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464 papers

Verbal and Visuospatial Working Memory Performance During the CO2 Challenge Model of Anxiety.

Dunger W et al. · Jul 1, 2026

Objective Anxiety influences working memory performance, but the effects on clinical neuropsychological assessments of working memory are not well known. Methods We examined the effect of anxiety, induced using the 7.5% carbon dioxide model of anxiety on standardized clinical neuropsychological tests of working memory and executive function in a single-blind, placebo-controlled, randomized, crossover within-subjects design. Results The CO 2 -challenge reduced spatial working memory performance and verbal working memory performance accuracy when task demands were high. The CO 2 -challenge increased effort and reduced processing efficiency across all verbal and spatial working memory tasks. Conclusions The CO 2 -challenge resulted in significant reductions in working memory performance and processing efficiency. These results encourage the routine assessment of anxiety when administering and interpreting neuropsychological measures of working memory function in clinical practice.

Neuroscience

Boundary Vector Cells Encode a Future-Biased Spectrum of Positions in the Rat.

Newman EL et al. · Jul 1, 2026

Spatial tuning is a hallmark property of neural firing in the hippocampal formation. Yet, that tuning is often less well correlated with the instantaneous current position of an animal than it is with an integrated version of the past or future state of the animal. Whether that encoding is biased toward past or future states and the extent to which it shows fixed versus multi-scale encoding varies across circuits and cell types. The temporal encoding properties of boundary vector cells of the subiculum are not well established. To address this here, we re-analyzed recordings of boundary vector cells (BVCs) described previously by Lever et al. (2009) with multiple approaches. In the first, we asked if adding a temporal offset between the rat position and the spiking of a BVC increased the apparent spatial tuning in the firing rate map. We found that aligning BVC spiking with future states maximized the rate map spatial tuning. These results were mirrored in a second analysis that, instead of optimizing rate map spatial tuning, optimized how well the firing rate map predicted the BVC spiking. The second analysis also allowed us to ask whether that encoding is focused on a particular temporal horizon or whether the encoding captures behavior at multiple scales. To this end, for a given recording, we asked "How much time-integration of the behavioral state is the observed spiking most consistent with?" We observed a wide spectrum of time-constants of integration across cells, indicating that BVCs form a multiscale encoding of future states. The distribution of both offsets and integration rates observed across BVCs did not differ significantly from other, non-BVC, subiculum neurons. Taken together, these findings indicate that BVCs, along with other subiculum neurons, form a multi-scale encoding of future states.

Neuroscience

Diffusion-weighted Imaging Distortion in Prostate MRI: A Cross-sectional Study Comparing Supine and Prone Positioning.

Lee KL et al. · Jul 1, 2026

Objectives Diffusion weighted imaging (DWI) is a key component of multiparametric (mp) prostate MRI. DWI using echo-planar techniques is susceptible to distortion at the recto-prostatic air-tissue interface. This study was to determine whether prone patient positioning reduces adjacent rectal air and DW image distortion when compared with standard-of-care supine positioning. Materials and methods This prospective study included consecutive patients undergoing mpMRI for suspected PCa between 2023 and 2024. Prostate segmentation was performed on DW and contrast-enhanced images. DWI distortion was measured quantitatively. Qualitative image quality of DWI and T2-weighted imaging (T2WI) was evaluated using PI-QUAL version 2; a separate 5-point clinically based Likert scale was employed to evaluate the volume of rectal air adjacent to the prostate. Results Fifty-two patients were enrolled. In total, 58% of patients expressed a preference for supine imaging versus 20% for prone imaging. Qualitative DWI image quality improved significantly in the prone position [median: 4 (3 to 4)] versus supine [3 (1 to 4)]; P 4 cm 3 of supine rectal air (n = 19), distortion was significantly reduced by prone imaging [3.49 mm (2.84 to 4.03)] compared with supine [4.60 mm (3.17 to 5.95)]; P = 0.02. The mean additional scanning time for the necessary prone imaging was 8 minutes 18 seconds. Conclusions Prone positioning significantly reduces DWI distortion artefact when rectal air is present, but consistently results in degraded T2WI quality.

Medicine

PolyProline Predictor: A web server for empirical sequence-based prediction of polyproline II helices.

