (1.2%, 1.2%), coagulase-negative Staphylococcus (5.8%, 4.3%), H. influenzae (7.4%, 11.7%), M. catarrhalis (2.3%, 4.7%) and S. pneumoniae (7.0%, 6.2%). There was no statistically significant association between clinical signs of trachoma and presence or load of any of the non-Ct infections that were assayed. Inter-individual variations in the conjunctival microbiome were characterised by differences in the levels of Corynebacterium, Proprionibacterium, Helicobacter and Paracoccus, but diversity and relative abundance of these specific genera did not differ significantly between cases and controls.

Discussion

It is unlikely that the prevalent trachoma-like follicular conjunctivitis in the Solomon Islands has a dominant bacterial aetiology. Before implementing community-wide azithromycin distribution for trachoma, policy makers should consider that clinical signs of trachoma can be observed in the absence of any detectable azithromycin-susceptible organism.
Fundamental constraints in synchronous muscle limit superfast motor control in vertebrates
Authors: Mead AF , Osinalde N. , Ørtenblad N. , Nielsen J. , Brewer J. , Vellema M. , Adam I. , Scharff C. , Song Y. , Frandsen U. , Blagoev B. , Kratchmarova I. , Elemans CPH
Published: May 2017

Superfast muscles (SFM) are extremely fast synchronous muscles capable of contraction rates up to 250 Hz, enabling precise motor execution at the millisecond time scale. To allow such speed, the archetypal SFM, found in the toadfish swimbladder, has hallmark structural and kinetic adaptations at each step of the conserved excitation-contraction coupling (ECC) pathway. More recently SFM phenotypes have been discovered in most major vertebrate lineages, but it remains unknown whether all SFM share ECC adaptations for speed, and if SFM arose once, or from independent evolutionary events. Here we use genomic analysis to identify the myosin heavy chain genes expressed in bat and songbird SFM to achieve rapid actomyosin crossbridge kinetics and demonstrate that these are evolutionarily and ontologically distinct. Furthermore, by quantifying cellular morphometry and calcium signal transduction combined with force measurements we show that all known SFM share multiple functional adaptations that minimize ECC transduction times. Our results suggest that SFM evolved independently in sound producing organs in ray-finned fish, birds, and mammals, and that SFM phenotypes operate at a maximum operational speed set by fundamental constraints in synchronous muscle. Consequentially, these constraints set a fundamental limit to the maximum speed of fine motor control.
TheKobresia pygmaeaecosystem of the Tibetan highlands – origin, functioning and degradation of the world’s largest pastoral alpine ecosystem
Authors: Miehe Georg , Schleuss Per-Marten , Seeber Elke , Babel Wolfgang , Biermann Tobias , Braendle Martin , Chen Fahu , Coners Heinz , Foken Thomas , Gerken Tobias , Graf Hans-F. , Guggenberger Georg , Hafner Silke , Holzapfel Maika , Ingrisch Johannes , Kuzyakov Yakov , Lai Zhongping , Lehnert Lukas , Leuschner Christoph , Liu Jianquan , Liu Shibin , Ma Yaoming , Miehe Sabine , Mosbrugger Volker , Noltie Henry J. , Opgenoorth Lars , Schmidt Joachim , Spielvogel Sandra , Unteregelsbacher Sebastian , Wang Yun , Willinghöfer Sandra , Xu Xingliang , Yang Yongping , Zhang Shuren , Wesche Karsten
Published: May 2017

Kobresiapastures in the eastern Tibetan highlands occupy 450000 km2and form the world’s largest pastoral alpine ecosystem. The main constituent is an endemic dwarf sedge,Kobresia pygmaea, which forms a lawn with a durable turf cover anchored by a felty root mat, and occurs from 3000 m to nearly 6000 m a.s.l. The existence and functioning of this unique ecosystem and its turf cover have not yet been explained against a backdrop of natural and anthropogenic factors, and thus its origin, drivers, vulnerability or resilience remain largely unknown. Here we present a review on ecosystem diversity, reproduction and ecology of the key species, pasture health, cycles of carbon (C), water and nutrients, and on the paleo-environment. The methods employed include molecular analysis, grazing exclusion, measurements with micro-lysimeters and gas exchange chambers,13C and15N labelling, eddy-covariance flux measurements, remote sensing and atmospheric modelling.

