We study the CDF
W
-mass, muon
g
-
2
, and dark matter observables in a local
U
(
1
)
L
μ
-
L
τ
model in which the new particles include three vector-like leptons (
E
1
,
E
2
,
N
), a new gauge boson
...Z
′
, a scalar
S
(breaking
U
(
1
)
L
μ
-
L
τ
), a scalar dark matter
X
I
and its partner
X
R
. We find that the CDF
W
-mass disfavors
m
E
1
=
m
E
2
=
m
N
or
s
L
=
s
R
=
0
where
s
L
(
R
)
is mixing parameter of left (right)-handed fields of vector-like leptons. A large mass splitting between
E
1
and
E
2
is favored when the differences between
s
L
and
s
R
becomes small. The muon
g
-
2
anomaly can be simultaneously explained for appropriate difference between
m
E
1
(
s
L
)
and
m
E
2
(
s
R
)
, and some regions are excluded by the diphoton signal data of the 125 GeV Higgs. Combined with the CDF
W
-mass, muon
g
-
2
anomaly and other relevant constraints, the correct dark matter relic density is mainly obtained in two different scenarios: (i)
X
I
X
I
→
Z
′
Z
′
,
S
S
for
m
Z
′
(
m
S
)
<
m
X
I
and (ii) the co-annihilation processes for
m
i
n
(
m
E
1
,
m
E
2
,
m
N
,
m
X
R
)
close to
m
X
I
. Finally, we use the direct searches for
2
ℓ
+
E
T
miss
event at the LHC to constrain the model, and show the allowed mass ranges of the vector-like leptons and dark matter.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Conspectus Immune checkpoint blockade (ICB) therapy elicits antitumor response by inhibiting immune suppressor components, including programmed cell death protein 1 and its ligand (PD-1/PD-L1) and ...cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Despite improved therapeutic efficacy, the clinical response rate is still unsatisfactory as revealed by the fact that only a minority of patients experience durable benefits. Additionally, “off-target” effects after systemic administration remain challenging for ICB treatment. To this end, the local and targeted delivery of ICB agents instead could be a potential solution to maximize the therapeutic outcomes while minimizing the side effects. In this Account, our recent studies directed at the development of different strategies for the local and targeted delivery of ICB agents are discussed. For example, transdermal microneedle patches loaded with anti-programmed death-1 antibody (aPD1) and anti-CTLA4 were developed to facilitate sustained release of ICB agents at the diseased sites. Triggered release could also be achieved by various stimuli within the tumor microenvironment, including low pH and abnormally expressed enzymes. Recently, the combination of an anti-programmed death-ligand 1 antibody (aPD-L1) loaded hollow-structured microneedle patch with cold atmospheric plasma (CAP) therapy was also reported. Microneedles provided microchannels to facilitate the transdermal transport of CAP and further induce immunogenic tumor cell death, which could be synergized by the local release of aPD-L1. In addition, in situ formed injectable or sprayable hydrogels were tailored to deliver immunomodulatory antibodies to the surgical bed to inhibit tumor recurrence after primary tumor resection. In paralell, inspired by the unique targeting ability of platelets toward the inflammatory sites, we engineered natural platelets decorated with aPD-L1 for targeted delivery after tumor resection to inhibit tumor recurrence. We further constructed a cell–cell combination delivery platform based on conjugates of platelets and hematopoietic stem cells (HSCs) for leukemia treatment. With the homing ability of HSCs to the bone marrow, the HSC–platelet–aPD1 assembly could effectively deliver aPD1 in an acute myeloid leukemia mouse model. Besides living cells, we also leveraged HEK293T-derived vesicles with PD1 receptors on their surfaces to disrupt the PD-1/PD-L1 immune inhibitory pathway. Moreover, the inner space of the vesicles allowed the packaging of an indoleamine 2,3-dioxygenase inhibitor, further reinforcing the therapeutic efficacy. A similar approach has also been demonstrated by genetically engineering platelets overexpressing PD1 receptor for postsurgical treatment. We hope the local and targeted ICB agent delivery methods introduced in this collection would further inspire the development of advanced drug delivery strategies to improve the efficiency of cancer treatment while alleviating side effects.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Alternative splicing (AS) regulates multiple biological processes including flowering, circadian and stress response in plant. Although accumulating evidences indicate that AS is developmentally ...regulated, how AS responds to developmental cues is not well understood. Early fruit growth mainly characterized by active cell division and cell expansion contributes to the formation of fruit morphology and quality traits. Transcriptome profiling has revealed the coordinated complex regulation of gene expression in the process. High throughput RNA sequencing (RNA-seq) technology is advancing the genome-wide analysis of AS events in plant species, but the landscape of AS in early growth fruit is still not available for tomato (Solanum lycopersicum), a model plant for fleshy fruit development study.
