The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve ...performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACAVIS neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACAVIS neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACAVIS neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.
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•Top-down frontal sensory projections are selectively recruited after error trials•30-Hz optogenetic stimulation of top-down neurons promotes post-error performance•Post-error performance adjustment requires anticipatory top-down activity•30-Hz optogenetic top-down stimulation promotes a hallmark feature of attention
Norman et. al found that behavioral errors recruit frontal sensory projections in mice. 30-Hz optogenetic stimulation of this pathway modulates performance following errors in behaving mice and recapitulates neurophysiological hallmarks of attention in anesthetized mice. Frontal sensory projections therefore link error monitoring with attention adjustments for behavioral adaptation.
Movement of transposons causes insertions, deletions, and chromosomal rearrangements potentially leading to premature lethality in Drosophila melanogaster. To repress these elements and combat ...genomic instability, eukaryotes have evolved several small RNA-mediated defense mechanisms. Specifically, in Drosophila somatic cells, endogenous small interfering (esi)RNAs suppress retrotransposon mobility. EsiRNAs are produced by Dicer-2 processing of double-stranded RNA precursors, yet the origins of these precursors are unknown. We show that most transposon families are transcribed in both the sense (S) and antisense (AS) direction in Dmel-2 cells. LTR retrotransposons Dm297, mdg1, and blood, and non-LTR retrotransposons juan and jockey transcripts, are generated from intraelement transcription start sites with canonical RNA polymerase II promoters. We also determined that retrotransposon antisense transcripts are less polyadenylated than sense. RNA-seq and small RNA-seq revealed that Dicer-2 RNA interference (RNAi) depletion causes a decrease in the number of esiRNAs mapping to retrotransposons and an increase in expression of both S and AS retrotransposon transcripts. These data support a model in which double-stranded RNA precursors are derived from convergent transcription and processed by Dicer-2 into esiRNAs that silence both sense and antisense retrotransposon transcripts. Reduction of sense retrotransposon transcripts potentially lowers element-specific protein levels to prevent transposition. This mechanism preserves genomic integrity and is especially important for Drosophila fitness because mobile genetic elements are highly active.
Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis ...and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing.
Twenty-two tRCCs underwent targeted sequencing Memorial Sloan Kettering Cancer Center (MSK)-IMPACT; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number-altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan-Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing.
Copy-number aberrant tRCCs were associated with poor overall survival (
= 0.03). Pediatric patients had tumors with lower FCNAg (
= 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution.
promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes.
Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.
Background:
Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS).
Objective:
To investigate the treatment effect of ibudilast ...on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis SPRINT-MS).
Methods:
A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model.
Results:
There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = −0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001).
Conclusion:
In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome’s clinical importance.
Axonal damage in the corpus callosum is prevalent in multiple sclerosis (MS). Although callosal damage is associated with disrupted functional connectivity between hemispheres, it is unclear how this ...relates to cognitive and physical disability. We investigated this phenomenon using advanced measures of microstructural integrity in the corpus callosum and surface-based homologous inter-hemispheric connectivity (sHIC) in the cortex. We found that sHIC was significantly decreased in primary motor, somatosensory, visual, and temporal cortical areas in a group of 36 participants with MS (29 relapsing–remitting, 4 secondary progressive MS, and 3 primary-progressive MS) compared with 42 healthy controls (cluster level,
p
< 0.05). In participants with MS, global sHIC correlated with fractional anisotropy and restricted volume fraction in the posterior segment of the corpus callosum (
r
= 0.426,
p
= 0.013;
r
= 0.399,
p
= 0.020, respectively). Lower sHIC, particularly in somatomotor and posterior cortical areas, was associated with cognitive impairment and higher disability scores on the Expanded Disability Status Scale (EDSS). We demonstrated that higher levels of sHIC attenuated the effects of posterior callosal damage on physical disability and cognitive dysfunction, as measured by the EDSS and Brief Visuospatial Memory Test-Revised (interaction effect,
p
< 0.05). We also observed a positive association between global sHIC and years of education (
r
= 0.402,
p
= 0.018), supporting the phenomenon of “brain reserve” in MS. Our data suggest that preserved sHIC helps prevent cognitive and physical decline in MS.
