Late-Stage Modification of Aminoglycoside Antibiotics Overcomes Bacterial Resistance Mediated by APH(3') Kinases

The continuous emergence of antimicrobial resistance is causing a threat to patients infected by multidrug‐resistant pathogens. In particular, the clinical use of aminoglycoside antibiotics, broad‐spectrum antibacterials of last resort, is limited due to rising bacterial resistance. One of the major resistance mechanisms in Gram‐positive and Gram‐negative bacteria is phosphorylation of these amino sugars at the 3’‐position by O‐phosphotransferases [APH(3’)s]. Structural alteration of these antibiotics at the 3’‐position would be an obvious strategy to tackle this resistance mechanism. However, the access to such derivatives requires cumbersome multi‐step synthesis, which is not appealing for pharma industry in this low‐return‐on‐investment market. To overcome this obstacle and combat bacterial resistance mediated by APH(3’)s, we introduce a novel regioselective modification of aminoglycosides in the 3’‐position via palladium‐catalyzed oxidation. To underline the effectiveness of our method for structural modification of aminoglycosides, we have developed two novel antibiotic candidates overcoming APH(3’)s‐mediated resistance employing only four synthetic steps

The effects of acute CRAM supplementation on reaction time and subjective measures of focus and alertness in healthy college students

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to examine the effect of acute and prolonged (4-weeks) ingestion of a supplement designed to improve reaction time and subjective measures of alertness, energy, fatigue, and focus compared to placebo.</p> <p>Methods</p> <p>Nineteen physically-active subjects (17 men and 2 women) were randomly assigned to a group that either consumed a supplement (21.1 ± 0.6 years; body mass: 80.6 ± 9.4 kg) or placebo (21.3 ± 0.8 years; body mass: 83.4 ± 18.5 kg). During the initial testing session (T1), subjects were provided 1.5 g of the supplement (CRAM; α-glycerophosphocholine, choline bitartrate, phosphatidylserine, vitamins B3, B6, and B12, folic acid, L-tyrosine, anhydrous caffeine, acetyl-L-carnitine, and naringin) or a placebo (PL), and rested quietly for 10-minutes before completing a questionnaire on subjective feelings of energy, fatigue, alertness and focus (PRE). Subjects then performed a 4-minute quickness and reaction test followed by a 10-min bout of exhaustive exercise. The questionnaire and reaction testing sequence was then repeated (POST). Subjects reported back to the lab (T2) following 4-weeks of supplementation and repeated the testing sequence.</p> <p>Results</p> <p>Reaction time significantly declined (p = 0.050) between PRE and POST at T1 in subjects consuming PL, while subjects under CRAM supplementation were able to maintain (p = 0.114) their performance. Significant performance declines were seen in both groups from PRE to POST at T2. Elevations in fatigue were seen for CRAM at both T1 and T2 (p = 0.001 and p = 0.000, respectively), but only at T2 for PL (p = 0.029). Subjects in CRAM maintained focus between PRE and POST during both T1 and T2 trials (p = 0.152 and p = 0.082, respectively), whereas significant declines in focus were observed between PRE and POST in PL at both trials (p = 0.037 and p = 0.014, respectively). No difference in alertness was seen at T1 between PRE and POST for CRAM (p = 0.083), but a significant decline was recorded at T2 (p = 0.005). Alertness was significantly lower at POST at both T1 and T2 for PL (p = 0.040 and p = 0.33, respectively). No differences in any of these subjective measures were seen between the groups at any time point.</p> <p>Conclusion</p> <p>Results indicate that acute ingestion of CRAM can maintain reaction time, and subjective feelings of focus and alertness to both visual and auditory stimuli in healthy college students following exhaustive exercise. However, some habituation may occur following 4-weeks of supplementation.</p

To what extent are land resource managers preparing for high-end climate change in Scotland?

