Background: Surgical site infections are among the most common healthcare-associated infections, especially in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this retrospective study was to examine postoperative infectious complications according to preoperative screening findings of nasal and rectal swabs. Methods: Two hundred four consecutive patients received nasal and rectal swab examination for multidrug-resistant (MDR) bacteria within 30 days before the operation in patients where CRS and HIPEC were planned. Inclusion criteria were as follows: confirmed peritoneal metastases (histologically and/or cytologically); age under 85 years; adequate renal, liver, and bone marrow function; no sign of infection preoperatively; resectable disease; and CRS and HIPEC procedure. If surgical site infection occurred, the microbial spectrum of the site was assessed. One hundred twenty-one patients (63 female [52.1%] and 58 male [47.9%]) met the criteria and were further analyzed retrospectively. Statistical correlations between postoperative complications and risk factors were investigated by univariate and multivariate analysis. Results: Postoperative complications in total were observed in 57 patients (47.1%) with major complications (Clavien-Dindo grades 3-4) in 15 patients (12.4%) and infectious complications in 37 (30.6%) patients. The overall prevalence of nasal MRSA carriage was 3.28%, and the overall prevalence of rectal MDR bacteria carriage was 10.7%. In propensity score analysis, colonized patients compared to noncolonized patients showed increased total complications (CD1-5, p = 0.025), infectious complications (p = 0.028), surgical site infections (p = 0.022) as well as pneumonia (p = 0.016). Multivariate analysis showed that in addition to preoperative rectal colonization, American Society of Anesthesiologists score was a risk factor for postoperative complications. Conclusions: Preoperative 3-MRGN and vancomycin-resistant enterococcus colonization were associated with increased complications and surgical site infections. Special antimicrobial treatment pathways are necessary for these patients to reduce postoperative complications due to colonization.
View lessBackground: Robust clinical evidence on the efficacy and safety of endoscopic lung volume reduction (ELVR) with one-way valves in patients with severe lung emphysema with chronic hypercapnic respiratory failure is lacking. Objective: The aim of this study was to compare patient characteristics, clinical outcome measures, and incidences of adverse events between patients with severe COPD undergoing ELVR with one-way valves and with either a partial pressure of carbon dioxide (pCO(2)) of <= 45 mm Hg or with pCO(2) >45 mm Hg. Methods: This was a multicentre prospective study of patients with severe lung disease who were evaluated based on lung function, exercise capacity (6-min walk test [6-MWT]), and quality-of-life tests. Results: Patients with pCO(2) <= 45 mm Hg (n = 157) and pCO(2) >45 mm Hg (n = 40) showed similar baseline characteristics. Patients with pCO(2) <= 45 mm Hg demonstrated a significant increase in forced expiratory volume in 1 s (p < 0.001), a significant decrease in residual volume (RV) (p < 0.001), and significant improvements in the quality of life and 6-MWT at the 3-month follow-up. Patients with pCO(2) >45 mm Hg had significant improvements in RV only (p < 0.05). There was a significant decrease in pCO(2) between baseline and follow-up in hypercapnic patients, relative to the decrease in patients with pCO(2) <= 45 mm Hg (p = 0.008). Patients who were more hypercapnic at baseline showed a greater reduction in pCO(2) after valve placement (r = -0.38, p < 0.001). Pneumothorax was the most common adverse event in both groups. Conclusions: ELVR with one-way valves seems clinically beneficial with a remarkably good safety profile for patients with chronic hypercapnic respiratory failure.
View lessA mechanism known as Pavlovian-to-instrumental transfer (PIT) describes a phenomenon by which the values of environmental cues acquired through Pavlovian conditioning can motivate instrumental behavior. PIT may be one basic mechanism of action control that can characterize mental disorders on a dimensional level beyond current classification systems. Therefore, we review human PIT studies investigating subclinical and clinical mental syndromes. The literature prevails an inhomogeneous picture concerning PIT. While enhanced PIT effects seem to be present in non-substance-related disorders, overweight people, and most studies with AUD patients, no altered PIT effects were reported in tobacco use disorder and obesity. Regarding AUD and relapsing alcohol-dependent patients, there is mixed evidence of enhanced or no PIT effects. Additionally, there is evidence for aberrant corticostriatal activation and genetic risk, e.g., in association with high-risk alcohol consumption and relapse after alcohol detoxification. In patients with anorexia nervosa, stronger PIT effects elicited by low caloric stimuli were associated with increased disease severity. In patients with depression, enhanced aversive PIT effects and a loss of action-specificity associated with poorer treatment outcomes were reported. Schizophrenic patients showed disrupted specific but intact general PIT effects. Patients with chronic back pain showed reduced PIT effects. We provide possible reasons to understand heterogeneity in PIT effects within and across mental disorders. Further, we strengthen the importance of reliable experimental tasks and provide test-retest data of a PIT task showing moderate to good reliability. Finally, we point toward stress as a possible underlying factor that may explain stronger PIT effects in mental disorders, as there is some evidence that stress per se interacts with the impact of environmental cues on behavior by selectively increasing cue-triggered wanting. To conclude, we discuss the results of the literature review in the light of Research Domain Criteria, suggesting future studies that comprehensively assess PIT across psychopathological dimensions.