To evaluate the intrinsic and extrinsic microstructural factors contributing to atrophy within individual thalamic subregions in multiple sclerosis using in vivo high-gradient diffusion MRI.
In this ...cross-sectional study, 41 people with multiple sclerosis and 34 age and sex-matched healthy controls underwent 3T MRI with up to 300 mT/m gradients using a multi-shell diffusion protocol consisting of eight b-values and diffusion time of 19 ms. Each thalamus was parcellated into 25 subregions for volume determination and diffusion metric estimation. The soma and neurite density imaging model was applied to obtain estimates of intra-neurite, intra-soma, and extra-cellular signal fractions for each subregion and within structurally connected white matter trajectories and cortex.
Multiple sclerosis-related volume loss was more pronounced in posterior/medial subregions than anterior/ventral subregions. Intra-soma signal fraction was lower in multiple sclerosis, reflecting reduced cell body density, while the extra-cellular signal fraction was higher, reflecting greater extra-cellular space, both of which were observed more in posterior/medial subregions than anterior/ventral subregions. Lower intra-neurite signal fraction in connected normal-appearing white matter and lower intra-soma signal fraction of structurally connected cortex were associated with reduced subregional thalamic volumes. Intrinsic and extrinsic microstructural measures independently related to subregional volume with heterogeneity across atrophy-prone thalamic nuclei. Extrinsic microstructural alterations predicted left anteroventral, intrinsic microstructural alterations predicted bilateral medial pulvinar, and both intrinsic and extrinsic factors predicted lateral geniculate and medial mediodorsal volumes.
Our results might be reflective of the involvement of anterograde and retrograde degeneration from white matter demyelination and cerebrospinal fluid-mediated damage in subregional thalamic volume loss.
Supramolecular Cu(II) complexes were prepared from two trifunctional β-diketone ligands. The ligands (CH3Si(phacH)3 and CH3Si(phprH)3, represented by LH3) contain three aryl-β-diketone moieties ...joined by an organosilicon group. The complexes have the empirical formula Cu3L2, as expected for combinations of Cu2+ and L3–. Several metal–organic polyhedra (MOPs) Cu3L2 n are possible (n = 1–10); a dodecahedron (Cu30L20; n = 10; estimated diameter of ca. 5 nm) should be the most stable because its internal bond angles would come closest to ideal values. Atomic force microscopy (AFM), performed on samples deposited from solution onto mica substrates, revealed a distribution of sample heights in the 0.5–3.0 nm range. The most commonly observed heights were 0.5–1.5 nm, corresponding to the smallest possible molecules (Cu3L2, i.e., n = 1). Some molecular cubes (Cu12L8; ca. 2.5 nm) or larger molecules or aggregates may be present as well. Equilibrium analytical ultracentrifugation (AUC) was also used to probe the compounds. A previously reported reference compound, the molecular square Cu4(m-pbhx)4 (M = 2241 g mol–1), behaved well in AUC experiments in four nonpolar organic solvents. AUC data for the new tris(β-diketonate) MOPs Cu3L2 n in toluene and fluorobenzene did not agree well with the theoretical results for a single solute. The data were fit well by a two-solute model, but these results were not consistent in the two solvents used, and some run-to-run variability was noted even in the same solvent. Also, the calculated molecular weights differed significantly from those expected for Cu3L2 n (Cu3(CH3Si(phac)3)2 n , multiples of 1322 g mol–1; or Cu3(CH3Si(phpr)3)2 n , multiples of 1490 g mol–1).
Background
Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine ...the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes.
Methods
Consecutive patients with mRCC referred for potential CN (2009‐2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition.
Results
Of 245 treatment‐naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio HR, 1.57; 95% confidence interval CI, 1.13‐2.19; P = .007; HR, 2.52; 95% CI, 1.74‐3.65; P < .001).
Conclusions
IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.
Cytoreductive nephrectomy modifies the overall systemic disease status. The changes have therapeutic and prognostic implications.
Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We ...present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling.
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