Summary
Desulfatibacillum alkenivorans AK‐01 serves as a model organism for anaerobic alkane biodegradation because of its distinctive biochemistry and metabolic versatility. The D. alkenivorans ...genome provides a blueprint for understanding the genetic systems involved in alkane metabolism including substrate activation, CoA ligation, carbon‐skeleton rearrangement and decarboxylation. Genomic analysis suggested a route to regenerate the fumarate needed for alkane activation via methylmalonyl‐CoA and predicted the capability for syntrophic alkane metabolism, which was experimentally verified. Pathways involved in the oxidation of alkanes, alcohols, organic acids and n‐saturated fatty acids coupled to sulfate reduction and the ability to grow chemolithoautotrophically were predicted. A complement of genes for motility and oxygen detoxification suggests that D. alkenivorans may be physiologically adapted to a wide range of environmental conditions. The D. alkenivorans genome serves as a platform for further study of anaerobic, hydrocarbon‐oxidizing microorganisms and their roles in bioremediation, energy recovery and global carbon cycling.
Metal-organic frameworks (MOFs) hold significant potential for use in gas storage, sensing and catalysis. To uncover this potential, MOF processing must develop in line with MOF materials. Here, ...direct ink writing-based 3D printing of UiO-66 MOF composites and their thermal treatment give mechanically stable yet highly porous composites effective for the catalytic breakdown of methyl-paraoxon, a simulant of highly toxic organophosphate nerve agents.
Summary
Background
In patients with multiple endocrine neoplasia type 1 (MEN‐1), pancreaticoduodenal (PD) neuroendocrine tumours (NETs) are associated with early mortality, yet the best treatment ...strategy remains uncertain.
Aim
To assess patient important outcomes (mortality and metastasis) of PD‐NETs and predictors of outcomes in patients with MEN‐1.
Methods
Retrospective cohort of patients with MEN‐1 who attended the Mayo Clinic, Rochester, MN from 1997 to 2014.
Results
We identified 287 patients with MEN‐1; 199 (69%) patients had 217 PD‐NETs. Among those with a PD‐NETs, 129 (65%) had surgery of which 90 (70%) had their primary surgery performed at Mayo Clinic. The median postoperative follow‐up was 8 years during which 13 (14%) patients died. The mean (±standard deviation) age of death was 51 (±9) years. Tumour size, metastasis at surgery or tumour type were not predictive of mortality, but for every year older at surgery, the odds of metastasis increased by 6%. Surgery was not performed in 70 (35%) patients. Among those who were observed/medically managed without known metastatic disease, mean tumour growth was 0·02 cm/year (range, −0·13–0·4 cm/year). Four patients (7%) died at a median age of 77 (range, 51–89) years.
Conclusion
PD‐NETs are common in patients with MEN‐1 and are associated with early mortality even after surgical intervention. Active surveillance is a viable option in nonaggressive PD‐NETs, although definitive factors identifying such patients are lacking. Therefore, counselling regarding risks and benefits of current treatment options remains integral to the care of patients with MEN‐1.
High frequency, in situ observations from 11 globally distributed sites for the period 1994–2014 and archived air measurements dating from 1978 onward have been used to determine the global growth ...rate of 1,1-difluoroethane (HFC-152a, CH3CHF2). These observations have been combined with a range of atmospheric transport models to derive global emission estimates in a top-down approach. HFC-152a is a greenhouse gas with a short atmospheric lifetime of about 1.5 years. Since it does not contain chlorine or bromine, HFC-152a makes no direct contribution to the destruction of stratospheric ozone and is therefore used as a substitute for the ozone depleting chlorofluorocarbons (CFCs) and hydrochlorofluorocarbons (HCFCs). The concentration of HFC-152a has grown substantially since the first direct measurements in 1994, reaching a maximum annual global growth rate of 0.84 ± 0.05 ppt yr−1 in 2006, implying a substantial increase in emissions up to 2006. However, since 2007, the annual rate of growth has slowed to 0.38 ± 0.04 ppt yr−1 in 2010 with a further decline to an annual average rate of growth in 2013–2014 of −0.06 ± 0.05 ppt yr−1. The annual average Northern Hemisphere (NH) mole fraction in 1994 was 1.2 ppt rising to an annual average mole fraction of 10.1 ppt in 2014. Average annual mole fractions in the Southern Hemisphere (SH) in 1998 and 2014 were 0.84 and 4.5 ppt, respectively. We estimate global emissions of HFC-152a have risen from 7.3 ± 5.6 Gg yr−1 in 1994 to a maximum of 54.4 ± 17.1 Gg yr−1 in 2011, declining to 52.5 ± 20.1 Gg yr−1 in 2014 or 7.2 ± 2.8 Tg-CO2 eq yr−1. Analysis of mole fraction enhancements above regional background atmospheric levels suggests substantial emissions from North America, Asia, and Europe. Global HFC emissions (so called “bottom up” emissions) reported by the United Nations Framework Convention on Climate Change (UNFCCC) are based on cumulative national emission data reported to the UNFCCC, which in turn are based on national consumption data. There appears to be a significant underestimate ( > 20 Gg) of “bottom-up” reported emissions of HFC-152a, possibly arising from largely underestimated USA emissions and undeclared Asian emissions.
