Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell exhaustion. Binding of PD-1 to its ligand, programmed ...death-ligand 1 (PD-L1), activates downstream signaling pathways and inhibits T cell activation. Moreover abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape, and the development of anti-PD-1/PD-L1 antibodies has recently become a hot topic in cancer immunotherapy. Here, we review the structure of PD-1 and PD-L1, the function of the PD-1/PD-L1 signaling pathway, the application of PD-1 or PD-L1 monoclonal antibodies and future directions for anti-PD-1/PD-L1 antibodies with combination therapies. Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade may require more studies, and this approach may be curative for patients with many types of cancer in the future.
The pore dimension and surface property directly dictate the transport of guests, endowing diverse gas selective adsorptions to porous materials. It is highly relevant to construct metal−organic ...frameworks (MOFs) with designable functional groups that can achieve feasible pore regulation to improve their separation performances. However, the role of functionalization in different positions or degrees within framework on the separation of light hydrocarbon has rarely been emphasized. In this context, four isoreticular MOFs (TKL‐104−107) bearing dissimilar fluorination are rationally screened out and afforded intriguing differences in the adsorption behavior of C2H6 and C2H4. Ortho‐fluoridation of carboxyl allows TKL‐105−107 to exhibit enhanced structural stabilities, impressive C2H6 adsorption capacities (>125 cm3 g−1) and desirable inverse selectivities (C2H6 over C2H4). The more modified ortho‐fluorine group and meta‐fluorine group of carboxyl have improved the C2H6/C2H4 selectivity and adsorption capacity, respectively, and the C2H6/C2H4 separation potential can be well optimized via linker fine‐fluorination. Meanwhile, dynamic breakthrough experiments proved that TKL‐105−107 can be used as highly efficient C2H6‐selective adsorbents for C2H4 purification. This work highlights that the purposeful functionalization of pore surfaces facilitates the assembly of highly efficient MOF adsorbents for specific gas separation.
The C2H6/C2H4 separation potential is successfully optimized by virtue of linker fine‐fluorination within an isoreticular cadmium‐organic framework platform. Due to the integrated balance between adsorption selectivity and capacity, fluorinated TKL‐105−107 exhibit distinct one‐step ethylene purification capabilities from C2H6/C2H4 mixtures, shedding light on the effect of tailor‐made fluorine functionalization on the advanced separation/purification applications.
Background Addictions are defined by a loss of flexible control over behavior. The development of response habits might reflect early changes in behavioral control. The following experiments examined ...the flexibility of alcohol-seeking after different durations of self-administration training and tested the role of the dorsal striatum in the control of flexible and habitual alcohol self-administration. Methods Rats were trained to lever-press to earn unsweetened ethanol (EtOH) (10%). The sensitivity of the lever-press response to devaluation was assessed by prefeeding the rats either EtOH or sucrose before an extinction test after different amounts of training (1, 2, 4, and 8 weeks). We subsequently tested the role of the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) in controlling alcohol seeking with reversible inactivation techniques (baclofen/muscimol: 1.0/.1 mmol/L, .3 μL/side). Results We find that operant responding for EtOH early in training is goal-directed and reduced by devaluation, but after 8 weeks of daily operant training, control has shifted to a habit-based system no longer sensitive to devaluation. Furthermore, after relatively limited training, when responding is sensitive to devaluation, inactivation of the DMS greatly attenuates the alcohol-seeking response, whereas inactivation of the DLS is without effect. In contrast, responding that is insensitive to devaluation after 8 weeks of training becomes sensitive to devaluation after inactivation of the DLS but is unaffected by inactivation of the DMS. Conclusions These experiments demonstrate that extended alcohol self-administration produces habit-like responding and that response control shifts from the DMS to the DLS across the course of training.
Background and Purpose
Lung oedema in association with suppressed fibrinolysis is a hallmark of lung injury. Here, we have tested whether plasmin cleaves epithelial sodium channels (ENaC) to resolve ...lung oedema fluid.
Experimental Approach
Human lungs and airway acid‐instilled mice were used for analysing fluid resolution. In silico prediction, mutagenesis, Xenopus oocytes, immunoblotting, voltage clamp, mass spectrometry, and protein docking were combined for identifying plasmin cleavage sites.
