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Metallo-β-lactamases (MBLs) are members of the structurally conserved but functionally diverse MBL-fold superfamily of metallohydrolases. MBLs are a major concern for global health care as they efficiently inactivate β-lactam antibiotics, including the "last-resort" carbapenems, and no clinically suitable inhibitors are currently available. Increasingly, promiscuous β-lactamase activity is also observed in other members of the superfamily, including from viruses, which represents an underexplored reservoir for future pathways to antibiotic resistance. Here, two such MBL-fold enzymes from Bacillus phages, the cyclic mononucleotide-degrading proteins ApycGoe3 and ApycGrass, are shown to degrade β-lactam substrates efficiently in vitro. In particular, ApycGrass displays a distinct preference for carbapenem substrates with a catalytic efficiency that is within one order of magnitude of the clinically relevant MBL NDM-1. Mutagenesis experiments also demonstrate that the loss of a metal-bridging aspartate residue reduces nuclease activity up to 35-fold but improves carbapenemase activity. In addition, we hypothesise that the oligomeric state significantly influences β-lactamase activity by modifying access to the active site pocket. Together, these observations hint at a possible new avenue of resistance via the spread of phage-borne MBL-fold enzymes with β-lactamase activity. [ABSTRACT FROM AUTHOR]

Rapid, continuous gambling formats are associated with higher risks for gambling-related harm in terms of excessive monetary and time expenditure. The current study investigated the effect on gambling response latency and persistence, of a new form of within-game intervention that required players to actively engage in response inhibition via monitoring for stop signals. Seventy-four experienced electronic gaming machine gamblers, with a mean age of 35.28 years, were recruited to participate in a rapid, continuous gambling task where real money could be won and lost. Participants were randomly allocated to either the control condition where no intervention was presented, or either a condition with a passive three minute break in play or a condition with a three minute intervention that required participants to engage in response inhibition. Although there was no main effect for experimental condition on gambling persistence, both interventions were effective in elevating response latency during a period of sustained losses. It was concluded that within-game interventions that create an enforced break in play are effective in increasing response latency between bets during periods of sustained losses. Furthermore, within-game interventions that require active involvement appear to be more effective in increasing response latency than standard, passive breaks in play., Author(s): Adrian Parke [sup.1] [sup.2], Patrick Dickinson [sup.3], Louise O'Hare [sup.4], Liam Wilson [sup.3], Greg Westerman-Hughes [sup.2], Kathrin Gerling [sup.5] Author Affiliations: (1) grid.15756.30, 000000011091500X, School of Education and Social [...]

Synthetic nicotinamide biomimetics (NCBs) have emerged as alternatives to the use of natural cofactors. The relatively low cost and ease of manufacture of NCBs may enable the scaling of biocatalytic reactions to produce bulk chemicals (e.g., biofuels and plastics). NCBs are also recognized by only a subset of NAD(P)/NAD(P)H-dependent enzymes, which potentially allows access to orthogonal redox cascades that can be run simultaneously within a single reactor. In the work presented here, a series of NCBs was prepared and tested for activity with alcohol dehydrogenases and ene-reductases. While the NCBs did not support enzymatic activity with the alcohol dehydrogenases, the observed rate of the ene-reductases with NCBs was greater than when incubated with the natural cofactor (consistent with previous observations). We obtained the structures of an ene-reductase and an alcohol dehydrogenase with an NCB bound in their active sites. While the NCB bound to the ene-reductases in a productive position and orientation for hydride transfer to the isoalloxazine ring of the flavin cofactor, the NCB failed to adopt a catalytically competent binding mode in the alcohol dehydrogenase. [ABSTRACT FROM AUTHOR]

Intussusception is a rare but well‐described cause of intestinal obstruction in several species, including cattle, and is often associated with enteritis, intestinal parasitism or intestinal neoplasia. Clinical signs are non‐specific and include anorexia with reduced faecal output. This report describes a 4‐year‐old Simmental bull that presented with anorexia and reduced faecal output, along with severe ruminal bloat and a large, dilated intestinal loop palpated rectally. Serum biochemistry identified severe hypochloraemia, consistent with proximal intestinal obstruction and a poor prognosis. Although supportive and symptomatic treatment was provided, the bull died before a definitive diagnosis could be made. Postmortem examination identified a segmental intestinal intussusception, within the proximal jejunum, which had resulted in intestinal obstruction. The primary cause of this intussusception was a retroflexed intestinal diverticulum, which formed the intussusceptum. [ABSTRACT FROM AUTHOR]