To evaluate pain responses following Pascal 20 ms multi-spot and 100 ms single-spot panretinal photocoagulation (PRP).
Single-centre randomised clinical trial. 40 eyes of 24 patients with ...treatment-naive proliferative diabetic retinopathy randomised to 20 and 100 ms PRP under topical 0.4% oxybuprocaine. A masked grader used a pain questionnaire within 1 h (numerical pain score (NPS)) and 1 month after treatment (numerical headache score (NHS)). Primary outcome measure was NPS immediately post-PRP. Secondary outcome measures were mean NHS scores and levels of photophobia reported within 4 weeks of primary PRP.
Mean laser fluence was significantly lower using 20 ms PRP (4.8 J/cm²) compared to 100 ms PRP (11.8 J/cm²); p < 0.001). Mean NPS scores for treatment were 2.4 (2.3) (mild) for 20 ms PRP group compared to 4.9 (3.3) (moderate) in 100 ms PRP group-a significant difference (95% CI 4.3 to 0.68; p = 0.006). Mean NHS score within 1 month was 1.5 (2.7) in 20 ms PRP group compared to 3.2 (3.5) in the 100 ms PRP group (p < 0.05). The median duration of photophobia after 20 ms PRP was 3 h, and significantly less compared to 100 ms PRP after which 72 h of photophobia was reported (p < 0.001).
Multi-spot 20 ms PRP was associated with significantly lower levels of anxiety, headache, pain and photophobia compared to 100 ms single-spot PRP treatment. Possible reasons include lower fluence, shorter-pulse duration, and spatial summation of laser nociception with multi-spot Pascal technique.
T cells play a critical role in the control of cancer. The development of immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, ...durable clinical benefit is observed in only a subset of patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within the tumor microenvironment (TME) to limit tumor evasion and improve patient outcomes. Adenosine has emerged as a potent immune suppressant within the TME, and CD73 is the major enzyme responsible for its extracellular production. CD73 can be co-opted within the TME to impair T-cell-mediated antitumor immunity and promote tumor growth. To target this pathway and block the formation of adenosine, we designed a novel, selective, and potent class of small-molecule inhibitors of CD73, including AB680 (quemliclustat), which is currently being tested in patients with cancer. AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity that were dampened by the formation of immunosuppressive adenosine by CD73. Furthermore, in an allogeneic mixed lymphocyte reaction where CD73-derived adenosine had a dominant suppressive effect in the presence of PD-1 blockade, AB680 restored T-cell activation and function. Finally, in a preclinical mouse model of melanoma, AB680 inhibited CD73 in the TME and increased the antitumor activity of PD-1 blockade. Collectively, these data provide a rationale for the inhibition of CD73 with AB680 in combination with ICB, such as anti-PD-1, to improve cancer patient outcomes.