Key Results
Plasmin improved lung fluid resolution in both human lungs ex vivo and injured mice. Plasmin activated αβγENaC channels in oocytes in a time‐dependent manner. Deletion of four consensus proteolysis tracts (αΔ432‐444, γΔ131‐138, γΔ178‐193, and γΔ410‐422) eliminated plasmin‐induced activation significantly. Further, immunoblotting assays identified 7 cleavage sites (K126, R135, K136, R153, K168, R178, K179) for plasmin to trim both furin‐cleaved C‐terminal fragments and full‐length human γENaC proteins. In addition, 9 new sites (R122, R137, R138, K150, K170, R172, R180, K181, K189) in synthesized peptides were found to be cleaved by plasmin. These cleavage sites were located in the finger and the thumb, particularly the GRIP domain of human ENaC 3D model composed of two proteolytic centres for plasmin. Novel uncleaved sites beyond the GRIP domain in both α and γ subunits were identified to interrupt the plasmin cleavage‐induced conformational change in ENaC channel complexes. Additionally, plasmin could regulate ENaC activity via the G protein signal.
Conclusion and Implications
Plasmin can cleave ENaC to improve blood‐gas exchange by resolving oedema fluid and could be a potent therapy for oedematous lungs.
High-temperature
, also called Jiang-flavor
, is the saccharifying and fermenting agent for brewing Jiang-flavor Baijiu. During the spontaneous solid-state fermentation of high-temperature
, ...variations in temperature and moisture lead to microbial diversity and various metabolites, contributing to the different colors of high-temperature
(customarily referred to as white
, black
, yellow
, and red
in production). We aimed to investigate the differences in microbial communities, physicochemical indices, and potential functions among different high-temperature
with different colors (labeled as QW, QB, QY, and QR) by amplicon sequencing. We found that
,
, and
were predominant in all samples;
and
were predominant in QB and QR; and
were predominant in QY. The results on the physicochemical characteristics indicated that compared with other
samples, QW exhibited higher protease activity and lower acidity, whereas QB showed the opposite results. QR had the highest esterification yield, and QY exhibited the highest saccharification but lowest esterification yield. Functional prediction demonstrated that the higher abundances of genes encoding bacterial enzymes of QW and QY were related to the considerably higher abundances of
in QW (59%) and QY (87%), respectively. The highest abundance of
in QB (80%) contributed to the highest abundance of genes encoding fungal enzymes in QB. This study revealed the microbial and functional dissimilarities of color-based high-temperature starters and helped facilitate the liquor fermentation process.
Targeted integration of transgenes can be achieved by strategies based on homologous recombination （HR）, mi- crohomology-mediated end joining （MMEJ） or non-homologous end joining （NHEJ）. The more ...generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining （HMEJ）-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and -800 bp of homology arms, and the targeted genome. We found no significant improve- ment of the targeting efficiency by the HMEJ-based method in either mouse embryonic stem cells or the neuroblas- toma cell line, N2a, compared to the HR-based method. However, the HMEJ-based method yielded a higher knock- in efficiency in HEK293T cells, primary astrocytes and neurons. More importantly, this approach achieved transgene integration in mouse and monkey embryos, as well as in hepatocytes and neurons in vivo, with an efficiency much greater than HR-, NHEJ- and MMEJ-based strategies. Thus, the HMEJ-based strategy may be useful for a variety of applications, including gene editing to generate animal models and for targeted gene therapies.
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•NKU-0821a exhibits preferential adsorption of C2H6 over C2H4.•C2H6 adsorption capacity as high as 96.07 cm3/g at ambient conditions.•NKU-0821a has a moderate adsorption enthalpy for ...C2H6.
High efficiency and energy-saving separation of C2H6/C2H4 mixtures to product high purity C2H4 is vital and very meaningful industrial task. However, it remains a formidable challenge to fabricate high-performance adsorbents with simultaneous high C2H6 uptake and moderate adsorption enthalpy. Here, we reported a microporous MOF (NKU-0821) with suitable aperture size and F atoms functional pore surface, which can capture efficiently C2H6 from C2H6/C2H4 mixture. Single-component adsorption experiments show that NKU-0821a (activated NKU-0821) exhibits preferred C2H6 uptake at the full-pressure region than C2H4. The corresponding C2H6 adsorption enthalpy of NKU-0821a is 27.3 kJ mol−1, which is lower than most famous C2H6-selective MOFs. The calculation of IAST selectivity and breakthrough experiments have shown NKU-0821a can effectively separate C2H6/C2H4 mixture under simulated industrial conditions. Moreover, GCMC simulations revealed the key role of fluorous surface.