The following combination of traits makesKobresia pygmaearesilient and highly competitive: dwarf habit, predominantly below-ground allocation of photo assimilates, mixed reproduction strategy with both seed production and clonal growth, and high genetic diversity. Growth ofKobresiapastures is co-limited by low rainfall during the short growing season and livestock-mediated nutrient withdrawal. Overstocking has caused pasture degradation and soil deterioration, yet the extent remains debated. In addition, we newly describe natural autocyclic processes of turf erosion initiated through polygonal cracking of the turf cover, and accelerated by soil-dwelling endemic small mammals. The major consequences of the deterioration of the vegetation cover and its turf include: (1) the release of large amounts of C and nutrients and (2) earlier diurnal formation of clouds resulting in (3) decreased surface temperatures with (4) likely consequences for atmospheric circulation on large regional and, possibly global, scales.

Paleo-environmental reconstruction, in conjunction with grazing experiments, suggests that the present grazing lawns ofKobresia pygmaeaare synanthropic and may have existed since the onset of pastoralism. The traditional migratory rangeland management was sustainable over millennia and possibly still offers the best strategy to conserve, and possibly increase, the C stocks in theKobresiaturf, as well as its importance for climate regulation.
Morphometric Similarity Networks Detect Microscale Cortical Organisation And Predict Inter-Individual Cognitive Variation
Authors: Seidlitz Jakob , Váša František , Shinn Maxwell , Romero-Garcia Rafael , Whitaker Kirstie J. , Vértes Petra E. , Reardon Paul Kirkpatrick , Clasen Liv , Messinger Adam , Leopold David A. , Fonagy Peter , Dolan Raymond J. , Jones Peter B. , Goodyer Ian M. ,   the NSPN Consortium, Raznahan Armin , Bullmore Edward T.
Published: May 2017

Macroscopic cortical networks are important for cognitive function, but it remains challenging to construct anatomically plausible individual structural connectomes from human neuroimaging. We introduce a new technique for cortical network mapping, based on inter-regional similarity of multiple morphometric parameters measured using multimodal MRI. In three cohorts (two human, one macaque), we find that the resulting morphometric similarity networks (MSNs) have a complex topological organisation comprising modules and high-degree hubs. Human MSN modules recapitulate known cortical cytoarchitectonic divisions, and greater inter-regional morphometric similarity was associated with stronger inter-regional co-expression of genes enriched for neuronal terms. Comparing macaque MSNs to tract-tracing data confirmed that morphometric similarity was related to axonal connectivity. Finally, variation in the degree of human MSN nodes accounted for about 40% of between-subject variability in IQ. Morphometric similarity mapping provides a novel, robust and biologically plausible approach to understanding how human cortical networks underpin individual differences in psychological functions.
Fitness, Physical Activity, and Cardiovascular Disease: Longitudinal and Genetic Analyses in the UK Biobank Study
Authors: Tikkanen Emmi , Gustafsson Stefan , Ingelsson Erik
Published: May 2017

Background

Exercise is inversely related with cardiovascular disease (CVD), but large-scale studies of incident CVD events are lacking. Moreover, little is known about genetic determinants of fitness and physical activity, and modifiable effects of exercise in individuals with elevated genetic risk of CVD. Finally, causal analyses of exercise traits are limited.

Methods

We estimated associations of grip strength, physical activity, and cardiorespiratory fitness with CVD and all-cause death in up to 502,635 individuals from the UK Biobank. We also examined these associations in individuals with different genetic burden on coronary heart disease (CHD) and atrial fibrillation (AF). Finally, we performed genome-wide association study (GWAS) of grip strength and physical activity, as well as Mendelian randomization analysis to assess the causal role of grip strength in CHD.

Findings

Grip strength, physical activity, and cardiorespiratory fitness showed strong inverse associations with incident cardiovascular events and all-cause death (for composite CVD; HR, 0.78, 95% CI, 0.77-0.80; HR, 0.94, 95% CI, 0.93-0.95, and HR, 0.67, 95% CI, 0.63-0.71, per SD change, respectively). We observed stronger associations of grip strength with CHD and AF for individuals in the lowest tertile of genetic risk (Pinteraction = 0.006, Pinteraction = 0.03, respectively), but the inverse associations were present in each category of genetic risk. We report 27 novel genetic loci associated with grip strength and 2 loci with physical activity, with the strongest associations in FTO (rs56094641, P=3.8×10-24) and SMIM2 (rs9316077, P=1.4×10-8), respectively. By use of Mendelian randomization, we provide evidence that grip strength is causally related to CHD.

Interpretation

Maintaining physical strength is likely to prevent future cardiovascular events, also in individuals with elevated genetic risk for CVD.