View lessBackground and Objective: Results of five randomized controlled trials (RCT) sequentially published in 2010-2013 suggested that aiming for higher, as opposed to lower oxygen saturation targets, reduces rates of mortality in infants <28 weeks of gestation, while increasing rates of severe retinopathy of prematurity (ROP). Two further RCTs published in 2011 and 2015 demonstrated that avoiding endotracheal intubation by minimally invasive surfactant administration reduces respiratory morbidity. Assuming that such data are likely to affect clinical practice and ultimate outcome, we analyzed population-level results in extremely preterm infants born across Germany during 2010-2017. Methods: We used mandatory German quality surveillance data to compare mortality and morbidities in preterm infants born between 24 weeks 0 days and 27 weeks 6 days of gestation in 2010-2013 versus 2014-2017. Results: Mortality decreased from 15.1% (1,366/9,058) in 2010-2013 to 12.7% (1,385/10,924) in 2014-2017, risk ratio (RR) 0.845 (95% confidence interval [CI], 0.784-0.901). Rates of severe ROP (>= grade 3) per survivor increased from 12.1% (930/7,692) to 13.3% (1.269/9,539), RR 1.100 (95% CI: 1.017-1.191). The lowest mortality and highest ROP rates were found in infants born in 2014. There was no change in rates of necrotizing enterocolitis, while those of bronchopulmonary dysplasia (BPD) decreased steadily between 2010 and 2017, alongside the increased proportion of infants who were never intubated. Conclusions: There was a moderate decline in mortality, an insignificant increase in severe ROP, and a steady decline of BPD in Germany during 2010-2017. Avoiding endotracheal intubation may have contributed to lowered BPD rates.
View lessIntroduction: There is evidence of an association between markers of cardiac injury and cognition in patients with cardiovascular disease. We hypothesized that levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with cognitive performance and cognitive decline in a population of predominantly healthy older adults. Methods: We included 1,226 predominantly healthy adults >= 60 years from the Berlin Aging Study II. Participants were recruited from the general population of the Berlin metropolitan area from 2009 to 2014. At baseline, participants underwent measurement of hs-cTnT and cognitive testing using the extended Consortium to Establish a Registry for Alzheimer's Disease (CERAD-Plus) battery. In addition, the Digit Symbol Substitution Test (DSST) was performed at baseline and at follow-up (7.3 +/- 1.4 years after the baseline visit). The CERAD test results were summarized into four cognitive domains (processing speed, executive function, visuo-construction, and memory). After summing-up the respective raw scores, we calculated standardized z scores. We performed unadjusted and adjusted linear regression models to assess links between hs-cTnT and cognitive domains. We used linear mixed models to analyze associations between hs-cTnT and cognitive decline according to changes in DSST scores over time. Results: The mean age of study participants at baseline was 68.5 (+/- 3.6) years, 49% were female, and median hs-cTnT levels were 6 ng/L (IQR 4-8 ng/L). We detected no significant association between hs-cTnT and different cognitive domains at baseline after adjustment for age, sex, education, and cardiovascular risk factors. Hs-cTnT was associated with cognitive decline, which remained statistically significant after full adjustment (adjusted beta-coefficient -0.82 (-1.28 to -0.36), p = 0.001). After stratification for sex, the association with hs-cTnT remained statistically significant in men but not in women. Conclusion: Higher hs-cTnT levels in older men are associated with cognitive decline measured with the DSST.