Using RNA-seq, we surveyed the AS patterns in tomato seedlings, flowers and young developing fruits and found that 59.3 % of expressed multi-exon genes underwent AS in these tissues. The predominant type of AS events is intron retention, followed by alternative splice donor and acceptor, whereas exon skipping has the lowest frequency. Although the frequencies of AS events are similar among seedlings, flowers and early growth fruits, the fruits generated more splice variants per gene. Further comparison of gene expression in early growth fruits at 2, 5 and 10 days post anthesis revealed that 5206 multi-exon genes had at least one splice variants differentially expressed during early fruit development, whereas only 1059 out of them showed differential expression at gene level. We also identified 27 multi-exon genes showing differential splicing during early fruit growth. In addition, the study discovered 2507 new transcription regions (NTRs) unlinked to the annotated chromosomal regions, from where 956 putative protein coding transcripts and 1690 putative long non-coding RNAs were identified.
Our genome-wide analysis of AS events reveals a distinctive AS pattern in early growth tomato fruits. The landscape of AS obtained in this study will facilitate future investigation on transcriptome complexity and AS regulation during early fruit growth in tomato. The newly found NTRs will also be useful for updating the tomato genome annotation.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During their lifetime, plants encounter numerous biotic and abiotic stresses with diverse modes of attack. Phytohormones, including salicylic acid (SA), ethylene (ET), jasmonate (JA), abscisic acid ...(ABA), auxin (AUX), brassinosteroid (BR), gibberellic acid (GA), cytokinin (CK) and the recently identified strigolactones (SLs), orchestrate effective defense responses by activating defense gene expression. Genetic analysis of the model plant
has advanced our understanding of the function of these hormones. The SA- and ET/JA-mediated signaling pathways were thought to be the backbone of plant immune responses against biotic invaders, whereas ABA, auxin, BR, GA, CK and SL were considered to be involved in the plant immune response through modulating the SA-ET/JA signaling pathways. In general, the SA-mediated defense response plays a central role in local and systemic-acquired resistance (SAR) against biotrophic pathogens, such as Pseudomonas syringae, which colonize between the host cells by producing nutrient-absorbing structures while keeping the host alive. The ET/JA-mediated response contributes to the defense against necrotrophic pathogens, such as
, which invade and kill hosts to extract their nutrients. Increasing evidence indicates that the SA- and ET/JA-mediated defense response pathways are mutually antagonistic.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neurological diseases such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease are among the intractable diseases for which appropriate drugs and treatments are lacking. ...Proteolysis targeting chimera (PROTAC) technology is a novel strategy to solve this problem. PROTAC technology uses the ubiquitin-protease system to eliminate mutated, denatured, and harmful proteins in cells. It can be reused, and utilizes the protein destruction mechanism of the cells, thus making up for the deficiencies of traditional protein degradation methods. It can effectively target and degrade proteins, including proteins that are difficult to identify and bind. Therefore, it has extremely important implications for drug development and the treatment of neurological diseases. At present, the targeted degradation of mutant BTK, mHTT, Tau, EGFR, and other proteins using PROTAC technology is gaining attention. It is expected that corresponding treatment of nervous system diseases can be achieved. This review first focuses on the recent developments in PROTAC technology in terms of protein degradation, drug production, and treatment of central nervous system diseases, and then discusses its limitations. This review will provide a brief overview of the recent application of PROTAC technology in the treatment of central nervous system diseases.
Count time series (e.g., daily deaths) are a very common type of data in environmental health research. The series is generally autocorrelated, while the widely used generalized linear model is based ...on the assumption of independent outcomes. None of the existing methods for modelling parameter-driven count time series can obtain consistent and reliable standard error of parameter estimates, causing potential inflation of type I error rate.
We proposed a new maximum significant ρ correction (MSRC) method that utilizes information of significant autocorrelation coefficient ρ estimate within 5 orders by moment estimation. A Monte Carlo simulation was conducted to evaluate and compare the finite sample performance of the MSRC and classical unbiased correction (UB-corrected) method. We demonstrated a real-data analysis for assessing the effect of drunk driving regulations on the incidence of road traffic injuries (RTIs) using MSRC in Shenzhen, China. Moreover, there is no previous paper assessing the time-varying intervention effect and considering autocorrelation based on daily data of RTIs.
Both methods had a small bias in the regression coefficients. The autocorrelation coefficient estimated by UB-corrected is slightly underestimated at high autocorrelation (≥ 0.6), leading to the inflation of the type I error rate. The new method well controlled the type I error rate when the sample size reached 340. Moreover, the power of MSRC increased with increasing sample size and effect size and decreasing nuisance parameters, and it approached UB-corrected when ρ was small (≤ 0.4), but became more reliable as autocorrelation increased further. The daily data of RTIs exhibited significant autocorrelation after controlling for potential confounding, and therefore the MSRC was preferable to the UB-corrected. The intervention contributed to a decrease in the incidence of RTIs by 8.34% (95% CI, -5.69-20.51%), 45.07% (95% CI, 25.86-59.30%) and 42.94% (95% CI, 9.56-64.00%) at 1, 3 and 5 years after the implementation of the intervention, respectively.
