Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. ...Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immunemediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
BACKGROUND: After weight loss, total energy expenditure--in particular, energy expenditure at low levels of physical activity--is lower than predicted by actual changes in body weight and ...composition. An important clinical issue is whether this reduction, which predisposes to weight regain, persists over time. OBJECTIVE: We aimed to determine whether this disproportionate reduction in energy expenditure persists in persons who have maintained a body-weight reduction of greater-than-or-equal10% for >1 y. DESIGN: Seven trios of sex- and weight-matched subjects were studied in an in-patient setting while receiving a weight-maintaining liquid formula diet of identical composition. Each trio consisted of a subject at usual weight (Wtinitial), a subject maintaining a weight reduction of greater-than-or-equal10% after recent (5-8 wk) completion of weight loss (Wtloss₋recent), and a subject who had maintained a documented reduction in body weight of >10% for >1 y (Wtloss₋sustained). Twenty-four-hour total energy expenditure (TEE) was assessed by precise titration of fed calories of a liquid formula diet necessary to maintain body weight. Resting energy expenditure (REE) and the thermic effect of feeding (TEF) were measured by indirect calorimetry. Nonresting energy expenditure (NREE) was calculated as NREE = TEE - (REE +TEF). RESULTS: TEE, NREE, and (to a lesser extent) REE were significantly lower in the Wtloss₋sustained and Wtloss₋recent groups than in the Wtinitial group. Differences from the Wtinitial group in energy expenditure were qualitatively and quantitatively similar after recent and sustained weight loss. CONCLUSION: Declines in energy expenditure favoring the regain of lost weight persist well beyond the period of dynamic weight loss.
In many fisheries, some component of the catch is usually released. Quantifying the effects of capture and release on fish survival is critical for determining which practices are sustainable, ...particularly for threatened species. Using a standardized fishing technique, we studied sublethal (blood physiology and reflex impairment assessment) and lethal (post-release mortality with satellite tags) outcomes of fishing stress on 5 species of coastal sharks (great hammerhead, bull, blacktip, lemon, and tiger). Species-specific differences were detected in whole blood lactate, partial pressure of carbon dioxide, and pH values, with lactate emerging as the sole parameter to be significantly affected by increasing hooking duration and shark size. Species-specific differences in reflex impairment were also found; however, we did not detect any significant relationships between reflex impairment and hooking duration. Taken together, we ranked each species according to degree of stress response, from most to least disturbed, as follows: hammerhead shark > blacktip shark > bull shark > lemon shark > tiger shark. Satellite tagging data revealed that nearly 100% of all tracked tiger sharks reported for at least 4 wk after release, which was significantly higher than bull (74.1%) and great hammerhead (53.6%) sharks. We discuss which mechanisms may lead to species-specific differences in sensitivity to fishing and suggest that observed variation in responses may be influenced by ecological and evolutionary phenomena. Moreover, our results show that certain species (i.e. hammerhead sharks in this study) are inherently vulnerable to capture stress and mortality resulting from fisheries interactions and should receive additional attention in future conservation strategies.
Access to the electromagnetic spectrum is an ever-growing challenge for radar. Future radar will be required to mitigate RF interference from other RF sources, relocate to new frequency bands while ...maintaining quality of service, and share frequency bands with other RF systems. The spectrum sensing, multioptimization (SS-MO) technique was recently investigated as a possible solution to these challenges. Prior results have indicated significant improvement in the signal-to-interference plus noise ratio at the cost of a high computational complexity. However, the optimization computational cost must be manageable in real time to address the dynamically changing spectral environment. In this paper, a bioinspired filtering technique is investigated to reduce the computational complexity of SS-MO. The proposed technique is analogous to the processing of the thalamus in the human brain in that the number of samples input to SS-MO is significantly decreased, thus, resulting in a reduction in computational complexity. The performance and computational complexity of SS-MO and the proposed technique are investigated. Both techniques are used to process a variety of measured spectral data. The results indicate a significant decrease in computational complexity for the proposed approach while maintaining performance of the SS-MO technique.
► Relates seasonal variation in composition to bioethanol and biomethane production. ► Complements published paper on thermochemically derived biofuels. ► Contains optimisation conditions for ...fermentation of kelps to ethanol. ► The optimal harvest date for fermentation and anaerobic digestion of kelp is July.