View lessIntroduction: Noninterventional study (NIS) on application and effectiveness of primary G-CSF prophylaxis with lipegfilgrastim in primary breast cancer patients undergoing dose-dense (dd) or intense-dose-dense (idd) chemotherapy (CTx) regimen in daily clinical practice. Methods: Prospective, multicenter, single-arm, NIS in 41 private practices and 27 hospitals in Germany. Results: Data analysis of 282 patients with a mean age of 49 years (93.6% of patients <65 years) was performed. Hormone receptor status was triple negative in 29.8% of patients, and 81.9% of patients were HER2 negative. A total of 73.8% of patients received "EC dd -> taxane CTx." Patients received lipegfilgrastim prophylaxis in 97.5% of 1,121 documented dd/idd cycles. Overall, the study registered 275 events of SN (CTCAE grade 3 or 4) and 9 events of FN. During the first dd cycle, SN occurred in 33.3% and FN in 1.1% of patients. CTx delay or dose reduction due to neutropenia was required in 2.5% of patients during the 4 dd cycles with lipegfilgrastim support. Overall, 314 adverse events (AEs) were reported from 107 patients and 27 serious AEs from 21 patients. None of the SAEs was "fatal," and CTCAE grade was mostly (89.6%) assessed as "1" or "2." According to the treating physicians, 99.3% of all patients benefitted from lipegfilgrastim prophylaxis, and tolerability was mostly rated "very good" or "good." Conclusion: These results suggest that primary lipegfilgrastim prophylaxis is effective and safe in clinical routine and is beneficial in primary breast cancer patients undergoing dd/idd-ETC CTx.
View lessPurpose: Interleukin 6 (IL-6), Oncostatin M (OSM), and downstream effector STAT3 are pro-tumorigenic agents in pancreatic ductal adenocarcinoma (PDAC). Glycoprotein 130 (gp130) is a compound of the IL-6 and OSM receptor complex that triggers STAT3 signaling. SC144 is a small molecule gp130 inhibitor with anticancer activity. This study examines the gp130 expression in human PDAC specimens and the in vitro effects of SC144 in PDAC cell lines.
Methods: Tissue micro-arrays were constructed from 175 resected human PDAC. The gp130 expression in tumor epithelium and stroma was determined by immunohistochemistry, and survival analysis was performed. Growth inhibition by SC144 was assessed in vitro using BrdU and MTT assays. Western blotting was performed to evaluate the SC144 effect on IL-6 and OSM signaling.
Results: Gp130 was expressed in the epithelium of 78.8% and the stroma of 9.4% of the tumor samples. The median overall survival for patients with or without epithelial gp130 expression was 16.7 months and 15.9 months, respectively (p = 0.830). Patients with no stromal gp130 expression showed poorer survival than patients with stromal gp130 expression (median 16.2 and 22.9 months, respectively), but this difference did not reach significance (p = 0.144). SC144 inhibited cell proliferation and viability and suppressed IL-6- and OSM-stimulated STAT3(Y705) phosphorylation in PDAC cells.
Conclusion: Gp130 is expressed in the epithelium of most human PDAC, but stromal expression is rare. The small molecule gp130 inhibitor SC144 potently inhibits PDAC progression in vitro and may abrogate IL-6 or OSM/gp130/STAT3 signaling. These results suggest gp130 as a novel drug target for pancreatic cancer therapy.
View lessObjective: To explore the characteristics of cancer patients who cryopreserved sperm/testicular tissue samples in the Cryobank of Charite-Universitatsmedizin Berlin between 2004 and 2019, and the ART utilization rate with associated outcomes.
Methods: Retrospective data were available for 506 cancer patients, of which 46 (9.1%) had used their samples for artificial reproductive technologies (ART). Corresponding cycle information was collected from external fertility centers.
Results: Our cohort included 53/506 (10.5%) patients aged < 18 years at diagnosis. While adolescents and adults mainly banked sperm, adolescents showed higher rates of testicular tissue cryopreservation before (11.8%, 6/51 vs. 6.4%, 26/406) and after treatment (16.7%, 4/24 vs. 7.8%, 13/167). At study conduction, storage had been ended for 44.8% (269/601) of samples. The majority of samples used for ART were requested within the first 3 years after cryopreservation (71.5%, 28/39, range = 0-12 years). Pregnancy rate was 51.4% (19/37 cycles), resulting in 11 singleton births, 3 twin pairs, and 4 miscarriages.
Conclusion: With the new advantage of public health insurance coverage of fertility preservation (FP) in Germany, an increased utilization has already been noticed in our center, emphasizing the necessity of further knowledge for individual counseling. Adolescent cancer patients need to be addressed specifically, as these patients show especially low cryopreservation rates.