Funding

National Institutes of Health (1 R01 HL135313-01), Knut and Alice Wallenberg Foundation (2013.0126), and the Finnish Cultural Foundation.
Interactive Biology Cloud Lab Enables Authentic Inquiry-Based Science Learning at MOOC Scale
Authors: Hossain Zahid , Bumbacher Engin , Brauneis Alison , Diaz Monica , Saltarelli Andy , Blikstein Paulo , Riedel-Kruse Ingmar
Published: May 2017

The Next Generation Science Standards (NGSS) and other national frameworks are calling for much more sophisticated approaches to STEM education, centered around the integration of complex experimentation (including real labs, not just simulations), data collection and analysis, modeling, and data-driven argumentation, i.e., students can behave like real scientists. How to implement such complex approaches in scalable ways is an unsolved challenge - both for presential and distance education. Here we report on the iterative design and large-scale deployment of an open online course with a “biology cloud experimentation lab” (using living cells) that engaged remote learners (> 300 students) in the scientific practices of experimentation, modeling and data analysis to investigate the phototaxis of a microorganism. We demonstrate (1) the robustness and scalability of the cloud lab technology (> 2, 300 experiments run), (2) the design principles and synergistic integration of multiple UI and learning activities and suitable data formats to facilitate NGSS-aligned science activities, and (3) design features that leverages the natural variability of real biology experiments to instigate authentic inquiry. This platform and course content are now suited for large-scale adaptation in formal K-16 education; and we provide recommendations for inquiry-based science learning in general.
Age-related differences in the influence of task-irrelevant information on the neural bases of phonological and semantic processes
Authors: Diaz Michele T. , Johnson Micah A. , Burke Deborah M. , Truong Trong-Kha , Madden David J.
Published: May 2017

Although aging is often associated with cognitive decline, there is considerable variability among individuals and across domains of cognition. Within language, several indicators of semantic processing show stability throughout the lifespan. However, older adults have increased difficulty with phonological aspects of language, especially in language production. While these behavioral patterns are established, the neurobiology associated with these behaviors are less clear. Previously we have shown that, older adults were slower and less accurate in phonological compared to semantic decisions, and that older adults didn’t exhibit brain-behavior relationships. In the present study, we examined phonological and semantic processes in the presence of task-irrelevant information. Older and younger adults made phonological and semantic decisions about pictures in the presence of either phonologically-related or semantically-related words, which were unrelated to the task. Behavioral results indicated that overall older adults had slower reaction times and lower accuracy compared to younger adults, and that all adults were less efficient when making phonological compared to semantic decisions. Patterns of brain activation for the semantic condition showed that all adults engaged typical left-hemisphere language regions, and that this activation was positively correlated with efficiency. In contrast, the phonological condition elicited activation in bilateral precuneus and cingulate, but only younger adults showed a significant relationship between activation and efficiency. Our results suggest that the relationship between behavior and neural activation when processing phonological information declines with age, but that the core semantic system continues to be engaged throughout the lifespan, even in the presence of task-irrelevant information.
Boosting the localization precision of dSTORM by biocompatible metal-dielectric coated glass coverslips
Authors: Heil Hannah S. , Schreiber Benjamin , Emmerling Monika , Hoefling Sven , Kamp Martin , Sauer Markus , Heinze Katrin G.
Published: May 2017

Super-resolution techniques such as direct Stochastic Optical Reconstruction Microscopy (dSTORM) have become versatile and well-established tools for biological imaging over the last century. Here, we theoretically and experimentally show that clever combination of different fluorescence modalities allows further improvements. We found that the interaction of fluorophores with plasmonic surfaces boost super-resolution performance in dSTORM approaches as it allows for tailoring the excitation and emission properties. The strength of the approach is that no further specialized microscope setup is required as the described enhancement solely rely on metal-dielectric coated glass coverslips that are straightforward to fabricate. Such biocompatible plasmonic nanolayers enhance the signal-to-noise ratio of dSTORM, and thus sharpens the localization precision by a factor of two.
Plant miRNA regulation is environmentally and developmentally-sensitive
Authors: von Born Patrick , Rubio-Somoza Ignacio
Published: May 2017

