Antipsychotic sensitization and tolerance refer to the increased and decreased drug effects due to past drug use, respectively. Both effects reflect the long-term impacts of antipsychotic treatment ...on the brain and result from the brain’s adaptive response to the foreign property of the drug. In this review, clinical evidence of the behavioral aspect of antipsychotic sensitization and tolerance is selectively reviewed, followed by an overview of preclinical literature that examines these behavioral characteristics and the related pharmacological and nonpharmacological factors. Next, recent work on the developmental impacts of adolescent antipsychotic sensitization and tolerance is presented and recent research that delineates the neurobiological mechanisms of antipsychotic sensitization and tolerance is summarized. A theoretical framework based on “drug learning and memory” principles is proposed to account for the phenomena of antipsychotic sensitization and tolerance. It is maintained that antipsychotic sensitization and tolerance follow basic principles of learning or acquisition (“induction”) and memory (“expression”). The induction and expression of both effects reflect the consequences of associative and nonassociative processing and are strongly influenced by various pharmacological, environmental, and behavioral factors. Drug-induced neuroplasticity, such as functional changes of striatal dopamine D2 and prefrontal serotonin (5-HT)2A receptors and their mediated signaling pathways, in principle, is responsible for antipsychotic sensitization and tolerance. Understanding the behavioral characteristics and neurobiological underpinnings of antipsychotic sensitization and tolerance has greatly enhanced our understanding of mechanisms of antipsychotic action, and may have important implications for future drug discovery and clinical practice.
The vertebrate adaptive immune system has well defined functions in maintaining tolerance to self‐tissues. Suppression of autoreactive T cells is dependent on the regulatory cytokine transforming ...growth factor‐β (TGF‐β) and regulatory T (Treg) cells, a distinct T cell lineage specified by the transcription factor Foxp3. Although TGF‐β promotes thymic Treg (tTreg) cell development by repressing T cell clonal deletion and peripheral Treg cell differentiation by inducing Foxp3 expression, a recent study shows that TGF‐β suppresses autoreactive T cells independent of Foxp3+ Treg cells. These findings imply that as an ancestral growth factor family member, TGF‐β may have been co‐opted as a T cell‐intrinsic mechanism of self‐tolerance control to assist the evolutionary transition of vertebrate adaptive immunity. Later, perhaps in placental mammals upon their acquisition of a TGF‐β regulatory element in the Foxp3 locus, the TGF‐β pathway is further engaged to induce peripheral Treg cell differentiation and expand the scope of T cell tolerance control to innocuous foreign antigens.
In ancestral vertebrates, TGF‐β signaling might be co‐opted to suppress autoreactive T cells (Taut). In non‐Eutherian jawed vertebrates, TGF‐β further supports thymic Treg cells (tTreg) development to repress Taut. In Eutherians, TGF‐β induces peripheral Treg cells (pTreg) differentiation to suppress allogenic T cells (Tallo) and commensal‐reactive T cells (Tcom).
One long‐standing issue in directed C−H functionalization is that either nitrogen or sulfur atoms present in heterocyclic substrates may bind preferentially to a transition‐metal catalyst rather than ...to the desired directing group. This competitive binding has largely hindered the application of C−H functionalization in late‐stage heterocycle drug discovery. Reported here is the use of an oxazoline‐based directing group capable of overriding the poisoning effect of a wide range of heterocycle substrates. The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper‐mediated C−H amination, hydroxylation, thiolation, arylation, and trifluoromethylation.
Override switch: A bidentate oxazoline‐based directing group (DG) allows copper‐mediated C−H amination, hydroxylation, thiolation, arylation, alkynylation, and trifluoromethylation. The directing group overrides the directing/poisoning effects of heterocyclic moieties.
We for the first time report the discovery of a series of highly efficient electrocatalysts,
i.e.
, transition metals anchored on N/O-codoped graphene, for nitrogen fixation
via
high-throughput ...screening combined with first-principles calculations. The catalytic performance can be effectively modulated by coordination engineering. Among 10 representative electrocatalysts (
i.e.
