Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression.

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification.

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.

Ultrasonic Control of Neural Activity through Activation of the Mechanosensitive Channel MscL.

Externally controlling the excitation of a neuronal subset through ion channels activation can modulate the firing pattern of an entire neural circuit in vivo. As nanovalves in the cell membrane, ion channels can be opened by light (optogenetics) or ultrasonic (sonogenetics) means. A thoroughly analyzed force sensor is the Escherichia coli mechano sensitive channel of large conductance (MscL). Here we expressed MscL in rat hippocampal neurons in a primary culture and showed that it could be activated by low-pressure ultrasound pulses. The gain-of-function mutation, I92L, sensitized MscL's sonic response, triggering action potentials at a peak negative pressure as low as 0.25 MPa. Further, the I92L MscL reliably elicited individual spikes by timed brief pulses, making excitation programmable. Because MscL opens to tension in the lipid bilayer, requiring no other proteins or ligands, it could be developed into a general noninvasive sonogenetic tool to manipulate the activities of neurons or other cells and potential nanodevices.

[I1363T mutation induces the defects in fast inactivation of human skeletal muscle voltage-gated sodium channel].

OBJECTIVE: To investigate the mechanism of congenital paramyotonia caused by human skeletal muscle voltage-gated sodium channel hNav1.4 mutant I1363T. METHODS: The conservation of the mutant site were detecled by using amino acid sequence alignment; the C-terminal mCherry fusion hNav1.4 was constructed, and the expression and distribution of wild type and hNav1.4 mutant I1363T were determined by confocal microscopy; the steady-state activation, fast inactivation and window current of wild type and hNav1.4 mutant I1363T were examined by whole-cell patch clamp. RESULTS: Alignment of the amino acid sequences revealed that Ile1363 is highly conserved in human sodium channels. There was no significant difference in expression level and distribution between wild type and I1363T. Although no significant differences were observed between I1363T mutant and wild type in the activation upon channel gating, the V0.5 of voltage-dependence of fast inactivation of I1363T mutant[(-59.01±0.26) mV] shifted 9 mV towards depolarization as compared with wild type[(-68.03±0.34) mV], and the slope factor of voltage-dependence curve increased to (5.24±0.23) mV, compared with (4.55±0.21) mV of the wild type. Moreover, I1363T showed the larger window current than that of the wild type. CONCLUSIONS: I1363T causes the defect in fast inactivation of hNav1.4, which may increase the excitability of muscle cells and be responsible for myotonia. The increased window current of I1363T may result in an increase of inward Na+ current, could subsequently inactivate the channels and lead to loss of excitability and paralysis.

N1366S mutation of human skeletal muscle sodium channel causes paramyotonia congenita.

KEY POINTS: Paramyotonia congenita is a hereditary channelopathy caused by missense mutations in the SCN4A gene, which encodes the α subunit of the human skeletal muscle voltage-gated sodium channel NaV1.4. Affected individuals suffered from myotonia and paralysis of muscles, which were aggravated by exposure to cold. We report a three-generation Chinese family with patients presenting paramyotonia congenita and identify a novel N1366S mutation of NaV1.4. Whole-cell electrophysiological recordings of the N1366S channel reveal a gain-of-function change of gating in response to cold. Modelling and molecular dynamic simulation data suggest that an arginine-to-serine substitution at position 1366 increases the distance from N1366 to R1454 and disrupts the hydrogen bond formed between them at low temperature. We demonstrate that N1366S is a disease-causing mutation and that the temperature-sensitive alteration of N1366S channel activity may be responsible for the pronounced paramyotonia congenita symptoms of these patients. ABSTRACT: Paramyotonia congenita is an autosomal dominant skeletal muscle channelopathy caused by missense mutations in SCN4A, the gene encoding the α subunit of the human skeletal muscle voltage-gated sodium channel NaV1.4. We report a three-generation family in which six members present clinical symptoms of paramyotonia congenita characterized by a marked worsening of myotonia by cold and by the presence of clear episodes of paralysis. We identified a novel mutation in SCN4A (Asn1366Ser, N1366S) in all patients in the family but not in healthy relatives or in 500 normal control subjects. Functional analysis of the channel protein expressed in HEK293 cells by whole-cell patch clamp recording revealed that the N1366S mutation led to significant alterations in the gating process of the NaV1.4 channel. The N1366S mutant displayed a cold-induced hyperpolarizing shift in the voltage dependence of activation and a depolarizing shift in fast inactivation, as well as a reduced rate of fast inactivation and accelerated recovery from fast inactivation. In addition, homology modelling and molecular dynamic simulation of N1366S and wild-type NaV1.4 channels indicated that the arginine-to-serine substitution disrupted the hydrogen bond formed between N1366 and R1454. Together, our results suggest that N1366S is a gain-of-function mutation of NaV1.4 at low temperature and the mutation may be responsible for the clinical symptoms of paramyotonia congenita in the affected family and constitute a basis for studies into its pathogenesis.