•Mono-fermentation of chicken manure was performed for several hundred days.•Controlled recirculation of ammonia stripped fermenter-liquid was applied.•Ammonia-levels during fermentation were ...steadily controlled.•Stable process was performed at levels of total ammonia nitrogen of above 6g/L.
The effects of ammonia concentration on the performance and stability of mono-fermentation of chicken manure were investigated in a lab-scale continuous stirred tank reactor at 40°C. Technical stripping was performed to remove ammonia from the liquid fraction of digestate, and the entire product was recycled to the fermenter to control ammonia concentration in the fermenter. Organic loading rate (OLR) of 5.3gVS/(Ld) was achieved with an average free ammonia nitrogen (FAN) concentration of 0.77g/L and a specific gas yield of 0.39L/gVS. When OLR was increased to 6.0gVS/(Ld), stable operation could be obtained with an average FAN concentration of 0.86g/L and a specific gas yield of 0.27L/gVS. Mono-fermentation of chicken manure was successfully carried out at high ammonia concentrations. Controlled recirculation of treated liquid fraction of digestate could be a solution in large-scale application for both: to avoid ammonia inhibition and minimize digestate.
In this study, we investigate the driving forces behind the changes in residential energy consumption (REC) in China’s urban and rural areas over the 2001–2012 period. Based on the logarithmic mean ...Divisia index method, the REC changes are decomposed into seven driving forces, which are climate change, energy price, energy expenditure mix, energy cost share (in total expenditure), expenditure share (in income), per capita income and population effects. According to the results, climate effect due to increasing days with abnormal temperature, energy cost share effect characterized by more expenditure to be paid for energy use, income effect describing constant income growth in the residential sector definitely increase REC in both urban and rural areas. In contrast, energy prices and energy expenditure mix effects negatively contribute to the REC increase, respectively because of the increase in energy prices and the transition from the low-priced energy to high-priced energy. Expenditure share and population effects play opposite roles in urban and rural areas, and the reasons and implications are analysed in depth.
•We investigate driving factors behind urban and rural REC changes in China.•Contribution from climate change effect to REC changes is first measured.•Climate, energy cost share and income effects obviously increase REC in both areas.•Energy prices and energy expenditure mix effects decrease the REC.•Expenditure share and population effects show heterogeneity in both areas.
Three series of copper hydride clusters Cu
8
H
6
L
6
2+
(
1
), Cu
4
HX
2
L
4
+
where X
−
= Cl
−
(
2a
), Br
−
(
2b
), I
−
(
2c
), N
3
−
(
2d
) and SCN
−
(
2e
), and Cu
4
HX
3
L
3
where X
−
= Br
−
(
...3b
) and I
−
(
3c
) (L = 2-(diphenylphosphino)pyridine, dppy) were synthesized and characterized by single-crystal X-Ray crystallography and standard spectroscopic techniques. The metal core of
1
, Cu
8
, can be described as a bicapped octahedron, while those of
2
and
3
series adopt tetrahedral structures. The hydride positions were deduced from difference electron density maps and corroborated by NMR and DFT calculations. For
1
, there are two μ
4
-H
−
, one each in the two tetrahedral cavities of the two capping atoms and four μ
3
-H
−
on the six triangular faces around the waist of the octahedron. For Cu
4
HX
2
L
4
+
and Cu
4
HX
3
L
3
series, the single μ
4
-H
−
resides in the center of the Cu
4
tetrahedron. It was found that these three series of copper clusters are intimately connected and can convert from one to another under specific reaction conditions. Their transformation pathways were investigated in detail. Spontaneous resolution to form optically pure enantiomeric single crystals was observed for Cu
4
H(SCN)
2
L
4
+
(
2e
) and Cu
4
HBr
3
L
3
(
3b
). Photoluminescence was observed for Cu
4
HX
2
L
4
+
, as well as Cu
4
HX
3
L
3
with strong emissions from green to yellow regions.
Synthesis, structures and interconversion of three related classes of copper hydride clusters
Cu
8
H
6
(L)
6
2+
Cu
4
HX
3
(L)
3
and
Cu
4
HX
2
(L)
4
+
.
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