HighFold: accurately predicting structures of cyclic peptides and complexes with head-to-tail and disulfide bridge constraints.

In recent years, cyclic peptides have emerged as a promising therapeutic modality due to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes is crucial for unlocking invaluable insights about protein target-cyclic peptide interaction, which can facilitate the development of novel-related drugs. However, conducting experimental observations is time-consuming and expensive. Computer-aided drug design methods are not practical enough in real-world applications. To tackles this challenge, we introduce HighFold, an AlphaFold-derived model in this study. By integrating specific details about the head-to-tail circle and disulfide bridge structures, the HighFold model can accurately predict the structures of cyclic peptides and their complexes. Our model demonstrates superior predictive performance compared to other existing approaches, representing a significant advancement in structure-activity research. The HighFold model is openly accessible at https://github.com/hongliangduan/HighFold.

LncRNADisease v3.0: an updated database of long non-coding RNA-associated diseases.

Systematic integration of lncRNA-disease associations is of great importance for further understanding their underlying molecular mechanisms and exploring lncRNA-based biomarkers and therapeutics. The database of long non-coding RNA-associated diseases (LncRNADisease) is designed for the above purpose. Here, an updated version (LncRNADisease v3.0) has curated comprehensive lncRNA (including circRNA) and disease associations from the burgeoning literatures. LncRNADisease v3.0 exhibits an over 2-fold increase in experimentally supported associations, with a total of 25440 entries, compared to the last version. Besides, each lncRNA-disease pair is assigned a confidence score based on experimental evidence. Moreover, all associations between lncRNAs/circRNAs and diseases are classified into general associations and causal associations, representing whether lncRNAs or circRNAs can directly lead to the development or progression of corresponding diseases, with 15721 and 9719 entries, respectively. In a case study, we used the data of LncRNADisease v3.0 to calculate the phenotypic similarity between human and mouse lncRNAs. This database will continue to serve as a valuable resource for potential clinical applications related to lncRNAs and circRNAs. LncRNADisease v3.0 is freely available at http://www.rnanut.net/lncrnadisease.

Simultaneously Regulated Highly Polarized and Long-Lived Valley Excitons in WSe2/GaN Heterostructures.

Interlayer excitons, with prolonged lifetimes and tunability, hold potential for advanced optoelectronics. Previous research on the interlayer excitons has been dominated by two-dimensional heterostructures. Here, we construct WSe2/GaN composite heterostructures, in which the doping concentration of GaN and the twist angle of bilayer WSe2 are employed as two ingredients for the manipulation of exciton behaviors and polarizations. The exciton energies in monolayer WSe2/GaN can be regulated continuously by the doping levels of the GaN substrate, and a remarkable increase in the valley polarizations is achieved. Especially in a heterostructure with 4°-twisted bilayer WSe2, a maximum polarization of 38.9% with a long lifetime is achieved for the interlayer exciton. Theoretical calculations reveal that the large polarization and long lifetime are attributed to the high exciton binding energy and large spin flipping energy during depolarization in bilayer WSe2/GaN. This work introduces a distinctive member of the interlayer exciton with a high degree of polarization and a long lifetime.

Manipulations of Electronic and Spin States in Co-Quantum Dot/WS2 Heterostructure on a Metal-Dielectric Composite Substrate by Controlling Interfacial Carriers.

Charge and spin are two intrinsic attributes of carriers governing almost all of the physical processes and operation principles in materials. Here, we demonstrate the manipulation of electronic and spin states in designed Co-quantum dot/WS2 (Co-QDs/WS2) heterostructures by employing a metal-dielectric composite substrate and via scanning tunneling microscope. By repeatedly scanning under a unipolar bias, switching the bias polarity, or applying a pulse through nonmagnetic or magnetic tips, the Co-QDs morphologies exhibit a regular and reproducible transformation between bright and dark dots. First-principles calculations reveal that these tunable characters are attributed to the variation of density of states and the transition of magnetic anisotropy energy induced by carrier accumulation. It also suggests that the metal-dielectric composite substrate is successful in creating the interfacial potential for carrier accumulation and realizes the electrically controllable modulations. These results will promote the exploration of electron-matter interactions in quantum systems and provide an innovative way to facilitate the development of spintronics.

