Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

The distribution, ecology and predicted habitat use of the Critically Endangered angelshark (Squatina squatina) in coastal waters of Wales and the central Irish Sea.

The angelshark (Squatina squatina) has the northernmost range of any angel shark species, but there is limited information on its distribution, habitat use and ecology at higher latitudes. To address this, Angel Shark Project: Wales gathered 2231 S. squatina records and 142 anecdotal resources from fishers, coastal communities and archives. These spanned the coastal waters of Wales and the central Irish Sea and were dated from 1812 to 2020, with 97.62% of records within 11.1 km (6 nm) of the coast. Commercial, recreational and charter boat fishers provided the majority of S. squatina records (97.18%), with significantly more sightings from three decades (1970s, 1980s and 1990s) and in the months of September, June, August and July (in descending order). The coastal area between Bardsey Island and Strumble Head had the most S. squatina records (n = 1279), with notable concentrations also found in Carmarthen Bay, Conwy Bay and the Outer Severn Estuary. Species distribution models (SDM) identified four environmental variables that had significant influence on S. squatina distribution, depth, chlorophyll-a concentration, sea surface temperature (SST) and salinity, and these varied between the quarters (Q) of the year. SDM model outputs predicted a larger congruous area of suitable habitat in Q3 (3176 km2 ) compared to Q2 (2051 km2 ), with suitability along the three glacial moraines (Sarn Badrig, Sarn-y-Bwch and Sarn Cynfelyn) strongly presented. Comparison of modelled environmental variables at the location of S. squatina records for each Q identified reductions in depth and salinity, and increases in chlorophyll-a and SST when comparing Q2 or Q3 with Q1 or Q4. This shift may suggest S. squatina are making seasonal movements to shallow coastal waters in Q2 and Q3. This is supported by 23 anecdotal resources and may be driven by reproductive behaviour, as there were 85 records of S. squatina individuals ≤60 cm in the dataset, inferred as recently born or juvenile life-history stages. The results have helped fill significant evidence gaps identified in the Wales Angelshark Action Plan and immediate next research steps are suggested.

Agricultural Media Coverage of Farm Safety: Review of the Literature.

Agricultural media merit increased attention in addressing dynamic changes in safety aspects of one of the nation's most hazardous industries. Changes in farming, such as larger-scale, new "niche" enterprises and new technologies, bring new forms of risk to the safety of those who live and work on farms and ranches. At the same time, traditional agricultural media--commercial firms that publish farm periodicals and commercial radio/television stations and networks that provide farm programming--are changing dramatically. In the face of media convergence, these enterprises provide an increasing menu of agricultural information services delivered by print, radio, and television, plus a host of new electronic media. This review of literature addressed the role and importance of commercial agricultural media in the United States, the scope and pattern of their safety coverage, and the opportunities they represent. The review involved searches of 14 bibliographic databases, as well as reference lists of relevant studies and contacts with farm safety experts. Analysis of 122 documents suggested that limited focus has been directed to the role of commercial agricultural media in safety decisions on US farms. Findings revealed that they continue to serve an efficient, early-stage role in creating awareness and interest, providing information, forming attitudes, and stirring consideration of farm safety. Potentials are seen as expanding through the interactive features of social media and other new services offered by these media firms. Findings also identified research needs, 100 farm safety topics for reporting, and opportunities for strengthening safety coverage by commercial agricultural media.

Reflections on the cost of "low-cost" whole genome sequencing: framing the health policy debate.

The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy.

CAD/CAM and lithium disilicate: an anterior esthetic case study.

Digital technology has brought a new and exciting dimension to dental esthetics. Innovative ways to take impressions and create chair-side restorations are continuing to expand and new dental materials specifically made for CAD/CAM are allowing for extremely esthetic restorations. Lithium disilicate is one such material that is efficiently milled, has a favorable flexural strength, and provides highly esthetic chair-side restorations. The following is a case study that utilizes lithium disilicate for esthetic full coverage crowns on teeth #7, 8, 9, and 10.

Enhanced performance of dispenser printed MA n-type Bi2Te3 composite thermoelectric generators.

This work presents performance advancements of dispenser printed composite thermoelectric materials and devices. Dispenser printed thick films allow for low-cost and scalable manufacturing of microscale energy harvesting devices. A maximum ZT value of 0.31 has been achieved for mechanically alloyed (MA) n-type Bi2Te3-epoxy composite films with 1 wt % Se cured at 350 °C. The enhancement of ZT is a result of increase in the electrical conductivity through the addition of Se, which ultimately lowers the sintering temperature (350 °C). A 62 single-leg thermoelectric generator (TEG) prototype with 5 mm ×700 µm × 120 µm printed element dimensions was fabricated on a custom designed polyimide substrate with thick metal contacts. The prototype device produced a power output of 25 µW at 0.23 mA current and 109 mV voltage for a temperature difference of 20 °C, which is sufficient for low power generation for autonomous microsystem applications.

Evaluation of a chromogenic culture medium for isolation of Clostridium difficile within 24 hours.

Rapid and effective methods for the isolation of Clostridium difficile from stool samples are desirable to obtain isolates for typing or to facilitate accurate diagnosis of C. difficile-associated diarrhea. We report on the evaluation of a prototype chromogenic medium (ID C. difficile prototype [IDCd]) for isolation of C. difficile. The chromogenic medium was compared using (i) 368 untreated stool samples that were also inoculated onto CLO medium, (ii) 339 stool samples that were subjected to alcohol shock and also inoculated onto five distinct selective agars, and (iii) standardized suspensions of 10 C. difficile ribotypes (untreated and alcohol treated) that were also inoculated onto five distinct selective agars. Two hundred thirty-six isolates of C. difficile were recovered from 368 untreated stool samples, and all but 1 of these strains (99.6%) were recovered on IDCd within 24 h, whereas 74.6% of isolates were recovered on CLO medium after 48 h. Of 339 alcohol-treated stool samples cultured onto IDCd and five other selective agars, C. difficile was recovered from 218 samples using a combination of all media. The use of IDCd allowed recovery of 96.3% of isolates within 24 h, whereas 51 to 83% of isolates were recovered within 24 h using the five other media. Finally, when they were challenged with pure cultures, all 10 ribotypes of C. difficile generated higher colony counts on IDCd irrespective of alcohol pretreatment or duration of incubation. We conclude that IDCd is an effective medium for isolation of C. difficile from stool samples within 24 h.