Mechanosensitive channel MscL gating transitions coupling with constriction point shift.

The mechanosensitive channel of large conductance (MscL) acts as an "emergency release valve" that protects bacterial cells from acute hypoosmotic stress, and it serves as a paradigm for studying the mechanism underlying the transduction of mechanical forces. MscL gating is proposed to initiate with an expansion without opening, followed by subsequent pore opening via a number of intermediate substates, and ends in a full opening. However, the details of gating process are still largely unknown. Using in vivo viability assay, single channel patch clamp recording, cysteine cross-linking, and tryptophan fluorescence quenching approach, we identified and characterized MscL mutants with different occupancies of constriction region in the pore domain. The results demonstrated the shifts of constriction point along the gating pathway towards cytoplasic side from residue G26, though G22, to L19 upon gating, indicating the closed-expanded transitions coupling of the expansion of tightly packed hydrophobic constriction region to conduct the initial ion permeation in response to the membrane tension. Furthermore, these transitions were regulated by the hydrophobic and lipidic interaction with the constricting "hot spots". Our data reveal a new resolution of the transitions from the closed to the opening substate of MscL, providing insights into the gating mechanisms of MscL.

Clinical analysis and functional characterization of KCNQ2-related developmental and epileptic encephalopathy.

Background: Developmental and epileptic encephalopathy (DEE) is a condition characterized by severe seizures and a range of developmental impairments. Pathogenic variants in KCNQ2, encoding for potassium channel subunit, cause KCNQ2-related DEE. This study aimed to examine the relationships between genotype and phenotype in KCNQ2-related DEE. Methods: In total, 12 patients were enrolled in this study for genetic testing, clinical analysis, and developmental evaluation. Pathogenic variants of KCNQ2 were characterized through a whole-cell electrophysiological recording expressed in Chinese hamster ovary (CHO) cells. The expression levels of the KCNQ2 subunit and its localization at the plasma membrane were determined using Western blot analysis. Results: Seizures were detected in all patients. All DEE patients showed evidence of developmental delay. In total, 11 de novo KCNQ2 variants were identified, including 10 missense variants from DEE patients and one truncating variant from a patient with self-limited neonatal epilepsy (SeLNE). All variants were found to be loss of function through analysis of M-currents using patch-clamp recordings. The functional impact of variants on M-current in heteromericKCNQ2/3 channels may be associated with the severity of developmental disorders in DEE. The variants with dominant-negative effects in heteromeric channels may be responsible for the profound developmental phenotype. Conclusion: The mechanism underlying KCNQ2-related DEE involves a reduction of the M-current through dominant-negative effects, and the severity of developmental disorders in DEE may be predicted by the impact of variants on the M-current of heteromericKCNQ2/3 channels.

The structure and properties of lignin isolated from various lignocellulosic biomass by different treatment processes.