View lessPurpose: In recent years the tumor microenvironment and its interaction with the tumor has emerged into research focus with increased attention to the composition of Tumor-infiltrating lymphocytes. We wanted to quantify the composition of Regulatory T cells (Tregs) and T helper 17 cells (Th17 cells) and their prognostic impact in high-grade serous tubo-ovarian carcinoma.
Methods: Tregs and Th17 cells were determined by immunohistochemical analysis of CD25 FoxP3 and ROR gamma t, respectively on tissue microarrays of a cohort of 222 patients with reviewed histology and available clinical data. Expression was analyzed with Qupath for quantification and integration with clinical data enabled calculation of prognostic impact. For validation FOXP3 and RORC mRNA expression levels from 502 patients with HGSC in publicly available datasets were evaluated.
Results: An average percentage of 0.93 Tregs and of 0.06 Th17 cells was detected per cells in overall tissue. Optimal cut-offs were determined and higher Tregs were associated with a better overall survival in stroma (p = 0.006), tumor area (p = 0.0012) and overall tissue (p = 0.02). After accounting for well-known prognostic factors age at diagnosis, residual tumor and FIGO stage, this association remained significant for stromal Tregs with overall survival (p = 0.02). Survival analysis for Th17 cells revealed no significant association with survival rates. Moreover, lower Th17/Treg ratios had a positive impact on patient overall survival (p = 0.025 tumor, p = 0.049 stroma and p = 0.016 overall tissue).
Conclusion: Our results outline a positive prognostic effect for higher Tregs but not for Th17 in high grade serous tubo-ovarian carcinoma.
View lessPurpose: Based on the example of Gynaecological Cancer Centres (GCCs) certified by the German Cancer Society, this study evaluates the results of medical-guideline-derived quality indicators (QIs) for cervical cancer (CC) and ovarian cancer (OC), examines the development of indicator implementation over time as well as the status of guideline-compliant care and identifies improvement measures.
Methods: QI results for patients with CC and OC treated in GCCs between 2015 and 2019 are analysed. The median, overall proportion and standard deviation of each QI were calculated. Two-sided Cochran-Armitage tests were applied.
Results: QIs are divided into two categories: process-organization (PO-QIs) and treatment-procedures (TP-QIs), to allow a differentiated analysis for identifying improvement measures. PO-QIs that reflect the implementation of processes and structures show a high degree of application. PO-QIs have a tremendous influence on the quality of care and are easy to implement through SOPs. TP-QIs report on treatments that are performed in the GCC. TP-QIs that report on systemic therapies reach a plateau where the guideline is known, but patient-related-factors meaningfully prevent further increase. TP-QIs that report on surgical interventions fluctuate. The most relevant factors are practitioners' personal skills. Besides the discussion of results amongst peers during the audit, improvement measures could include surgical courses or coaching.
Conclusion: The analysis shows that a combination of different measures is necessary to anchor quality sustainably in health care and thus improve it.
View lessPurpose: Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes.
Methods: Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles.
Results: Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head-neck, 16 shoulder/hip, 14 trunk. Tumors were < 3 cm in 16, 3-5 cm in 28, 5-10 cm in 55, > 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% +/- 7.6 (95%CI) and 79.1% +/- 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size.
Conclusion: Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter.
View lessObjectives: Perioperative chemo-(radio-) therapy is the accepted standard in European patients with locally advanced adenocarcinoma of the esophagogastric junction or stomach (AEG/AS). However, 30-85% of patients do not respond to this treatment. The aim of our study was the identification of predictive biomarkers in pre-therapeutic endoscopic tumor biopsies from patients with histopathologic response (Becker-1) versus non-response (Becker-2/3) to preoperative chemotherapy.
Methods: Formalin-fixed paraffin-embedded biopsies from 36 Caucasian patients (Becker-1 n = 11, Becker-2 n = 7, Becker-3 n = 18) with AEG/AS, taken prior to neoadjuvant chemotherapy were selected. For RNA expression analysis, we employed the NanoString nCounter System. To identify genomic alterations like single nucleotide variants (SNV), copy number variation (CNV) and fusion events, we used Illumina TST170 gene panel. For HER2 and FGFR2 protein expression, immunostaining was performed. Furthermore, we analyzed the microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection status by EBER in situ hybridization.