Regulation mechanism and bioactivity characteristic of surfactin homologues with C14 and C15 fatty acid chains.

BACKGROUND: Surfactin, a green lipopeptide bio-surfactant, exhibits excellent surface, hemolytic, antibacterial, and emulsifying activities. However, a lack of clear understanding of the synthesis regulation mechanism of surfactin homologue components has hindered the customized production of surfactin products with different biological activities. RESULTS: In this study, exogenous valine and 2-methylbutyric acid supplementation significantly facilitated the production of C14-C15 surfactin proportions (up to 75% or more), with a positive correlation between the homologue proportion and fortified concentration. Subsequently, the branched-chain amino acid degradation pathway and the glutamate synthesis pathway are identified as critical pathways in regulating C14-C15 surfactin synthesis by transcriptome analysis. Overexpression of genes bkdAB and glnA resulted in a 1.4-fold and 1.3-fold increase in C14 surfactin, respectively. Finally, the C14-rich surfactin was observed to significantly enhance emulsification activity, achieving an EI24 exceeding 60% against hexadecane, while simultaneously reducing hemolytic activity. Conversely, the C15-rich surfactin demonstrated an increase in both hemolytic and antibacterial activities. CONCLUSION: This study presents the first evidence of a potential connection between surfactin homologue synthesis and the conversion of glutamate and glutamine, providing a theoretical basis for targeting the synthesis regulation and structure-activity relationships of surfactin and other lipopeptide compounds.

Metabolomics-derived biomarkers for biosafety assessment of Gd-based nanoparticle magnetic resonance imaging contrast agents.

With the rapid development of nanotechnology and biomedicine, numerous gadolinium (Gd)-based nanoparticle MRI contrast agents have been widely investigated. Due to the unique physicochemical properties of nanoparticles and the complexity of biological systems, the biosafety of Gd-based nanoparticle MRI contrast agents has been paid more and more attention. Herein, for the first time, we employed an ultra-high performance liquid chromatography-electrospray ionization quadrupole time-of-flight/mass spectrometry (UPLC-ESI-QTOF/MS)-based metabolomics approach to investigate the potential toxicity of Gd-based nanoparticle MRI contrast agents. In this work, NaGdF4 and PEG-NaGdF4 nanoparticles were successfully constructed and selected as the representative Gd-based nanoparticle MRI contrast agents for the metabolomics analysis. Based on the results of metabolomics, more metabolic biomarkers and pathways were identified in the NaGdF4 group than those in the PEG-NaGdF4 group. Careful analysis of these metabolic biomarkers and pathways suggested that NaGdF4 nanoparticles induced disturbance of pyrimidine and purine metabolism, inflammatory response, and kidney injury to a certain extent compared with PEG-NaGdF4 nanoparticles. These results indicated that Gd-based nanoparticle contrast agents modified with PEG had better biosafety. Additionally, it was demonstrated that the discovery of characteristic metabolomics biomarkers induced by nanoparticles would provide a new approach for biosafety assessment and stimulate the development of nanomedicine.

Exploration of rich-club reorganization in facial synkinesis: insights from structural and functional brain network analysis.

Facial palsy therapies based on cortical plasticity are in development, but facial synkinesis progress is limited. Studying neural plasticity characteristics, especially network organization and its constitutive elements (nodes/edges), is the key to overcome the bottleneck. We studied 55 participants (33 facial synkinesis patients, 22 healthy controls) with clinical assessments, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI). We analyzed rich-club organization and metrics of structural brain networks (rich-club coefficients, strength, degree, density, and efficiency). Functional brain network metrics, including functional connectivity and its coupling with the structural network, were also computed. Patients displayed reduced strength and density of rich-club nodes and edges, as well as decreased global efficiency. All nodes exhibited decreased nodal efficiency in patients. Patients had significantly increased functional connectivity and decreased structural-functional coupling strength in rich-club nodes, rich-club edges, and feeder edges. Our study indicates that facial synkinesis patients have weakened structural connections but enhanced functional transmission from rich-club nodes. The loss of connections and efficiency in structural network may trigger compensatory increases in functional connectivity of rich-club nodes. Two potential biomarkers, rich-club edge density and structural-functional coupling strength, may serve as indicators of disease outcome. These findings provide valuable insights into synkinesis mechanisms and offer potential targets for cortical intervention.