The structure and properties of lignin can vary depending on the type of lignocellulosic biomass it comes from and the separation techniques used, and also affects its suitability for different applications. In this work, the structure and properties of lignin isolated from moso bamboo, wheat straw, and poplar wood by different treatment processes were compared. Results show that deep eutectic solvent (DES) extracted lignin exhibits well-preserved structures (including ß-O-4, ß-ß, and ß-5 linkages), a low molecular weight (Mn = 2300-3200 g/mol), and relatively homogeneous lignin fragments (1.93 < PDI < 2.33) compared to dealkaline lignin (DL) and milled wood lignin (MWL). Besides, lignin samples extracted by DES have a regular nanostructure, higher carbon residue content (>40 %), and excellent antioxidant properties (the free radical scavenging index >20). Among the three types of biomass, the structural destruction of lignin in straw is the most obvious, which is due to the degradation of ß-O-4 and ß-ß linkages during DES treatment. These findings can contribute to a better understanding of the structural changes that occur in various treatment processes from different lignocellulosic biomass, and help maximize the targeted development of their applications based on the characteristics of lignin.

Multistage treatment of bamboo powder waste biomass: Highly efficient and selective isolation of lignin components.

Bamboo pulp and papermaking produce a lot of bamboo powder waste, and its resource utilization is of great significance for biomass refining and environmental protection. Here, we propose an integrated approach involving mechanical activation, hydrothermal extraction, and deep eutectic solvents (DESs) multiple delignification for the efficient separation of bamboo powder. Among seven carboxylic acids based DESs, choline chloride (ChCl)-lactic acid (La) DES (1:1) is the most effective, with over 78.0% lignin removal and 88.9% cellulose retained after mechanical-hydrothermal (180 °C, 5 h)-DES (110 °C, 12 h) treatment. Notably, 84.7% of delignification is achieved after three times of ChCl-La DES treatment at 70, 90, and 110 °C respectively. The delignification rate is negatively correlated with the amount of carboxyl group in the DESs. The lower the pKa value, the higher the delignification rate. Additionally, the selectivity for lignin is improved with decreasing solvent polarity. DES treatment effectively degrades the guaiacyl unit lignin fractions and disrupts several ß-aryl-ether bonds (e.g., ß-O-4, ß-ß, and ß-5). Furthermore, DESs exhibit good recyclability, with less than 10% reduction in delignification after three cycles. Theory calculations confirm that ChCl-carboxylic acid DESs could compete with lignin to break hydrogen bonds in lignocellulosic biomass by providing their chloride, hydroxyl, and carboxyl groups. Overall, this study demonstrates the practical significance of multistage treatment for the effective fractionation of biomass into its three components.

Clinical comparison and functional study of the L703P: a recurrent mutation in human SCN4A that causes sodium channel myotonia.

The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.

Hydrophobic Gate of Mechanosensitive Channel of Large Conductance in Lipid Bilayers Revealed by Solid-State NMR Spectroscopy.

The bacterial mechanosensitive channel of large conductance (MscL) functions as a pressure-relief safety valve to prevent cells from lysing during sudden hypo-osmotic shock. The hydrophobic gate of MscL in the closed state forms a barrier to the permeation of ions and water molecules and can be switched to the open state for releasing solutions and ions. Currently, the gate-constituting residues and the functional role of these residues in the hydrophobic gate of MscL remain elusive and controversial. Here, we employ magic angle spinning solid-state nuclear magnetic resonance (ssNMR) techniques and functional assays to investigate the hydrophobic gate of MscL from Methanosarcina acetivorans (Ma-MscL) in lipid bilayers. We obtain chemical shift assignments of ∼70% residues of Ma-MscL and predict its 3D structure. Based on the structural characterization, we identify that the residues I21-T30 in the transmembrane helix 1 constitute the hydrophobic gate by detecting water distributions in the transmembrane pore using ssNMR H/D exchange and water-edited experiments. By using ssNMR structural characterization and functional assays, we reveal that the packing of aromatic rings of F23 in each subunit of Ma-MscL is critical to the hydrophobic gate, and hydrophilic substitutions of the other functionally important residues A22 and G26 modulate channel gating by attenuating hydrophobicity of constriction of F23.

Differential Functional Changes of Nav1.2 Channel Causing SCN2A-Related Epilepsy and Status Epilepticus During Slow Sleep.