, V-N
4
@Gra, Tc-N
4
@Gra, V-O
1
N
3
@Gra, V-O
2
N
2
α
@Gra, V-O
2
N
2
β
@Gra, V-O
2
N
2
γ
@Gra, V-O
3
N
1
@Gra, Mo-O
3
N
1
@Gra, V-O
4
@Gra and Ru-O
4
@Gra), V-O
2
N
2
γ
@Gra possesses the lowest Δ
G
max
of 0.38 eV. Molecular dynamics simulation results indicate that all the predicted TM-O
x
N
y
@Gra (
x
+
y
= 4) have high stabilities and can be used as electrocatalysts under practical reaction conditions. The more charge on the adsorbed N
2
, the longer the N-N bond length and the greater the activation of N
2
. Interestingly, the linear combination of adsorption energy of different intermediates,
i.e.
, Δ
E
ads
(*N
2
− *N) + (*NNH − *N) + (*NH
2
− *N), can be used as a good descriptor to unveil the structure-property relations, and V-O
2
N
2
γ
@Gra possessed moderate adsorption energy, so it exhibits the highest catalytic activity for the electrocatalytic nitrogen reduction reaction (eNRR) among all investigated materials. Overall, through coordination engineering, the coordination environment and electronic structure of the active centers can be modulated properly, thereby regulating the catalytic activity effectively. We expect that our work will provide new insights into the rational design of electrocatalysts and effective modulation of the catalytic performance
via
coordination engineering. The present study opens up an important route for the development of efficient catalysts for the eNRR, and will inspire the follow-up experimental and theoretical efforts in this direction.
Several efficient catalysts for eNRR from a large family of transition metal anchored N/O-codoped graphene were uncovered
via
coordination engineering, high-throughput screening and first-principles calculations.
Au‐incorporation is a promising strategy to retard composition‐loss in Pt‐based catalyst. However, the unclear mechanism limits guided catalyst design and the performance optimization. Here, direct ...evidence is provided to validate the outward diffusion of Au atoms in Au‐core/Pt‐based‐shell structures. A Co interlayer is built between the Au‐core and PtCo‐based shell to exclude the possibility of atomic diffusion caused by interfacial alloying. In conjunction with the improved catalytic durability of the Au‐core@Pt‐based‐shell structure, it is reasonable to conclude that it is the subsurface segregated Au atoms rather than interfacial interaction that boosts the catalytic durability of Au‐core/Pt‐based‐shell structured catalysts towards oxygen reduction reaction. More importantly, by constructing Au‐core@Co‐interlayer@PtCoAu‐shell multilayer structure, the specific (1.730 mA cm−2) and mass (0.692 A mg−1Pt) activities are enhanced 7‐ and 4‐ fold relative to the commercial Pt/C. After 10 000 cycles of accelerated durability test, the mass activity loss for the multilayered catalyst is as low as 6.14% while the loss exceeds 35% for the commercial Pt/C catalyst. The improved catalytic performance of the Au@Co@PtCoAu multilayer structure can be ascribed to the finely modulated electronic structure and the compensated composition loss owing to the delicate structure and composition profile design.
PtAuCo‐shell‐based structures are achieved either by growth PtCo on Au nanoparticles or on Au@Co core–shell structures, demonstrating the outward segregation behavior of Au. The incorporation of Au improves the catalytic durability towards oxygen reduction reaction. The composition distribution profile illustrates that it is the subsurface segregated Au atoms rather than interfacial interaction boosts the catalytic durability of Au‐core/Pt‐based‐shell structures.
A Pd-catalyzed highly enantioselective three-component coupling of 1,3-dienes with aryl iodines and sodium dialkyl malonates has been successfully established by using a H8-BINOL-based ...phosphoramidite ligand. This reaction proceeded via a Pd-catalyzed cascade arylation and asymmetric allylic alkylation reaction, providing an efficient strategy for the enantioselective 1,2-difunctionalization of 1,3-dienes.