Genetic polymorphisms of bovine milk proteins affect the protein profile of the milk and, hence, certain technological properties, such as casein (CN) number and cheese yield. However, reports show ...that such polymorphisms may also affect the health-related properties of milk. Therefore, to gain insight into their digestion pattern and bioactive potential, β-CN was purified from bovine milk originating from cows homozygous for the variants A(1), A(2), B, and I by a combination of cold storage, ultracentrifugation, and acid precipitation. The purity of the isolated β-CN was determined by HPLC, variants were verified by mass spectrometry, and molar extinction coefficients at λ=280nm were determined. β-Casein from each of the variants was subjected to in vitro digestion using pepsin and pancreatic enzymes. Antioxidant and angiotensin-converting enzyme (ACE) inhibitory capacities of the hydrolysates were assessed at 3 stages of digestion and related to that of the undigested samples. Neither molar extinction coefficients nor overall digestibility varied significantly between these 4 variants; however, clear differences in digestion pattern were indicated by gel electrophoresis. In particular, after 60min of pepsin followed by 5min of pancreatic enzyme digestion, one ≈4kDa peptide with the N-terminal sequence (106)H-K-E-M-P-F-P-K- was absent from β-CN variant B. This is likely a result of the (122)Ser to (122)Arg substitution in variant B introducing a novel trypsin cleavage site, leading to the changed digestion pattern. All investigated β-CN variants exhibited a significant increase in antioxidant capacity upon digestion, as measured by the Trolox-equivalent antioxidant capacity assay. After 60min of pepsin + 120min of pancreatic enzyme digestion, the accumulated increase in antioxidant capacity was ≈1.7-fold for the 4 β-CN variants. The ACE inhibitory capacity was also significantly increased by digestion, with the B variant reaching the highest inhibitory capacity at the end of digestion (60min of pepsin + 120min of pancreatic enzymes), possibly because of the observed alternative digestion pattern. These results demonstrate that genetic polymorphisms affect the digestion pattern and bioactivity of milk proteins. Moreover, their capacity for radical scavenging and ACE inhibition is affected by digestion.
We present NMR data in the normal and superconducting states of CeCoIn5 for fields close to H(c2)(0)=11.8 T in the ab plane. Recent experiments identified a first-order transition from the normal to ...superconducting state for H>10.5 T, and a new thermodynamic phase below 290 mK within the superconducting state. We find that the Knight shifts of the In(1), In(2), and the Co are discontinuous across the first-order transition and the magnetic linewidths increase dramatically. The broadening differs for the three sites, unlike the expectation for an Abrikosov vortex lattice, and suggests the presence of static spin moments in the vortex cores. In the low-temperature and high-field phase, the broad NMR lineshapes suggest ordered local moments, rather than a long-wavelength quasiparticle spin density modulation expected for an FFLO phase.
The delivery of surface meltwater through englacial drainage systems to the bed of the Greenland Ice Sheet modulates ice flow through basal lubrication. Recent studies in Southeast Greenland have ...identified a perennial firn aquifer; however, there are few observations quantifying the input or residence time of water within the englacial system and it remains unknown whether water can be stored within solid ice. Using hourly stationary radar measurements, we present observations of englacial and episodic subglacial water in the ablation zone of Store Glacier in West Greenland. We find significant storage of meltwater in solid ice damaged by crevasses extending down to 48 m below the ice surface during the summer, which is released or refrozen during winter. This is a significant hydrological component newly observed in the ablation zone of Greenland that could delay the delivery of meltwater to the bed, changing the ice dynamic response to surface meltwater.
Plain Language Summary
Surface meltwater can drastically modify how glaciers flow. Depending on how and when it is delivered, meltwater can cause variable motion by modulating friction at the ice sheet base. Englacial water can control this behavior by either preventing water from reaching the bed or by delaying its release. In this paper, we present detailed observations of water storage within and at the bed of Store Glacier in West Greenland using hourly stationary ice penetrating radar measurements. In contrast to the previously discovered firn aquifer in high‐accumulation regions, at Store Glacier englacial water is present within a region of solid, damaged ice and persists until winter. This type of water storage has not been previously observed in solid ice and could explain some of the complex flow behavior of some Greenland glaciers.
Key Points
Englacial water storage was observed in damaged solid ice with a phase‐sensitive radar in the ablation zone of Store Glacier, West Greenland
Englacial water storage, intercepting a portion of surface meltwater, may contribute to the observed variability in glacial flow behavior
Coincident periodic subglacial drainage events indicate an active subglacial drainage network beneath the englacial storage
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