Background: Nav1.2 encoded by the SCN2A gene is a brain-expressed voltage-gated sodium channel known to be associated with neurodevelopment disorders ranging from benign familial neonatal infantile seizures (BFIS) to developmental and epileptic encephalopathy (DEE) and autism spectrum disorder. Interestingly, status epilepticus during slow sleep (ESES), which aggravates cognitive impairment, has been found in SCN2A-related epilepsy. However, the functional features and the relationship between SCN2A and ESES have not been researched. Method: We herein investigated the functional consequences of an unpublished de novo V911A and the other two published variants in patients with SCN2A-related disorder and ESES by whole-cell patch-clamp studies in transfected HEK293T cells. Results: The unpublished V911A and published K1933M variants detected in patients with DEE exhibited a profound gain-of-functional (GOF) change. Another published BFIS variant S863F significantly reduced current density as a loss-of-functional (LOF) change. The refractory epilepsy in the patient with V911A was controlled by using the precise treatment of oxcarbazepine (OXC) since the age of 3 months. ESES was found at 18 months during the seizure-free period. We finally chose an aggressive treatment for eliminating ESES by using methylprednisolone combined with levetiracetam and nitrazepam instead of the precise treatment of OXC. Conclusion: Both GOF and LOF variants in the SCN2A gene can lead to ESES among the phenotypes of DEE and BFIS. We should monitor the electroencephalogram regularly in the patients with SCN2A-related epilepsy even during their seizure-free period.

The role of adsorbed oleylamine on gold catalysts during synthesis for highly selective electrocatalytic reduction of CO2 to CO.

The low-coordinated sites of electrocatalysts favour hydrogen evolution, while the edge sites are active for CO2 reduction. Oleylamine is used to stabilize nanoparticles by adsorbing on the low-coordinated sites. The hydrogen evolution reaction was dramatically suppressed and the FECO remained >93% from -0.4 to -0.8 V (vs. RHE) when oleylamine ligands existed on the surface of a gold catalyst. More H+ and electrons were involved in the CO evolution reaction, which changed the rate-limiting step from single-electron transfer to the chemical reaction step. The results establish that the surface-adsorbed surfactants during catalyst synthesis have an important effect on CO2 electrocatalytic reduction.

Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy.

BACKGROUND: To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A-related developmental epileptic encephalopathy (DEE). METHODS: We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole-cell patch-clamp recording. RESULTS: The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast-inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature. CONCLUSION: These findings provided the insights into the phenotype-genotype-funotype relationships of SCN2A-related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.

Non-apoptotic cell death induced by opening the large conductance mechanosensitive channel MscL in hepatocellular carcinoma HepG2 cells.

Most anticancer therapies trigger apoptosis to eliminate malignant cells. However, the majority of malignant cancer cells are resistant to apoptosis due to genetic mutations or heterogeneity. Here, we report that opening the pore of the bacterial large conductance mechanosensitivity channel (MscL) provides a novel approach of inducing non-apoptotic cell death. The gain-of-function mutant V23A-MscL and chemically responsive mutant G26C-MscL can be functionally expressed in hepatocellular carcinoma HepG2 cells. V23A-MscL spontaneously opens, and G26C-MscL also responds to its chemical activator MTSET. Opening of the MscL channel causes increased intracellular Ca2+ concentration and suppressed cell growth and viability. MTSET-activated G26C channels induce necrosis, while V23A-MscL expression leads to cytoplasmic vacuolization cell death in HepG2 cells and suppresses tumor growth in a mouse model. We propose that MscL may act as a nanovalve through which intracellular homeostasis suffers a disruption and results in malignant tumor cell damage, leading to a new strategy for cancer therapy.

Insight into the synergism between MnO2 and acid sites over Mn-SiO2@TiO2 nano-cups for low-temperature selective catalytic reduction of NO with NH3.

The rational synthesis of low-temperature catalysts with high catalytic activity and stability is highly desirable for the selective catalytic reduction of NO with NH3. Here we synthesized a Mn-SiO2/TiO2 nano-cup catalyst via the coating of the mesoporous TiO2 layers on SiO2 spheres and subsequent inlay of MnO2 nanoparticles in the narrow annulus. This catalyst exhibited superior catalytic SCR activities and stability for low-temperature selective catalytic reduction of NO with NH3, with NO conversion of ∼100%, N2 selectivity above 90% at a temperature ∼140 °C. The characterization results, such as BET, XRD, H2-TPR, O2/NH3-TPD and XPS, indicated that this nano-cup structure catalyst possesses high concentration and dispersion of Mn4+ active species, strong chemisorbed O- or O2 2- species and highly stable MnO X active components over the annular structures of the TiO2 shell and SiO2 sphere, and thus enhanced the low-temperature SCR performance.