Background：Pelvic lymph node metastasis （LNM） is an important prognostic factor in cervical cancer.Cervical squamous cell carcinoma accounts for approximately 75-80% of all cervical cancers.Analyses ...of the effects of the number of positive lymph nodes （LNs）,unilateral vcrsus bilateral pelvic LNM and a single group versus multiple groups of pelvic LNM on survival and recurrence of cervical squamous cell carcinoma are still lacking.The study aimed to analyze the effects of the number of positive pelvic LNs and a single group versus multiple groups of pelvic LNM on survival and recurrence.Methods：We performed a retrospective review of 296 patients diagnosed with Stage ⅠA-ⅡB cervical squamous cell carcinoma who received extensive/sub-extensive hysterectomy with pelvic lymphadenectomy/pelvic LN sampling at Peking University People＇s Hospital from November 2004 to July 2013.Ten clinicopathological variables were evaluated as risk factors for pelvic LNM：Age at diagnosis,gravidity,clinical stage,histological grade,tumor diameter,lymph-vascular space involvement （LVSI）,depth of cervical stromal invasion,uterine invasion,parametrial invasion,and neoadjuvant chemotherapy.Results：The incidence of pelvic LNM was 20.27% （60/296 cases）.Pelvic LNM （P =0.00） was significantly correlated with recurrence.Pelvic LNM （P =0.00）,the number of positive pelvic LNs （P =0.04） and a single group versus multiple groups of pelvic LNM （P =0.03）had a significant influence on survival.Multivariate analysis revealed that LVSI （P =0.00）,depth of cervical stromal invasion （P =0.00）and parametrial invasion （P =0.03） were independently associated with pelvic LNM.Conclusions：Patients with pelvic LNM had a higher recurrence rate and poor survival outcomes.Furthermore,more than 2 positive pelvic LNs and multiple groups of pelvic LNM appeared to identify patients with worse survival outcomes in node-positive ⅠA-ⅡB cervical squamous cell carcinoma.LVSI,parametrial invasion,and depth of cervical stromal invasion were identified as independent clinicopathological risk factors for pelvic LNM.
Harvesting the narrow bandgap excitons of charge‐transfer (CT) complexes for the achievement of near‐infrared (NIR) emission has attracted intensive attention for its fundamental importance and ...practical application. Herein, the triphenylene (TP)‐2,3,5,6‐tetrafluoro‐7,7,8,8‐tetracyanoquinodimethane (F4TCNQ) CT organic complex is designed and fabricated via the supramolecular self‐assembly process, which demonstrates the NIR emission with a maximum peak of 770 nm and a photoluminescence quantum yield (PLQY) of 5.4%. The segregated stacking mode of TP‐F4TCNQ CT complex based on the multiple types of intermolecular interaction has a low CT degree of 0.00103 and a small counter pitch angle of 40° between F4TCNQ and TP molecules, which breaks the forbidden electronic transitions of CT state, resulting in the effective NIR emission. Acting as the promising candidates for the active optical waveguide in the NIR region beyond 760 nm, the self‐assembled TP‐F4TCNQ single‐crystalline organic microwires display an ultralow optical‐loss coefficient of 0.060 dB µm−1. This work holds considerable insights for the exploration of novel NIR‐emissive organic materials via an universal “cocrystal engineering” strategy.
Through changing mixed stacking into segregated stacking mode, triphenylene (TP)‐2,3,5,6‐tetrafluoro‐7,7,8,8‐tetracyanoquinodimethane (F4TCNQ) charge‐transfer (CT) complex demonstrates a low CT degree and a small counter pitch angle between TP and F4TCNQ molecules, benefiting for breaking the forbidden electronic transitions of CT state for realizing the near‐infrared emission with a maximum peak of 770 nm and a photoluminescence quantum yield of 5.4%.
Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes. The evolutionarily conserved GATOR complex regulates ...mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects. Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy, recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR- and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment.
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