López-Sánchez R et al. · Jul 1, 2026

Polyproline II (PPII) helices are extended left-handed secondary structures increasingly recognized for their roles in molecular recognition, signaling and within intrinsically disordered regions of proteins. Despite their functional importance, predicting regions with propensity to form PPII helices from sequence alone remains challenging due to subtle sequence determinants and their frequent misclassification as random coil. Here, we present PolyProline Predictor (PPP), a user-friendly web server (https://rmni.iqf.csic.es/software/polypropre/) for empirical, sequence-based prediction of PPII helices. Unlike machine learning approaches, PPP aligns query sequences against a curated database of experimentally validated PPII helices, providing an interpretable, composition-, and position-sensitive similarity map. PPP successfully identified conserved PPII motifs in diverse proteins, and predicted the presence of similar motifs in regions lacking experimental structures but modeled by AlphaFold as extended PPII conformations, such as glycine-rich plant proteins, mycobacterial PE_PGRS virulence factors, and the "disordered" C-terminal tails of GroEL and its homologs, as well as the amyloid-flanking region of the necroptosis effector RIPK3. Molecular dynamics simulations further supported persistent PPII helical bundles in three glycine-rich mycobacterial proteins and more heterogeneous, transient PPII populations in plant proteins and RIPK3. Circular dichroism and nuclear magnetic resonance (NMR) spectroscopy validated these predictions for RIPK3, revealing partially populated PPII conformations flanking its amyloid core. Such motifs may regulate its amyloid assembly, offering structural insight into mechanisms of functional amyloid formation. By combining experimental evidence with interpretable prediction, PPP fills a critical gap in bioinformatics tools and enables systematic exploration of regions with propensity to form PPII helices across proteomes, redefining the structural landscape of low-complexity regions.

Biochemistry, Genetics and Molecular Biology

Early Versus Late Wake-Up Call After Out-Of-Hospital Cardiac Arrest: Protocol for a Multicenter Randomized Comparison Within the Danish Out-of-Hospital Cardiac Arrest (DANOHCA) Trial.

Grejs AM et al. · Jul 1, 2026

Background Survivors of out-of-hospital cardiac arrest (OHCA) who remain comatose after return of spontaneous circulation are routinely sedated and mechanically ventilated during early post-resuscitation care. Although prolonged sedation has traditionally been considered necessary, contemporary normothermia-based temperature control allows earlier wake-up call. The optimal timing of an early wake-up call remains unknown and may influence overall mortality, neurological recovery, duration of mechanical ventilation, and length of hospital stay. Methods The Danish Out-of-Hospital Cardiac Arrest (DANOHCA) trial (clinicaltrials.gov identifier: NCT05895838; and euclinicaltrials.eu, identifier: 2024-515,997-28-00) is an investigator-initiated, multicenter, randomized clinical trial using a 2 × 2 × 2 × 2 factorial design evaluating four interventions in patients resuscitated from OHCA. The present protocol describes the comparison of an early versus late wake-up call strategy. Adult patients (≥ 18 years) with presumed cardiac-cause of OHCA, sustained return of spontaneous circulation, and persistent unconsciousness on intensive care unit admission are randomized 1:1 to early wake-up call (≤ 6 h after randomization) or late wake-up call (28-36 h after randomization). Wake-up call includes interruption of sedation, assessment of neurology, and may be followed by extubation if predefined neurological and respiratory criteria are fulfilled. The primary endpoint is days alive and out of hospital within 30 days after randomization. Analyses will follow a modified intention-to-treat principle. Perspectives Optimizing post-resuscitation care remains a cornerstone in managing comatose cardiac arrest survivors and improving outcomes. We hypothesize that sedation for 28-36 h leads to more days alive outside of the hospital in 30 days compared to sedation for ≤ 6 h. Trial registration EudraCT number: 2016-003265-26; EU CTIS no 2024-515997-28-00; ClinicalTrials.gov identifier: NCT05895838.

Medicine

Outcomes of Liver Transplant Versus Partial Hepatectomy for Perihilar Cholangiocarcinoma Patients Requiring Arterial Reconstruction.