Integrative metagenomics, volatilomics and chemometrics for deciphering the microbial structure and core metabolic network during Chinese rice wine (Huangjiu) fermentation in different regions.

Huangjiu is a spontaneously fermented alcoholic beverage, that undergoes intricate microbial compositional changes. This study aimed to unravel the flavor and quality formation mechanisms based on the microbial metabolism of Huangjiu. Here, metagenome techniques, chemometrics analysis, and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) metabolomics combined with microbial metabolic network were employed to investigate the distinctions and relationship between the microbial profiles and the quality characteristics, flavor metabolites, functional metabolic patterns of Huangjiu across three regions. Significant variations (P < 0.05) were observed in metabolic rate of physicochemical parameters and biogenic amine concentration among three regions. 8 aroma compounds (phenethyl acetate, phenylethyl alcohol, isobutyl alcohol, ethyl octanoate, ethyl acetate, ethyl hexanoate, isoamyl alcohol, and diethyl succinate) out of 448 volatile compounds were identified as the regional chemical markers. 25 dominant microbial genera were observed through metagenomic analysis, and 13 species were confirmed as microbial markers in three regions. A metabolic network analysis revealed that Saccharomycetales (Saccharomyces), Lactobacillales (Lactobacillus, Weissella, and Leuconostoc), and Eurotiales (Aspergillus) were the predominant populations responsible for substrate, flavor (mainly esters and phenylethyl alcohol) metabolism, Lactobacillales and Enterobacterales were closely linked with biogenic amine. These findings provide scientific evidence for regional microbial contributions to geographical characteristics of Huangjiu, and perspectives for optimizing microbial function to promote Huangjiu quality.

High-resolution bin-based linkage mapping uncovers the genetic architecture and heterosis-related loci of plant height in indica-japonica derived populations.

Plant height (PH) is an important trait affecting the plant architecture, seed yield, and harvest index. However, the molecular mechanisms underlying PH heterosis remain unclear. In addition, useful PH-related genes must be urgently identified to facilitate ideal plant architecture breeding in rice (Oryza sativa L.). In the present study, to explore rice quantitative trait loci (QTLs) and heterosis-related loci of PH in rice, we developed a high-generation (>F15 ) population of 272 recombinant inbred lines (RIL) from a cross of two elite varieties, Luohui 9 (indica/xian) × RPY geng (japonica/geng), and two testcross hybrid populations derived from the crosses of RILs and two cytoplasmic male sterile lines (YTA [indica] and Z7A [japonica]). Using deep resequencing data, a high-density genetic map containing 4758 bin markers was constructed, with a total map distance of 2356.41 cM. Finally, 31 PH-related QTLs for different PH component lengths or tiller numbers across five seasons were identified. Two major environment-specific PH QTLs were stably detected in Hainan (qPH-3.1) or Hubei (qPH-5.1), which have undergone significant functional alterations in rice with changes in geographical environment. Based on comparative genomics, gene function annotation, homolog identification, and existing literature (pioneering studies), candidate genes for multiple QTLs were fine-mapped, and the candidate genes qPH-3.1 and qPH-5.1 for PH were further validated using CRISPR-Cas9 gene editing. Specifically, qPH-3.1 was characterized as a pleiotropic gene, and the qPH-3.1 knockout line showed reduced PH, delayed heading, a decreased seed setting rate, and increased tiller numbers. Importantly, 10 PH heterosis-related QTLs were identified in the testcross populations, and a better-parent heterosis locus (qBPH-5.2) completely covered qPH-5.1. Furthermore, the cross results of fixed-genotype RILs verified the dominant effects of qPH-3.1 and qPH-5.1. Together, these findings further our understanding of the genetic mechanisms of PH and offer multiple highly reliable gene targets for breeding rice varieties with ideal architecture and high yield potential in the immediate future.

Chloroplast inner envelope protein FtsH11 is involved in the adjustment of assembly of chloroplast ATP synthase under heat stress.