Development and fitness of any organism rely on properly controlled gene expression. This is especially true for plants, as their development is determined by both internal and external cues. MicroRNAs (miRNAs) are embedded in the genetic cascades that integrate and translate those cues into developmental programs. miRNAs negatively regulate their target genes mainly post-transcriptionally through two co-existing mechanisms; mRNA cleavage and translational inhibition. It is unclear whether the efficiency of miRNA-guided regulation is generally influenced by factors like ambient temperature or developmental stage. Here we show that plant miRNA accumulation, as well as miRNAs’ mode of action can be temperature- and development-sensitive. Higher temperatures tend to induce a more pronounced accumulation of mature miRNAs. Both parameters have also an impact on the expression patterns of the core players involved in miRNA performance. We show that efficiency of miRNA-mediated gene silencing declines with age during vegetative development in a temperature-dependent manner. Co-existence of cleavage and translational inhibition was also found to be dependent on temperature and developmental stage. Therefore, each miRNA family specifically regulates their respective targets, while temperature and growth influence the performance of miRNA-dependent regulation in a more general way.
Cerebellar Degeneration Affects Cortico-Cortical Connectivity In Motor Learning Networks
Authors: Tzvi Elinor , Zimmermann Christoph , Bey Richard , Muente Thomas F. , Nitschke Matthias , Kraemer Ulrike M.
Published: May 2017

The cerebellum plays an important role in motor learning as part of a cortico-striato-cerebellar network. Patients with cerebellar degeneration typically show impairments in different aspects of motor learning, including implicit motor sequence learning. How cerebellar dysfunction affects interactions in this cortico-striato-cerebellar network is poorly understood. The present study investigated the effect of cerebellar degeneration on activity in causal interactions between cortical and subcortical regions involved in motor learning. We found that cerebellar patients showed learning-related increase in activity in two regions known to be involved in learning and memory, namely parahippocampal cortex and cerebellar Crus I. The cerebellar activity increase was observed in non-learners of the patient group whereas learners showed an activity decrease. Dynamic causal modelling analysis revealed that modulation of M1 to cerebellum and putamen to cerebellum connections were significantly more negative for sequence compared to random blocks in controls, replicating our previous results, and did not differ in patients. In addition, a separate analysis revealed a similar effect in connections from SMA and PMC to M1 bilaterally. Again, neural network changes were associated with learning performance in patients. Specifically, learners showed a negative modulation from right SMA to right M1 that was similar to controls, whereas this effect was close to zero in non-learners. These results highlight the role of cerebellum in motor learning and demonstrate the functional role cerebellum plays as part of the cortico-striato-cerebellar network.
Modifying and reacting to the environmental pH drives bacterial interactions
Authors: Ratzke Christoph , Gore Jeff
Published: May 2017

Microbes usually exist in communities consisting of myriad different but interacting species. These interactions are typically mediated through environmental modifications; microbes change the environment by taking up resources and excreting metabolites, which affects the growth of both themselves and also other microbes. A very common environmental modification is a change of the environmental pH. Here we show that changing and reacting to the pH leads to a feedback loop that can determine the fate of bacterial populations. We find experimentally that these pH changes can decide the fate of bacterial populations; they can either facilitate or inhibit growth, and in extreme cases will cause extinction of the bacterial population. Moreover, modifying the pH can determine the interactions between different species. Understanding how single species change the pH and react to it allowed us to estimate their pairwise interaction outcomes. Those interactions lead to a set of generic interaction motifs—bistability, succession, murder suicide, and mutualism—that may be independent of which environmental parameter is modified and thus reoccur in different microbial systems.
Selection-driven cost-efficiency optimisation of transcripts modulates gene evolutionary rate in bacteria
Authors: Seward Emily A. , Kelly Steven
Published: May 2017

Background

Most amino acids are encoded by multiple synonymous codons. However synonymous codons are not used equally and this biased codon use varies between different organisms. It has previously been shown that both selection acting to increase codon translational efficiency and selection acting to decrease codon biosynthetic cost contribute to differences in codon bias. However, it is unknown how these two factors interact or how they affect molecular sequence evolution.

Results

Through analysis of 1,320 bacterial genomes we show that bacterial genes are subject to multi-objective selection-driven optimisation of codon use. Here, selection acts to simultaneously decrease transcript biosynthetic cost and increase transcript translational efficiency, with highly expressed genes under the greatest selection. This optimisation is not simply a consequence of the more translationally efficient codons being less expensive to synthesise. Instead, we show that tRNA gene copy number alters the cost-efficiency trade-off of synonymous codons such that for many species such that selection acting on transcript biosynthetic cost and translational efficiency act in opposition. Finally, we show that genes highly optimised to reduce cost and increase efficiency show reduced rates of synonymous and non-synonymous mutation.