Background and objectives: Multiple reforms aimed at improving the Chinese population's health have been introduced in recent years, including several designed to improve access to innovative drugs. We sought to review current factors affecting access to innovative drugs in China and to anticipate future trends. Methods: Targeted reviews of published literature and statistics on the Chinese healthcare system, medical insurance and reimbursement processes were conducted, as well as interviews with five Chinese experts involved in the reimbursement of innovative drugs. Results: Drug reimbursement in China is becoming increasingly centralized due to the removal of provincial pathways, the establishment of the National Healthcare Security Administration and the implementation of the National Reimbursement Drug List (NRDL), which is now the main route for drug reimbursement in China. There is also an increasing number of other channels via which patients may access innovative treatments, including various types of commercial insurance and special access. Health technology assessment (HTA) and health economic evidence are becoming pivotal elements of the NRDL decision-making process. Alongside the optimization of HTA decision making, innovative risk-sharing agreements are anticipated to be increasingly leveraged in the future to optimize access to highly specialized technologies and encourage innovation while safeguarding limited healthcare funds. Conclusions: Drug public reimbursement in China continues to align more closely with approaches widely used in Europe in terms of HTA, health economics and pricing. Centralization of decision-making processes for public reimbursement of innovative drugs allows consistency in assessment and access, which optimizes the improvement of the Chinese population's health. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to identify risk factors associated with the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE). Methods: We conducted a systematic literature review of studies focusing on adult patients classified as having SLE‐related PAH by searching the electronic databases Embase, Medline, Medline in‐progress, Wanfang, China National Knowledge Infrastructure, Ichushi Web, Kmbase, and KoreaMed. Based on the findings, we conducted a Delphi survey to build expert consensus on issues related to screening for PAH in patients with SLE and on the importance and feasibility of measuring the identified factors in clinical practice. Results: We included 21 eligible studies for data synthesis. Sixteen factors were associated with an increased risk of SLE‐PAH: pericardial effusion, serositis, longer duration of SLE, arthritis, acute and subacute cutaneous lupus, scleroderma pattern on nailfold capillaroscopy, diffusion capacity of carbon monoxide in the lungs (DLCO) <70% predicted, interstitial lung disease, thrombocytopenia, and seven serological factors. Six factors were associated with a decreased risk of SLE‐PAH: malar/acute rash, hematologic disorder, renal disorder, higher Systemic Lupus Erythematosus Disease Activity Index score, and two serological factors. Among these, there were six risk factors on which the panelists reached strong or general consensus (peak tricuspid regurgitation velocity on echocardiography >2.8 m/s, pericardial effusion, DLCO <70% predicted, scleroderma pattern on nailfold capillaroscopy, brain natriuretic peptide >50 ng/l, and N‐terminal pro–brain natriuretic peptide >300 ng/l). The Delphi panel confirmed the need for a screening tool to identify patients with SLE at high risk of developing PAH and provided consensus on the importance and/or practicality of measuring the identified factors. Conclusion: The risk factors we identified could be used in a screening algorithm to identify patients with SLE with a high risk of developing PAH to facilitate early diagnosis, which could improve prognosis and management of these patients. [ABSTRACT FROM AUTHOR]

Multiplex optical detection in live cells is challenging due to overlapping signals and poor signal‐to‐noise associated with some chemical reporters. To address this, the application of spectral phasor analysis to stimulated Raman scattering (SRS) microscopy for unmixing three bioorthogonal Raman probes within cells is reported. Triplex detection of a metallacarborane using the B−H stretch at 2480–2650 cm−1, together with a bis‐alkyne and deuterated fatty acid can be achieved within the cell‐silent region of the Raman spectrum. When coupled to imaging in the high‐wavenumber region of the cellular Raman spectrum, nine discrete regions of interest can be spectrally unmixed from the hyperspectral SRS dataset, demonstrating a new capability in the toolkit of multiplexed Raman imaging of live cells. [ABSTRACT FROM AUTHOR]

In this investigation, speech acts targeted for instruction in ELT (English Language Teaching) textbooks commonly used in Hong Kong were examined using relational content analysis. The aim was to discover which speech acts are frequently presented or not evident, so that this information could be compared to that which has been found in prior studies in other locations. This is important because, from a pedagogical viewpoint, teachers need to ensure textbooks help students learn to use as wide a range of speech acts as possible. As textbooks also need to provide clear examples and information to help learners understand how and when to use speech acts, in this research, the presentation of the speech acts was examined to identify the pragmalinguistic and sociopragmatic information. It was found that there was a tendency to include certain speech acts much more frequently than others, and that some were not included at all. There was also a general lack of clear pragmalinguistic (such as the presentation of indirect speech acts) and sociopragmatic information (such as dealing with high degrees of social distance) presented. This suggests that these factors could be given further consideration and that there are improvements that could be made to both the way that textbooks are written and selected for use. Therefore, this study contributes valuable information about the speech acts in Hong Kong ELT textbooks to and has important implications for both textbook writers and English teachers regarding the field of pragmatics. [ABSTRACT FROM AUTHOR]

Marek's disease (MD) is caused by virulent strains of Gallid alphaherpesvirus type 2 (MD virus serotype 1; MDV 1) and frequently causes a lymphoproliferative disorder in poultry and other galliform birds worldwide. However, within the peafowl (Phasianinae) subfamily, there are only rare confirmed reports of MD. Here we report MD in an Indian peafowl (Pavo cristatus), which clinically presented with hindlimb paraparesis and intraocular swelling of the right eye. Soft, off-white to tan masses within the right eye, sciatic nerves and coelomic cavity were identified at post-mortem examination which effaced the cranial pole of the kidneys and diffusely effaced the testes. Lymphoid neoplasia was identified histologically at all of these sites and there was extensive hepatic lymphoid cell infiltration, which had not been grossly evident. The T-cell origin of the lymphoid cells was confirmed by immunohistochemistry for CD3 antigen. A virulent strain of MDV 1 was detected by real-time polymerase chain reaction in DNA samples extracted from the kidney and testes. As MD is rare in peafowl it should be considered as a differential diagnosis for intraocular and coelomic masses with associated clinical signs. [ABSTRACT FROM AUTHOR]