The maintenance of a proton gradient across the thylakoid membrane is an integral aspect of photosynthesis that is mainly established by the splitting of water molecules in photosystem II and plastoquinol oxidation at the cytochrome complex, and it is necessary for the generation of ATP in the last step of photophosphorylation. Although environmental stresses, such as high temperatures, are known to disrupt this fundamental process, only a few studies have explored the molecular mechanisms underlying proton gradient regulation during stress. The present study identified a heat-sensitive mutant that displays aberrant photosynthesis at high temperatures. This mutation was mapped to AtFtsH11, which encodes an ATP-dependent AAA-family metalloprotease. We showed that AtFtsH11 localizes to the chloroplast inner envelope membrane and is capable of degrading the ATP synthase assembly factor BFA3 under heat stress. We posit that this function limits the amount of ATP synthase integrated into the thylakoid membrane to regulate proton efflux from the lumen to the stroma. Our data also suggest that AtFtsH11 is critical in stabilizing photosystem II and cytochrome complexes at high temperatures, and additional studies can further elucidate the specific molecular functions of this critical regulator of photosynthetic thermotolerance.

Ecological succession and functional characteristics of lactic acid bacteria in traditional fermented foods.

Fermented foods are important parts of traditional food culture with a long history worldwide. Abundant nutritional materials and open fermentation contribute to the diversity of microorganisms, resulting in unique product quality and flavor. Lactic acid bacteria (LAB), as important part of traditional fermented foods, play a decisive role in the quality and safety of fermented foods. Reproduction and metabolic of microorganisms drive the food fermentation, and microbial interaction plays a major role in the fermentation process. Nowadays, LAB have attracted considerable interest due to their potentialities to add functional properties to certain foods or as supplements along with the research of gut microbiome. This review focuses on the characteristics of diversity and variability of LAB in traditional fermented foods, and describes the principal mechanisms involved in the flavor formation dominated by LAB. Moreover, microbial interactions and their mechanisms in fermented foods are presented. They provide a theoretical basis for exploiting LAB in fermented foods and improving the quality of traditional fermented foods. The traditional fermented food industry should face the challenge of equipment automation, green manufacturing, and quality control and safety in the production.

Study of Nonlinear Excitation Circuits for Fluxgate Magnetometer.

This paper presents the common methods and corresponding drawbacks concerning nonlinear analysis of fluxgate excitation circuits and emphasizes the importance of nonlinear analysis for these circuits. With regard to the nonlinearity of the excitation circuit, this paper proposes the use of the core-measured hysteresis curve for mathematical analysis and the use of a nonlinear model that considers the coupling effect of the core and winding and influence of the historical magnetic field on the core for simulation analysis. The feasibility of mathematical calculations and simulation for the nonlinear study of fluxgate excitation circuit is verified via experiments. The results demonstrate that, in this regard, the simulation is four times better than a mathematical calculation. The simulation and experimental results of the excitation current and voltage waveforms under different excitation circuit parameters and structures are essentially consistent, with a difference in current of no more than 1 mA, thereby verifying the effectiveness of the nonlinear excitation analysis method.

Genome-Wide Identification and Evolution Analysis of the CYP76 Subfamily in Rice (Oryza sativa).

The CYP76 subfamily, a member of the CYP superfamily, plays crucial roles in the biosynthesis of phytohormones in plants, involving biosynthesis of secondary metabolites, hormone signaling, and response to environmental stresses. Here, we conducted a genome-wide analysis of the CYP76 subfamily in seven AA genome species: Oryza sativa ssp. japonica, Oryza sativa ssp. indica, Oryza rufipogon, Oryza glaberrima, Oryza meridionalis, Oryza barthii, and Oryza glumaepatula. These were identified and classified into three groups, and it was found that Group 1 contained the largest number of members. Analysis of cis-acting elements revealed a large number of elements related to jasmonic acid and light response. The gene duplication analysis revealed that the CYP76 subfamily expanded mainly in SD/WGD and tandem forms and underwent strong purifying selection during evolution. Expression pattern analysis of OsCYP76s in various developmental stages revealed that the majority of OsCYP76s exhibit relatively restricted expression patterns in leaves and roots. We further analyzed the expression of CYP76s in O. sativa, japonica, and O. sativa, indica under cold, flooding, drought, and salt abiotic stresses by qRT-PCR. We found that OsCYP76-11 showed a huge increase in relative expression after drought and salt stresses. After flooding stress, OsiCYP76-4 showed a greater increase in expression compared to other genes. CYP76 in japonica and indica showed different response patterns to the same abiotic stresses, revealing functional divergence in the gene family during evolution; these may be the key genes responsible for the differences in tolerance to indica japonica. Our results provide valuable insights into the functional diversity and evolutionary history of the CYP76 subfamily and pave the way for the development of new strategies for improving stress tolerance and agronomic traits in rice.