Laminaria digitata is a highly prevalent kelp growing off the coast of the UK but has rarely been considered as a source of biomass to date. This study shows it can be used as a feedstock in both ethanol fermentation and anaerobic digestion for methane production. The study optimised several parameters in the fermentation of L. digitata and investigated the suitability of the macroalgae through the year using samples harvested every month. For both methane and ethanol production, minimum yields were seen in material harvested in March when the carbohydrates laminarin and mannitol were lowest. July material contained the highest combined laminarin and mannitol content and maximum yields of 167mL ethanol and 0.219m3 kg−1L. digitata.
The essential functions of a bacterial pathogen reflect the most basic processes required for its viability and growth, and represent potential therapeutic targets. Most screens for essential genes ...have assayed a single condition—growth in a rich undefined medium—and thus have not distinguished genes that are generally essential from those that are specific to this particular condition. To help define these classes for Pseudomonas aeruginosa , we identified genes required for growth on six different media, including a medium made from cystic fibrosis patient sputum. The analysis used the Tn-seq circle method to achieve high genome coverage and analyzed more than 1,000,000 unique insertion positions (an average of one insertion every 6.0 bp). We identified 352 general and 199 condition-specific essential genes. A subset of assignments was verified in individual strains with regulated expression alleles. The profile of essential genes revealed that, compared with Escherichia coli , P. aeruginosa is highly vulnerable to mutations disrupting central carbon-energy metabolism and reactive oxygen defenses. These vulnerabilities may arise from the stripped-down architecture of the organism’s carbohydrate utilization pathways and its reliance on respiration for energy generation. The essential function profile thus provides fundamental insights into P. aeruginosa physiology as well as identifying candidate targets for new antibacterial agents.
Significance There is an urgent need for new antibiotics active against resistant bacterial pathogens like Pseudomonas aeruginosa . Target-directed drug development provides a potential path to such drugs, and essential gene products represent potential targets. Accordingly, the work reported here defines a highly verified set of such functions for P. aeruginosa required for growth under a variety of different conditions.
Context. Measurable amounts of Be could have been synthesised primordially if the Universe were non-homogeneous or in the presence of late decaying relic particles. Aims. We investigate the Be ...abundance in the extremely metal-poor star 2MASS J1808-5104 (Fe/H = −3.84) with the aim of constraining inhomogeneities or the presence of late decaying particles. Methods. High resolution, high signal-to-noise ratio (S/N) UV spectra were acquired at ESO with the Kueyen 8.2 m telescope and the UVES spectrograph. Abundances were derived using several model atmospheres and spectral synthesis code. Results. We measured log(Be/H) = −14.3 from a spectrum synthesis of the region of the Be line. Using a conservative approach, however we adopted an upper limit two times higher, i.e. log(Be/H) < −14.0. We measured the O abundance from UV–OH lines and find O/H = −3.46 after a 3D correction. Conclusions. Our observation reinforces the existing upper limit on primordial Be. There is no observational indication for a primordial production of 9Be. This places strong constraints on the properties of putative relic particles. This result also supports the hypothesis of a homogeneous Universe, at the time of nucleosynthesis. Surprisingly, our upper limit of the Be abundance is well below the Be measurements in stars of similar O/H. This may be evidence that the Be–O relation breaks down in the early Galaxy, perhaps due to the escape of spallation products from the gas clouds in which stars such as 2MASS J1808-5104 have formed.
Let
Ω
⊂
C
be an open set. We show that
∂
¯
has closed range in
L
2
(
Ω
)
if and only if the Poincaré–Dirichlet inequality holds. Moreover, we give necessary and sufficient potential-theoretic ...conditions for the
∂
¯
-operator to have closed range in
L
2
(
Ω
)
. We also give a new necessary and sufficient potential-theoretic condition for the Bergman space of
Ω
to be infinite dimensional.
A sufficient condition for the infinite dimensionality of the Bergman space of a pseudoconvex domain is given. This condition holds on any pseudoconvex domain that has at least one smooth boundary ...point of finite type in the sense of D’Angelo.
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