We explore the individual and institutional conditions and the climate information used to underpin decision-making for adaptation to high-end climate change (HECC) scenarios in a land resource management context. HECC refers to extreme projections with global annual temperature increases of over 4 °C. We analyse whether HECC scenarios are used in the adaptation decision-making of stakeholders who will tackle the potential problem. We also explore whether the adaptation actions being considered are pertinent only to future climate change or whether other drivers and information types are used in decision-making (including non-climate drivers). We also address the role of knowledge uncertainty in adaptation decision-making. Decision-makers perceive HECC as having a low probability of occurrence and so they do not directly account for HECC within existing actions to address climate change. Such actions focus on incremental rather than transformative solutions in which non-climate drivers are at least as important, and in many cases more important, than climate change alone. This reflects the need to accommodate multiple concerns and low risk options (i.e. incremental change). Uncertainty in climate change information is not a significant barrier to decision-making and stakeholders indicated little need for more climate information in support of adaptation decision-making. There is, however, an identified need for more information about the implications of particular sectoral and cross-sectoral impacts under HECC scenarios. The outcomes of this study provide evidence to assist in contextualising climate change information by creating usable, cross-sectoral, decision-centred information

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

PDRs4All IV. An embarrassment of riches: Aromatic infrared bands in the Orion Bar

(Abridged) Mid-infrared observations of photodissociation regions (PDRs) are dominated by strong emission features called aromatic infrared bands (AIBs). The most prominent AIBs are found at 3.3, 6.2, 7.7, 8.6, and 11.2 $\mu$m. The most sensitive, highest-resolution infrared spectral imaging data ever taken of the prototypical PDR, the Orion Bar, have been captured by JWST. We provide an inventory of the AIBs found in the Orion Bar, along with mid-IR template spectra from five distinct regions in the Bar: the molecular PDR, the atomic PDR, and the HII region. We use JWST NIRSpec IFU and MIRI MRS observations of the Orion Bar from the JWST Early Release Science Program, PDRs4All (ID: 1288). We extract five template spectra to represent the morphology and environment of the Orion Bar PDR. The superb sensitivity and the spectral and spatial resolution of these JWST observations reveal many details of the AIB emission and enable an improved characterization of their detailed profile shapes and sub-components. While the spectra are dominated by the well-known AIBs at 3.3, 6.2, 7.7, 8.6, 11.2, and 12.7 $\mu$m, a wealth of weaker features and sub-components are present. We report trends in the widths and relative strengths of AIBs across the five template spectra. These trends yield valuable insight into the photochemical evolution of PAHs, such as the evolution responsible for the shift of 11.2 $\mu$m AIB emission from class B$_{11.2}$ in the molecular PDR to class A$_{11.2}$ in the PDR surface layers. This photochemical evolution is driven by the increased importance of FUV processing in the PDR surface layers, resulting in a "weeding out" of the weakest links of the PAH family in these layers. For now, these JWST observations are consistent with a model in which the underlying PAH family is composed of a few species: the so-called 'grandPAHs'.Comment: 25 pages, 10 figures, to appear in A&

PDRs4All II: JWST's NIR and MIR imaging view of the Orion Nebula

The JWST has captured the most detailed and sharpest infrared images ever taken of the inner region of the Orion Nebula, the nearest massive star formation region, and a prototypical highly irradiated dense photo-dissociation region (PDR). We investigate the fundamental interaction of far-ultraviolet photons with molecular clouds. The transitions across the ionization front (IF), dissociation front (DF), and the molecular cloud are studied at high-angular resolution. These transitions are relevant to understanding the effects of radiative feedback from massive stars and the dominant physical and chemical processes that lead to the IR emission that JWST will detect in many Galactic and extragalactic environments. Due to the proximity of the Orion Nebula and the unprecedented angular resolution of JWST, these data reveal that the molecular cloud borders are hyper structured at small angular scales of 0.1-1" (0.0002-0.002 pc or 40-400 au at 414 pc). A diverse set of features are observed such as ridges, waves, globules and photoevaporated protoplanetary disks. At the PDR atomic to molecular transition, several bright features are detected that are associated with the highly irradiated surroundings of the dense molecular condensations and embedded young star. Toward the Orion Bar PDR, a highly sculpted interface is detected with sharp edges and density increases near the IF and DF. This was predicted by previous modeling studies, but the fronts were unresolved in most tracers. A complex, structured, and folded DF surface was traced by the H2 lines. This dataset was used to revisit the commonly adopted 2D PDR structure of the Orion Bar. JWST provides us with a complete view of the PDR, all the way from the PDR edge to the substructured dense region, and this allowed us to determine, in detail, where the emission of the atomic and molecular lines, aromatic bands, and dust originate

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days