The proposed MSRC method provides a reliable and consistent approach for modelling parameter-driven time series with autocorrelated count data. It offers improved estimation compared to existing methods. The strict drunk driving regulations can reduce the risk of RTIs.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing‐radiation beams. However, the efficacy of radiotherapy is usually limited by tumor ...hypoxia‐associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core–shell nanoparticles based poly(lactic‐co‐glycolic) acid (PLGA) are fabricate, by encapsulating water‐soluble catalase (Cat), an enzyme that can decompose H2O2 to generate O2, inside the inner core, and loading hydrophobic imiquimod (R837), a Toll‐like‐receptor‐7 agonist, within the PLGA shell. The formed PLGA‐R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune‐suppressive tumor microenvironment. The tumor‐associated antigens generated postradiotherapy‐induced immunogenic cell death in the presence of such R837‐loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next‐generation radiotherapy strategy to enable synergistic whole‐body therapeutic responses after local treatment, greatly promising for clinical translation.
Radiotherapy with polylactic‐co‐glycolic acid‐R837@Cat nanoparticles is able to induce immunogenic cell death and generate tumor debris as tumor‐associated antigens, which, with the help of those adjuvant nanoparticles, can induce robust antitumor immune responses. With further combination of checkpoint blockade, such treatment effectively targets distant metastatic tumors with a strong abscopal effect, and offers a long‐term immune memory protective effect afterward.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Flavonoids ubiquitously distribute to the terrestrial plants and chalcone isomerase (CHI)-catalyzed intramolecular and stereospecific cyclization of chalcones is a committed step in the production of ...flavonoids. However, so far the bona fide CHIs are found only in vascular plants, and their origin and evolution remains elusive.
We conducted transcriptomic and/or genomic sequence search, subsequent phylogenetic analysis, and detailed biochemical and genetic characterization to explore the potential existence of CHI proteins in the basal bryophyte liverwort species and the lycophyte Selaginella moellendorffii.
We found that both liverwort and Selaginella species possess canonical CHI-fold proteins that cluster with their corresponding higher plant counterparts. Among them, some members exhibited bona fide CHI activity, which catalyze stereospecific cyclization of both 6′-hydroxychalcone and 6′-deoxychalcone, yielding corresponding 5-hydroxy and 5-deoxyflavanones, resembling the typical type II CHIs currently known to be ‘specific’ for legume plants. Expressing those primitive bona fide CHIs in the Arabidopsis chi mutant restores the seed coat transparent testa phenotype and the accumulation of flavonoids.
These findings, in contrast to our current understanding of the evolution of enzymatic CHIs, suggest that emergence of the bona fide type II CHIs is an ancient evolution event that occurred before the divergence of liverwort lineages.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
BIRC5 is an immune-related gene that inhibits apoptosis and promotes cell proliferation. It is highly expressed in most tumors and leads to poor prognosis in cancer patients. This study aimed to ...analyze the relationship between the expression level of BIRC5 in different tumors and patient prognosis, clinical parameters, and its role in tumor immunity. Genes co-expressed with BIRC5 were analyzed, and functional enrichment analysis was performed. The relationship between BIRC5 expression and the immune and stromal scores of tumors in pan-cancer patients and the infiltration level of 22 tumor-infiltrating lymphocytes (TILs) was analyzed. The correlation of BIRC5 with immune checkpoints was conducted. Functional enrichment analysis showed that genes co-expressed with BIRC5 were significantly associated with the mitotic cell cycle, APC/C-mediated degradation of cell cycle proteins, mitotic metaphase, and anaphase pathways. Besides, the high expression of BIRC5 was significantly correlated with the expression levels of various DNA methyltransferases, indicating that BIRC5 regulates DNA methylation. We also found that BIRC5 was significantly correlated with multiple immune cells infiltrates in a variety of tumors. This study lays the foundation for future research on how BIRC5 modulates tumor immune cells, which may lead to the development of more effective targeted tumor immunotherapies.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•The topology optimization method is firstly employed for bionic heat sinks.•The performance of the heat sinks are studied by numerically and experimentally.•Different optimization goals for ...temperature uniformity can lead to different results.•The optimal heat sinks is superior to the conventional heat sinks in terms of the performance.•The CFD results agree well with the experimental results.
In this paper, topology optimization method is applied to bionic domain, and in order to improve the thermal performance of heat sinks, two topological heat sinks are obtained under two objectives. One objective is minimize the temperature difference and pressure drop, and another is minimize the average temperature and pressure drop. The topological heat sink designed by topology optimization with the minimum temperature difference and the pressure drop as a goal is named as M2, while that designed with the minimum average temperature and the pressure drop as a goal is called M3. The flow and thermal performance of these two topological flow channel heat sinks are investigated numerically. The results show that for Re = 2056.8, the temperature difference of the topological heat sink M2 is reduced by 57.35% compared to conventional spider web heat sink M1, while that of the topological heat sink M3 is reduced by 10.64% compared to M1. In addition, the thermal resistance of the topological heat sinks are smaller than the conventional spider web heat sink. Through analysis, it can be known that M2 has the best comprehensive heat dissipation capacity. In order to verify the correctness of the numerical simulation, M2 is manufactured, and the heat transfer performance of M2 is investigated experimentally. The experimental results of the optimal heat sink agree well with the calculated results.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