Results: Heat map and principal component analyses showed no clustering by means of gene expression according to regression grade. Concerning two recently proposed predictive markers, our data showed equal distribution for MSI (Becker-1: 2; Becker-2: 1; Becker-3: 3; out of 29 tested) and EBV infection was rare (1/32). We could not reveal discriminating target genes concerning SNV, but found a higher mutational burden in non-responders versus responders and fusion (in 6/14) and CNV events (in 5/14) exclusively in Becker-3.
Conclusions: Although we could not identify discriminating target genes, our data suggest that molecular alterations are in general more prevalent in patients with AEG/AS belonging to the non-responding Becker group 3.
View lessPurpose: Adrenal gland metastases (AGMs) are a common manifestation of metastatic tumor spread, especially in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In patients with a limited systemic tumor burden, effective treatments for AGMs are needed. Due to varying fractionation schemes and limited reports, short-course treatment results for stereotactic body radiotherapy (SBRT) for AGMs are lacking. This work analyzes the outcomes of short-course SBRT for AGMs.
Methods: Patients who underwent robotic SBRT for AGMs with one to five fractions were eligible for analysis.
Results: In total, data from 55 patients with 72 AGMs from two institutions were analyzed. Most AGMs originated from renal cell carcinoma (38%) and NSCLC (35%). The median follow-up was 16.4 months. The median prescription dose and isodose line were 24 Gy and 70%, respectively. Most patients (85%) received SBRT with just one fraction. The median biologically effective dose assuming an alpha/beta ratio of 10 (BED10) was 80.4 Gy. The local control and progression-free survival after 1 and 2 years were 92.9%, 67.8%, and 46.2%, as well as 24.3%, respectively. Thirteen patients (24%) suffered from grade 1 or 2 toxicities. The BED10 showed a significant impact on LC (p < 0.01). Treatments with a BED10 equal to or above the median were associated with a better LC (p < 0.01).
Conclusion: Robotic SBRT is an efficient and safe treatment modality for AGM. Treatment-associated side effects are sporadic and manageable. Results suggest short-course SBRT to be a preferable and time-saving treatment option for the management of AGMs if an adequate BED10 can be safely applied.
View lessPurpose: The pathogenic mechanism of the hip-spine syndrome is still poorly elucidated. Some studies have reported a reduction in low back pain after total hip arthroplasty (THA). However, the biomechanical mechanisms of THA acting on the lumbar spine are not well understood. The aim of the study is to evaluate the influence of THA on (1) the lumbar lordosis and the lumbar flexibility and (2) the lumbar intervertebral disc height.
Methods: A total of 197 primary THA patients were prospectively enrolled. Pre- and post-operative biplanar stereoradiography was performed in standing and sitting positions. Spinopelvic parameters (lumbar lordosis (LL), pelvic tilt, sacral slope, pelvic incidence), sagittal spinal alignment (sagittal vertical axis, PI-LL mismatch (PI-LL)) and lumbar disc height index (DHI) for each segment (L1/2 to L5/S1) were evaluated. The difference between standing and sitting LL (Delta LL=LLstanding - LLsitting) was determined as lumbar flexibility. Osteochondrosis intervertebralis was graded according to Kellgren and Lawrence (0-4), and patients were assigned to subgroups (mild: 0-2; severe: 3-4).
Results: Lumbar flexibility increased significantly after THA (pre: 22.04 +/- 12.26 degrees; post: 25.87 +/- 12.26 degrees; p < 0.001), due to significant alterations in LL in standing (pre: 51.3 +/- 14.3 degrees; post: 52.4 +/- 13.8 degrees; p < 0.001) and sitting (pre: 29.4 +/- 15.4 degrees; post: 26.7 +/- 15.4 degrees; p = 0.01). Delta LL increased significantly in both subgroups stratified by osteochondrosis (pre/post: Delta LLmild: 25.4 (+/- 11.8)/29.4 +/- 12.0 degrees; p < 0.001; Delta LLsevere: 17.5 (+/- 11.4)/21.0 +/- 10.9 degrees; p = 0.003). The DHI increased significantly from pre-operatively to post-operatively in each lumbar segment. PI-LL mismatch decreased significantly after THA (pre: 3.5 degrees; post: 1.4 degrees; p <0.001).