A novel strategy for preparation of rice bran protein oleogels based on high internal phase emulsion template.

BACKGROUND: Oleogels have been extensively explored as fat substitutes with no trans fatty acids and low saturated fatty acids in recent years as a result of increased health problems found to be related to the intake of trans and saturated fatty acids. RESULTS: Herein, high internal phase emulsion (HIPE) stabilized by rice bran protein (RBP) was prepared and further utilized as a template for preparation of RBP oleogels. RBP HIPE with the strongest rheological properties was obtained at pH 5.0 as a result of appropriate structural deformation, surface charge and a high three-phase contact angle at this pH. However, RBP oleogels prepared at pH 9.0 exhibited the highest yield stress after drying process. At this pH, RBP showed higher resistance to deformation caused by water evaporation. This highlighted the importance of structural stability of protein network on rheological properties of the resultant oleogels. Furthermore, with an increase in drying temperature, RBP oleogels exhibited higher yield stress and gel strength because water was better removed as a result of an enhanced capability to overcome the capillary pressure of emulsion. CONCLUSION: The present study further revealed the structure-activity relationship between protein, HIPE and oleogel, and also provided theoretical support for the development of protein-based oleogel. © 2023 Society of Chemical Industry.

Atomic Molybdenum for Synthesis of Ammonia with 50% Faradic Efficiency.

The electrochemical dinitrogen (N2 ) reduction reaction (NRR) under ambient conditions has gained significant interest as an environmentally friendly alternative to the traditional Haber-Bosch process for the synthesis of ammonia (NH3 ). However, up to now, most of the reported NRR electrocatalysts with satisfactory catalytic activities have been hindered by the large overpotential in N2 activation. The preparation of highly efficient Mo-based NRR electrocatalyst in acidic electrolytes under ambient conditions is demonstrated here, consisting of stabilized single Mo atoms anchored on holey nitrogen-doped graphene synthesized through a convenient potassium-salt-assisted activation method. At -0.05 V versus a reversible hydrogen electrode (RHE), an electrode consisting of the resultant electrocatalyst immobilized on carbon fiber paper can attain an exceptional Faradaic efficiency of 50.2% and a NH3 yield rate of 3.6 µg h-1 mgcat-1 with low overpotentials. Density functional theory calculations further unveil that compared to the original graphene without holes, the edge coordinated Mo atoms and the existence of vacancies on holey graphene lower the overpotential of N2 reduction, thereby promoting the NRR catalytic activity. This work could provide new guidelines for future designs in single-atom catalysis that would be beneficial to ambient N2 fixation, and replacement of classical synthesis processes that are very energy-intensive.

Changing epidemiology of hepatocellular carcinoma in Asia.

Liver cancer is the fifth most common cancer and the second leading cause of malignant death in Asia, and Asia reports 72.5% of the world's cases in 2020. As the most common histological type, hepatocellular carcinoma (HCC) accounts for the majority of incidence and mortality of liver cancer cases. This review presents the changing epidemiology of HCC in Asian countries in recent years. Globally, aged, male and Asian populations remain the group with the highest risk of HCC. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are still the leading risk factors of HCC with a slight decline in most Asian countries, which is mainly attributed to HBV vaccination of newborns, prevention of HCV horizontal transmission and treatment of chronic hepatitis. However, the prevalence of HCC caused by metabolic factors, including metabolic syndrome, obesity and non-alcoholic fatty liver diseases, is increasing rapidly in Asian countries, which may eventually become the major cause of HCC. Excessive alcohol consumption continues to be an important risk factor as the average consumption of alcohol is still growing. Hopefully, great effort has been made to better prevention and treatment of HCC in most Asian regions, which significantly prolongs the survival of HCC patients. Asian countries tend to use more aggressive intervention than European and American countries, but it remains unclear whether this preference is related to a better prognosis. In conclusion, HCC remains a major disease burden in Asia, and the management of HCC should be adjusted dynamically based on the changing epidemiology.

Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation.

This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.

Effects of butylphthalide injection on treatment of transient ischemic attack as shown by diffusion-weighted magnetic resonance imaging abnormality.

Background and Objective: Transient ischemic attack (TIA) is a serious condition that is often called a warning stroke. The risk of cerebral infarction in patients with TIA and positive DWI findings is greater than that in patients with TIA and normal DWI findings. Butylphthalide injection is a new type of brain protective drug. The study aimed to determine the efficacy and safety of butylphthalide injection for treating TIA as shown by DWI abnormality progressing to infarction.Methods: We studied 98 patients with positive DWI findings among 260 patients with TIA, and randomly divided into the experimental (treatment with butylphthalide injection) and control (treatment with aspirin) groups. The number of cerebral infarctions in the two groups was recorded on 7th, 14th, 30th and 90th day, and adverse reactions were observed. The number of cerebral infarctions was compared among the different ABCD2 scores of patients with TIA and positive DWI findings.Results: The incidence of cerebral infarction in the experimental group was significantly lower than that in the control group (p < .05). The incidence of cerebral infarction with an ABCD2 score less than 3 points was significantly lower than that with an ABCD2 score of more than 3 points (p < .05), with less adverse reactions.Conclusion: Butylphthalide injection is helpful and safe for preventing stroke following TIA, and treating TIA with positive DWI and progression to infarction.

Integrated RNA-Seq Analysis and Meta-QTLs Mapping Provide Insights into Cold Stress Response in Rice Seedling Roots.

Rice (Oryza sativa L.) is a widely cultivated food crop around the world, especially in Asia. However, rice seedlings often suffer from cold stress, which affects their growth and yield. Here, RNA-seq analysis and Meta-QTLs mapping were performed to understand the molecular mechanisms underlying cold tolerance in the roots of 14-day-old seedlings of rice (RPY geng, cold-tolerant genotype). A total of 4779 of the differentially expressed genes (DEGs) were identified, including 2457 up-regulated and 2322 down-regulated DEGs. The GO, COG, KEEG, and Mapman enrichment results of DEGs revealed that DEGs are mainly involved in carbohydrate transport and metabolism, signal transduction mechanisms (plant hormone signal transduction), biosynthesis, transport and catabolism of secondary metabolites (phenylpropanoid biosynthesis), defense mechanisms, and large enzyme families mechanisms. Notably, the AP2/ERF-ERF, NAC, WRKY, MYB, C2H2, and bHLH transcription factors participated in rice's cold-stress response and tolerance. On the other hand, we mapped the identified DEGs to 44 published cold-stress-related genes and 41 cold-tolerant Meta-QTLs regions. Of them, 12 DEGs were the published cold-stress-related genes and 418 DEGs fell into the cold-tolerant Meta-QTLs regions. In this study, the identified DEGs and the putative molecular regulatory network can provide insights for understanding the mechanism of cold stress tolerance in rice. In addition, DEGs in KEGG term-enriched terms or cold-tolerant Meta-QTLs will help to secure key candidate genes for further functional studies on the molecular mechanism of cold stress response in rice.

Genetics of Parkinson's disease and related disorders.

Parkinson's disease (PD) is a complex and heterogeneous neurological condition characterised mainly by bradykinesia, resting tremor, rigidity and postural instability, symptoms that together comprise the parkinsonian syndrome. Non-motor symptoms preceding and following clinical onset are also helpful diagnostic markers revealing a widespread and progressive pathology. Many other neurological conditions also include parkinsonism as primary or secondary symptom, confounding their diagnosis and treatment. Although overall disease course and end-stage pathological examination single out these conditions, the significant overlaps suggest that they are part of a continuous disease spectrum. Recent genetic discoveries support this idea because mutations in a few genes (α-synuclein, LRRK2, tau) can cause partially overlapping pathologies. Additionally, mutations in causative genes and environmental toxins identify protein homeostasis and the mitochondria as key mediators of degeneration of dopaminergic circuits in the basal ganglia. The evolving mechanistic insight into the pathophysiology of PD and related conditions will contribute to the development of targeted and effective symptomatic treatments into disease-modifying therapies that will reduce the burden of these dreadful conditions.