Conclusions

This analysis provides a simple mechanistic explanation for variation in evolutionary rate between genes that depends on selection-driven cost-efficiency optimisation of the transcript. These findings reveal how optimisation of resource allocation to mRNA synthesis is a critical factor that determines both the evolution and composition of genes.
A balance of outward and linear inward ionic currents is required for the generation of slow wave oscillations
Authors: Golowasch Jorge , Bose Amitabha , Guan Yinzheng , Salloum Dalia , Roeser Andrea , Nadim Farzan
Published: May 2017

Regenerative inward currents help produce slow oscillations through a negative-slope conductance region of their current-voltage relationship that is well approximated by a linear negative conductance. We used dynamic clamp injections of a linear current with this conductance,INL, to explore why some neurons can generate intrinsic slow oscillations whereas others cannot. We addressed this question, in synaptically isolated neurons of the crabCancer borealis, after blocking action potentials. The pyloric network consists of distinct pacemaker group and follower neurons, all of which express the same complement of ionic currents. When the pyloric dilator (PD) neuron, a member of the pacemaker group, was injected withINLusing dynamic clamp, it consistently produced slow oscillations. In contrast, the lateral pyloric (LP) or ventral pyloric (VD) follower neurons, failed to oscillate withINL. To understand these distinct behaviors, we compared outward current levels of PD, LP and VD neurons. We found that LP and VD neurons had significantly larger high-threshold potassium currents (IHTK) than PD, and LP had lower transient potassium current,IA. ReducingIHTKpharmacologically enabled both LP and VD neurons to produce oscillations withINL, whereas modifyingIAlevels did not affectINL-induced oscillations. Using phase-plane and bifurcation analysis of a simplified model cell, we demonstrate that large levels ofIHTKcan blockINL-induced oscillatory activity, whereas generation of oscillations is almost independent ofIAlevels. These results demonstrate the importance of a balance between inward pacemaking currents and high-threshold K+current levels in determining slow oscillatory activity.
Thermal acclimation mitigates cold-induced paracellular leak from theDrosophilagut
Authors: MacMillan Heath A. , Yerushalmi Gil , Jonusaite Sima , Kelly Scott P. , Donini Andrew
Published: May 2017

When chilled to temperatures below their critical thermal minimum, chill susceptible insects can suffer tissue damage and die. The mechanisms that cause this chilling injury are not well understood but a growing body of evidence suggests that a loss of ion and water homeostasis in the cold leads to hemolymph hyperkalemia that depolarizes cells, leading to cell death. The apparent root of this cascade of issues is the net leak of osmolytes down their concentration gradients in the cold. Many insects, however, are capable of adjusting their thermal physiology, and cold-acclimatedDrosophilacan maintain homeostasis and avoid chilling injury better than warm-acclimated flies. Here, we test whether the cold-induced loss of osmotic homeostasis is associated with a loss of epithelial barrier function inDrosophila, and provide the first evidence of cold-induced epithelial barrier failure in an invertebrate. Flies exposed to 0° C had increased rates of paracellular leak through the gut epithelia, but cold acclimation reduced paracellular permeability, both before and during cold stress, and improved cold tolerance. This adjustment in barrier function was associated with changes in the abundance of select septate junction proteins and the appearance of a tortuous ultrastructure in subapical intercellular regions of contact between adjacent midgut epithelial cells. Thus, cold causes paracellular leak in a chill susceptible insect and cold acclimation can mitigate this effect, at least partly through changes in the composition and structure of transepithelial barriers.

Summary Statement:

Chilling disrupts barrier function of the gut of flies and cold acclimation can mitigate this problem through changes in paracellular occluding junctions.
Multi-omic analysis of a hyper-diverse plant metabolic pathway reveals evolutionary routes to biological innovation
Authors: Moghe Gaurav D. , Leong Bryan J. , Hurney Steven , Daniel Jones A. , Last Robert L.
Published: May 2017

The diversity of life on Earth is a result of continual innovations in molecular networks influencing morphology and physiology. Plant specialized metabolism produces hundreds of thousands of compounds, offering striking examples of these innovations. To understand how this novelty is generated, we investigated the evolution of the Solanaceae family-specific, trichome-localized acylsugar biosynthetic pathway using a combination of mass spectrometry, RNA-seq, enzyme assays, RNAi and phylogenetics in non-model species. Our results reveal that hundreds of acylsugars are produced across the Solanaceae family and even within a single plant, revealing this phenotype to be hyper-diverse. The relatively short biosynthetic pathway experienced repeated cycles of innovation over the last 100 million years that include gene duplication and divergence, gene loss, evolution of substrate preference and promiscuity. This study provides mechanistic insights into the emergence of plant chemical novelty, and offers a template for investigating the ∼300,000 non-model plant species that remain underexplored.