Knockout of OsNRAMP5 enhances rice tolerance to cadmium toxicity in response to varying external cadmium concentrations via distinct mechanisms.

OsNRAMP5 is a transporter responsible for cadmium (Cd) and manganese (Mn) uptake and root-to-shoot translocation of Mn in rice plants. Knockout of OsNRAMP5 is regarded as an effective approach to minimize Cd uptake and accumulation in rice. It is vital to evaluate the effects of knocking out OsNRAMP5 on Cd and Mn accumulation, as well as Cd tolerance of rice plants in response to varying environmental Cd concentrations, and to uncover the underlying mechanism, which until now, has remained largely unexplored. This study showed that knockout of OsNRAMP5 decreased Cd uptake, but simultaneously facilitated Cd translocation from roots to shoots. The effect of OsNRAMP5 knockout on reducing root Cd uptake weakened, however its effect on improving root-to-shoot Cd translocation was constant with increasing environmental Cd concentrations. As a result, its mutation dramatically reduced Cd accumulation in shoots under low and moderate Cd stress, but inversely increased that under high Cd conditions. Interestingly, Cd tolerance of its knockout mutants was persistently enhanced, irrespective of lower or higher Cd concentrations in shoots, compared with that of wild-type plants. Knockout of OsNRAMP5 mitigated Cd toxicity by dramatically diminishing Cd uptake at low or moderate external Cd concentrations. Remarkably, its knockout effectively complemented deficient mineral nutrients in shoots, thereby indirectly enhancing rice tolerance to severe Cd stress. Additionally, its mutation conferred preferential delivery of Mn to young leaves and grains. These results have important implications for the application of the OsNRAMP5 mutation in mitigating Cd toxicity and lowering the risk of excessive Cd accumulation in rice grains.

Overexpression of OsLCT2, a Low-Affinity Cation Transporter Gene, Reduces Cadmium Accumulation in Shoots and Grains of Rice.

Cadmium (Cd)-contaminated rice is a serious issue affecting food safety. Understanding the molecular regulatory mechanisms of Cd accumulation in rice grains is crucial to minimizing Cd concentrations in grains. We identified a member of the low-affinity cation transporter family, OsLCT2 in rice. It was a membrane protein. OsLCT2 was expressed in all tissues of the elongation and maturation zones in roots, with the strongest expression in pericycle and stele cells adjacent to the xylem. When grown in Cd-contaminated paddy soils, rice plants overexpressing OsLCT2 significantly reduced Cd concentrations in the straw and grains. Hydroponic experiment demonstrated its overexpression decreased the rate of Cd translocation from roots to shoots, and reduced Cd concentrations in xylem sap and in shoots of rice. Moreover, its overexpression increased Zn concentrations in roots by up-regulating the expression of OsZIP9, a gene responsible for Zn uptake. Overexpression of OsLCT2 reduces Cd accumulation in rice shoots and grains by limiting the amounts of Cd loaded into the xylem and restricting Cd translocation from roots to shoots of rice. Thus, OsLCT2 is a promising genetic resource to be engineered to reduce Cd accumulation in rice grains.

Anterior limb of the internal capsule tractography: relationship with capsulotomy outcomes in obsessive-compulsive disorder.

OBJECTIVES: Surgical procedures targeting the anterior limb of the internal capsule (aLIC) can be effective in patients with selected treatment-refractory obsessive-compulsive disorder (OCD). The aLIC consists of white-matter tracts connecting cortical and subcortical structures and show a topographical organisation. Here we assess how aLIC streamlines are affected in OCD compared with healthy controls (HCs) and which streamlines are related with post-capsulotomy improvement. METHODS: Diffusion-weighted MRI was used to compare white-matter microstructure via the aLIC between patients with OCD (n=100, 40 women, mean of age 31.8 years) and HCs (n=88, 39 women, mean of age 29.6 years). For each individual, the fractional anisotropy (FA) and streamline counts were calculated for each white-matter fibre bundle connecting a functionally defined prefrontal and subcortical region. Correlations between tractography measures and pre-capsulotomy and post-capsulotomy clinical outcomes (in obsessive-compulsive, anxiety and depression scores 6 months after surgery) were assessed in 41 patients with OCD. RESULTS: Hierarchical clustering dendrograms show an aLIC organisation clustering lateral and dissociating ventral and dorsal prefrontal-thalamic streamlines, findings highly relevant to surgical targeting. Compared with HCs, patients with OCD had lower aLIC FA across multiple prefrontal cortical-subcortical regions (p<0.0073, false discovery rate-adjusted). Greater streamline counts of the dorsolateral prefrontal-thalamic tracts in patients with OCD predicted greater post-capsulotomy obsessive-compulsive improvement (p=0.016). In contrast, greater counts of the dorsal cingulate-thalamic streamlines predicted surgical outcomes mediated by depressive and anxiety improvements. CONCLUSIONS: These findings shed light on the critical role of the aLIC in OCD and may potentially contribute towards precision targeting to optimise outcomes in OCD.