Poletto E et al. · Jul 1, 2026

Background and aims Liver resection (LR) and orthotopic liver transplantation (OLT) are therapeutic options for locally advanced perihilar cholangiocarcinoma (pCCA) requiring hepatic artery reconstruction (HAR). This study aimed to compare short- and long-term outcomes of LR and OLT. Outcomes were major vascular complications, 90-day mortality, overall survival (OS) and recurrence-free survival (RFS). Methods A cohort of patients undergoing LR with HAR from 10 Western centres was compared with an OLT cohort comprising patients who received or did not receive neoadjuvant chemoradiotherapy (NACR). Results 109 patients, 60 LR and 49 OLT (22 OLT no-NACR and 27 OLT NACR) were included. LR patients were older and had fewer Bismuth type 4 tumours (38.3% vs. 69.4%, p = 0.009). Positive margins (49.2% vs. 6.5%, p Conclusions LR and OLT for locally advanced pCCA had similar rates of major complications and post-operative mortality, but NACR was associated with increased vascular complications. Survival was difficult to compare in the groups due to their heterogeneity, but OLT, especially with NACR, seems to give better results than LR.

Medicine

Integrative Transcriptomic and Functional Analysis of PKMYT1 Reveals a Potential Therapeutic Target in Chronic Lymphocytic Leukemia.

Bispo ECI et al. · Jul 1, 2026

Chronic lymphocytic leukemia (CLL) is a clinically and molecularly heterogeneous disease. PKMYT1, a G2/M cell cycle kinase, has been implicated in tumor progression in several cancers, but its role in CLL remains unclear. We evaluated PKMYT1 expression in primary CLL samples and analyzed associations with cytogenetic features and clinical parameters. PKMYT1 expression was heterogeneous and correlated with adverse features, including complex karyotype and elevated leukocyte counts. Comparative transcriptomic analyses between high- and low-expression groups revealed enrichment of pathways related to chromatin remodeling, DNA repair, and mitotic regulation. In MEC1 cells, pharmacological PKMYT1 inhibition significantly reduced cancer cell viability. PCR analysis showed upregulation of TP53, CASP3, BAK, GSDMD, BCL2, CASP1, IL1β, RIPK1, and RIPK3, indicating activation of apoptotic, inflammasome-associated, and necroptotic pathways. Collectively, these findings demonstrate that PKMYT1 is heterogeneously expressed in CLL, associated with adverse cytogenetic and clinical features, and critical for cell survival, highlighting its potential as a therapeutic target.

Medicine

Agreement Between Methods Assessing Changes in Plasma Volume During Fluid Therapy-A Post Hoc Analysis of a Randomized Trial.

Grubb D et al. · Jul 1, 2026

Volume status of a patient is difficult to assess clinically. Methods to measure plasma volume as well as changes in plasma volume in connection with fluid therapy are therefore valuable for research purposes and could potentially be used bedside to guide fluid therapy in individual patients. The objective of the present study was to evaluate hematocrit as a marker of changes in plasma volume and an anthropometric formula to estimate absolute plasma volume against the reference method, plasma volume measurements using radiolabeled albumin. A total of 64 postoperative patients received 10 mL/kg of albumin. The plasma volumes were measured with the reference method (radiolabeled albumin) at baseline, after 30 and 180 min. Plasma volumes were compared with plasma volumes derived from either the baseline measurements and subsequent changes in hematocrit (calibrated method) or from an anthropometric formula and subsequent hematocrit changes (anthropometric method). Bland-Altman plots were used to test agreements between methods. The mean difference in plasma volume between the anthropometric and the reference method at baseline was -0.1 mL/kg (95% CI -2.1 to 1.8) with lower and upper LOA of -18.0 and 17.0 mL/kg. The agreement remained essentially unchanged after fluid therapy (mean difference -0.1 mL/kg (95% CI -1.8 to 1.5) with LOAs of -18.0 and 17.0 mL/kg). The mean difference between the calibrated and reference methods was -0.1 mL/kg (95% CI -0.9 to 0.7) with LOAs of -9.4 and 9.2 mL/kg. The anthropometric formula yields low precision in predicting plasma volumes in postsurgical patients. Changes in hematocrit during fluid therapy cannot replace the reference method to assess changes in plasma volume in the individual patient because of the imprecision. EDITORIAL COMMENT: Clinical appreciation of plasma volume is relevant for assessing treatment where intravenous fluid resuscitation is involved. This analysis, using a reference method for plasma volume assessment, and comparing to simpler methods to estimate the same, demonstrates that there are important limitations with some simpler and readily acceptable methods to perform this estimation.