Transmembrane TM3b of Mechanosensitive Channel MscS Interacts With Cytoplasmic Domain Cyto-Helix.

The mechanosensitive channel MscS functions as an osmolyte emergency release-valve in the event of a sudden decrease in external environmental osmolarity. MscS has served as a paradigm for studying how channel proteins detect and respond to mechanical stimuli. However, the inter-domain interactions and structural rearrangements that occur in the MscS gating process remain largely unknown. Here, we determined the interactions between the transmembrane domain and cytoplasmic domain of MscS. Using in vivo cellular viability, single-channel electrophysiological recording, and cysteine disulfide trapping, we demonstrated that N117 of the TM3b helix and N167 of the Cyto-helix are critical residues that function at the TM3b-Cyto helix interface. In vivo downshock assays showed that double cysteine substitution at N117 and N167 failed to rescue the osmotic-lysis phenotype of cells in acute osmotic downshock. Single-channel recordings demonstrated that cysteine cross-linking of N117C and N167C led to a non-conductive channel. Consistently, coordination of the histidines of N117H and N167H caused a decrease in channel gating. Moreover, cross-linked N117 and N167 altered the gating of the severe gain-of-function mutant L109S. Our results demonstrate that N117-N167 interactions stabilize the inactivation state by an association of TM3b segments with ß-domains of the cytoplasmic region, providing further insights into the gating mechanism of the MscS channel.

Brv1 Is Required for Drosophila Larvae to Sense Gentle Touch.

How we sense touch is fundamental for many physiological processes. However, the underlying mechanism and molecular identity for touch sensation are largely unknown. Here, we report on defective gentle-touch behavioral responses in brv1 loss-of-function Drosophila larvae. RNAi and Ca2+ imaging confirmed the involvement of Brv1 in sensing touch and demonstrated that Brv1 mediates the mechanotransduction of class III dendritic arborization neurons. Electrophysiological recordings further revealed that the expression of Brv1 protein in HEK293T cells gives rise to stretch-activated cation channels. Purified Brv1 protein reconstituted into liposomes were found to sense stretch stimuli. In addition, co-expression studies suggested that Brv1 amplifies the response of mechanosensitive ion channel NOMPC (no mechanoreceptor potential C) to touch stimuli. Altogether, these findings demonstrate a molecular entity that mediates the gentle-touch response in Drosophila larvae, providing insights into the molecular mechanisms of touch sensation.

2D-QSPR/DFT studies of aryl-substituted PNP-Cr-based catalyst systems for highly selective ethylene oligomerization.

1-Hexene and 1-octene are important comonomers for the synthesis of high performance polyolefins. Recently, various N-substituted Cr-bis(diphenylphosphino)amine (PNP-Cr) catalysts show the potential as excellent candidates for highly selective ethylene trimerization/tetramerization. In this work, a series of aryl-substituted PNP-Cr catalysts were studied by two-dimensional quantitative structure-property relationship (QSPR) method based on density functional theory (DFT) calculations. The heuristic method (HM) and best multi-linear regression (BMLR) were used to establish the best linear regression models to describe the relationship between selectivities and catalyst structures. Both Cr(I) and Cr(II) active site models for ethylene trimerization/tetramerization were considered. It was found that 1) the relativity and stability of the models were increased by using self-defined descriptors based on DFT calculations; 2) Cr(I)/Cr(III) centers were the most plausible active sites for ethylene trimerization, while Cr(II)/Cr(IV) active sites were most possibly responsible for ethylene tetramerization; and 3) the skeleton structures of the PNP-Cr system with good complanation and symmetry were crucial for achieving excellent catalytic selectivity of 1-octene, while the PNP-Cr backbone with a large steric effect on N atom would benefit ethylene trimerization. Six new PNP ligands with high selectivity toward ethylene trimerization/tetramerization were predicted based on descriptor analysis and the best linear regression models providing a good basis for further development of novel catalyst systems with better performance.