Neuroanatomical Substrates and Predictors of Response to Capsulotomy in Intractable Obsessive-Compulsive Disorder.

BACKGROUND: Anterior capsulotomy that surgically targets fiber tracts connecting prefrontal cortex and subcortical nuclei is a therapeutic option for a subgroup of patients with treatment-refractory obsessive-compulsive disorder. The goal of this study was to investigate neural correlates to anterior capsulotomy and find predictors of clinical improvement following this procedure. METHODS: Structural and diffusion imaging data and clinical evaluation were acquired from 31 patients with refractory obsessive-compulsive disorder who underwent anterior capsulotomy. Of the 31 patients, 16 were clinical responders defined by a ≥35% reduction in the Yale-Brown Obsessive Compulsive Scale scores. Analysis of variance was applied on 2 levels (surgery and response) to examine alterations of gray matter volume and fiber tract integrity (measured by generalized fractional anisotropy). The correlation between preoperative data and clinical response was further investigated. RESULTS: After surgery, generalized fractional anisotropy was significantly decreased in the bilateral anterior limb of the internal capsule and anterior thalamic radiation, accompanied by a decrease in gray matter volume in the prefrontal cortex, anterior cingulate cortex, striatum, thalamus, and cerebellum. Moreover, atrophy of the right caudate was greater in responders than in nonresponders, which correlated with alteration in Yale-Brown Obsessive Compulsive Scale score. In addition, preoperative gray matter volume in the right inferior frontal gyrus and generalized fractional anisotropy in the left superior longitudinal fasciculus and right cingulum predicted improved response. More anterior location of the lesion area predicted better clinical response. CONCLUSIONS: These results demonstrate that reduced volume of the right caudate might be associated with therapeutic response of capsulotomy and might offer a potential predictor of treatment outcome and a guide for lesion site.

Divergent Structural Responses to Pharmacological Interventions in Orbitofronto-Striato-Thalamic and Premotor Circuits in Obsessive-Compulsive Disorder.

Prior efforts to dissect etiological and pharmacological modulations in brain morphology in obsessive-compulsive disorder (OCD) are often undermined by methodological and sampling constraints, yielding conflicting conclusions and no reliable neuromarkers. Here we evaluated alteration of regional gray matter volume including effect size (Cohen's d value) in 95 drug-naïve patients (age range: 18-55) compared to 95 healthy subjects (age: 18-63), then examined pharmacological effects in 65 medicated (age: 18-57) and 73 medication-free patients (age: 18-61). Robustness of statistical outcomes and effect sizes was rigorously tested with Monte Carlo cross-validation. Relative to controls, both drug-naïve and medication-free patients exhibited comparable volumetric increases mainly in the left thalamus (d=0.90, 0.82, respectively), left ventral striatum (d=0.88, 0.67), bilateral medial orbitofrontal cortex (d=0.86, 0.71; 0.90, 0.73), and left inferior temporal gyrus (d=0.83, 0.66), and decreased volumes in left premotor/presupplementary motor areas (d=-0.83, -0.71). Interestingly, abnormalities in the thalamus and medial orbitofrontal cortex were present in medicated patients whereas entirely absent in premotor and ventral striatum. It suggests that pharmacotherapy elicited divergent responses in orbitofronto-striato-thalamic and premotor circuits, which warrants the design of longitudinal studies investigating the potential of these neuromarkers in stratified treatments of OCD.