Medicine

Non-canonical and constitutive activation of small GTPases: more than an exception to the rule?

Kiers J et al. · Jul 1, 2026

The superfamily of small GTPases comprises over 150 members, clustered in different families (e.g., Ras, Rab, Rho), that together are essential for a wide range of cellular functions. Most GTPases behave as molecular on/off switches, with regulatory proteins controlling their cycling between the GDP-bound, inactive form and the GTP-bound, active form. However, there is a substantial number of small GTPases that do not adhere to this canonical mode of regulation. This can result from key sequence differences that maintain these GTPases mostly in the GTP-bound form. Alternatively, specific post-translational modifications, including ubiquitination or alternative lipidation, can activate these GTPases, for example, due to interference with their intrinsic GTP hydrolysis capacity. Such 'atypical' GTPases are often constitutively active and are furthermore characterized by fast turnover. Consequently, their output is much more a function of their expression levels, with proteasomal or lysosomal degradation limiting their signaling capacity. This review discusses recent insights into non-canonical activation of small GTPases. We also discuss modifications, in particular palmitoylation, which allows otherwise canonical GTPases to become (constitutively) active, escaping their usual regulatory mechanisms. Finally, we discuss the potential biological importance of non-canonical GTPase regulation. We focus on the difference in kinetics and signal duration between canonical cycling versus non-canonical activation, and discuss differences related to fast, external stimulation (e.g., by hormones and growth factors) versus slow, intrinsic signaling, linked to altered metabolism, autophagy, or disease.

Biochemistry, Genetics and Molecular Biology

Mex-3 RNA-binding family member A limits macrophage ferroptosis-associated injury linked to the SLC7A11/GPX4 pathway in diabetic atherosclerosis.

Ma Y et al. · Jul 1, 2026

Background Diabetes accelerates atherosclerotic plaque expansion and loss of stability, but the plaque-resident mechanisms through which the diabetic milieu promotes macrophage lipid-oxidative injury are not fully understood. Methods We used apolipoprotein E-deficient (ApoE -/- ) mice with Mex-3 RNA-binding family member A (MEX3A) deficiency and primary bone marrow-derived macrophage (BMDM) experiments under diabetic conditions to investigate the role of MEX3A in diabetic atherosclerosis and macrophage lipid-peroxidation injury. Results MEX3A loss worsened diabetic atherosclerosis while leaving body weight, glycaemia and lipid measurements largely unchanged relative to diabetes alone. MEX3A deficiency enlarged aortic lesions, enhanced lipid deposition, increased macrophage content, expanded necrotic cores and thinned fibrous caps, while reducing collagen content. In lesional macrophages, loss of MEX3A coincided with increased lipid reactive oxygen species, malondialdehyde, increased labile iron, 4-hydroxynonenal, a disturbed glutathione redox state, mitochondrial abnormalities compatible with ferroptotic stress, lower GPX4/SLC7A11 and higher ACSL4. CRISPR/Cas9-mediated Mex3a knockout in BMDMs recapitulated this phenotype, whereas restoring MEX3A blunted it. RNA immunoprecipitation-qPCR together with actinomycin D decay analyses demonstrated preferential recovery of Slc7a11 and Gpx4 transcripts with MEX3A and decreased stability of Slc7a11 and Gpx4 mRNAs after Mex3a knockout. GPX4 or SLC7A11 overexpression reduced lipid-peroxidation injury in Mex3a-knockout macrophages, whereas Gpx4 or Slc7a11 knockdown weakened the protection conferred by MEX3A re-expression. Ferrostatin-1 partially attenuated macrophage lipid peroxidation and plaque injury. Conclusions Together, these results place MEX3A among the protective regulators of diabetic plaque stability and support a MEX3ASLC7A11/GPX4-linked ferroptosis-associated mechanism in plaque macrophages. Key points MEX3A deficiency worsens diabetic atherosclerosis without further aggravating systemic metabolic indices. Loss of MEX3A promotes plaque lipid deposition, macrophage accumulation, necrotic core expansion and fibrous cap thinning. MEX3A limits macrophage lipid-peroxidation injury linked to the SLC7A11/GPX4 pathway. Ferrostatin-1 partially attenuates macrophage lipid peroxidation and plaque injury associated with MEX3A deficiency.

Medicine