Conclusion: The impact of THA on the spinopelvic complex was demonstrated by significantly improved lumbar flexibility and a gain in post-operative disc height. These results illustrate the close interaction between the pelvis and the vertebral column. The investigation provides new insights into the biomechanical patterns influencing the hip-spine syndrome.
View lessIn typical Dark Triad (DT) questionnaires, generic items oftentimes refer to “others” or “people” in general. Hence, respondents have to mentally aggregate their behavior across several kinds of “others” (e.g., work colleagues, family members, and friends). It remains unknown if individuals consider different kinds of interaction partners equally or if their self-reports contain “hidden” interaction partner-specific tendencies. To shed light on this issue, we assessed generic and contextualized DT items (referring to family, friends, work, and strangers; N = 814 from the general population). The correlated trait-correlated (method − 1) model was used to investigate preregistered research questions. On average, generic DT items showed the strongest association with work-contextualized DT items and the weakest association with family-contextualized DT items. However, the associations varied considerably across DT items and traits. In sum, our results suggest that hidden framings exist in some DT items, which may impact their ability to predict relevant criteria due to contextual (a)symmetries. The generalizability of the findings to other DT instruments, items, and participant groups should be examined in future research.
View lessThe question whether interference with the ubiquitous splicing machinery can lead to cell-type specific perturbation of cellular function is addressed here by T cell specific ablation of the general U5 snRNP assembly factor CD2BP2/U5–52K. This protein defines the family of nuclear GYF domain containing proteins that are ubiquitously expressed in eukaryotes with essential functions ascribed to early embryogenesis and organ function. Abrogating CD2BP2/U5–52K in T cells, allows us to delineate the consequences of splicing machinery interferences for T cell development and function. Increased T cell lymphopenia and T cell death are observed upon depletion of CD2BP2/U5–52K. A substantial increase in exon skipping coincides with the observed defect in the proliferation/differentiation balance in the absence of CD2BP2/U5–52K. Prominently, skipping of exon 7 in Mdm4 is observed, coinciding with upregulation of pro-apoptotic gene expression profiles upon CD2BP2/U5–52K depletion. Furthermore, we observe enhanced sensitivity of naïve T cells compared to memory T cells to changes in CD2BP2/U5–52K levels, indicating that depletion of this general splicing factor leads to modulation of T cell homeostasis. Given the recent structural characterization of the U5 snRNP and the crosslinking mass spectrometry data given here, design of inhibitors of the U5 snRNP conceivably offers new ways to manipulate T cell function in settings of disease.
View lessLocating sound sources such as prey or predators is critical for survival in many vertebrates. Terrestrial vertebrates locate sources by measuring the time delay and intensity difference of sound pressure at each ear1-5. Underwater, however, the physics of sound makes interaural cues very small, suggesting that directional hearing in fish should be nearly impossible6. Yet, directional hearing has been confirmed behaviourally, although the mechanisms have remained unknown for decades. Several hypotheses have been proposed to explain this remarkable ability, including the possibility that fish evolved an extreme sensitivity to minute interaural differences or that fish might compare sound pressure with particle motion signals7,8. However, experimental challenges have long hindered a definitive explanation. Here we empirically test these models in the transparent teleost Danionella cerebrum, one of the smallest vertebrates9,10. By selectively controlling pressure and particle motion, we dissect the sensory algorithm underlying directional acoustic startles. We find that both cues are indispensable for this behaviour and that their relative phase controls its direction. Using micro-computed tomography and optical vibrometry, we further show that D. cerebrum has the sensory structures to implement this mechanism. D. cerebrum shares these structures with more than 15% of living vertebrate species, suggesting a widespread mechanism for inferring sound direction.
View lessDue to the size and opacity of vertebrate brains, it has until now been impossible to simultaneously record neuronal activity at cellular resolution across the entire adult brain. As a result, scientists are forced to choose between cellular-resolution microscopy over limited fields-of-view or whole-brain imaging at coarse-grained resolution. Bridging the gap between these spatial scales of understanding remains a major challenge in neuroscience. Here, we introduce blazed oblique plane microscopy to perform brain-wide recording of neuronal activity at cellular resolution in an adult vertebrate. Contrary to common belief, we find that inferences of neuronal population activity are near-independent of spatial scale: a set of randomly sampled neurons has a comparable predictive power as the same number of coarse-grained macrovoxels. Our work thus links cellular resolution with brain-wide scope, challenges the prevailing view that macroscale methods are generally inferior to microscale techniques and underscores the value of multiscale approaches to studying brain-wide activity.
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