Contributors:Elena V. Volodina, Olga V. Sibiryakova, Ilya A. Volodin
Stag rutting calls are strongly different among subspecies of red deer Cervus elaphus. Studying sex-, age- and subspecies-related vocal variation may highlight the forces driving the evolution of vocal communication in this species after their expansion from Central Asia to Europe and North America, however, this information was lacking so far for any Asian subspecies of Cervus elaphus. We analysed frequency, temporal and power variables of contact and bugle calls, collected from 63 Siberian wapiti Cervus elaphus sibiricus, the most abundant Asian subspecies of red deer. The open-mouth (oral) and closed-mouth (nasal) contact calls were registered in all sex and age-classes, whereas the open-mouth bugles were found in both stags and hinds but not in the calves. The maximum fundamental frequency (f0max) of contact calls was similar between calves and hinds. Similarly to American subspecies, the small differences of f0 between calls of the young and adults in C. e. sibiricus suggests only a minor ontogenetic decrease of call fundamental frequency compared to European subspecies of red deer. At the same time, the call f0 of all sex and age-classes of C. e. sibiricus was substantially higher compared to those of European subspecies of red deer (C. e. hippelaphus, C. e. corsicanus, C. e. italicus and C. e. hispanicus), although lower than in any studied American subspecies (C. e. roosevelti and C. e. canadensis). These findings provide vocal cues to indicate subspecies of Cervus elaphus, in addition to existing molecular and morphological traits.
Contributors:Donglu Zhao, Alicia Addison, L Jeffrey Medeiros, Ken H Young, David Santos, Laura Lam, Jorge Romaguera, Felipe Samaniego, Krystle Nomie, Maria Badillo, Nicolaus Wagner-Bartak, Leo Zhang, Shaoying Li, Wendy Chen, Yasuhiro Oki, Hui Zhang, Hubert Chuang, Hun Lee, Maria DeLa Rosa, Luis Fayad, Frederick Hagemeister, Richard Champlin, Michael L Wang, Jason Westin, Francesco Turturro
Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.
Contributors:Frank Kauff, Julia Vereshchagina, Lars Hahn, Wolfgang Blau, Eckhart Weidmann, Mathias Rummel, Juergen Barth, Michael Sandherr, Axel Hinke, Ulrich von Gruenhagen, Norbert Niederle, Hans-Peter Boeck, Christoph Losem, Lothar Mueller, Ulrich Kaiser, Wolfram Brugger, Martina Stauch, Manfred Welslau, Christina Balser
Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma.
Phase entrainment of neural oscillations, the brain's adjustment to rhythmic stimulation, is a central component in recent theories of speech comprehension: the alignment between brain oscillations and speech sound improves speech intelligibility. However, phase entrainment to everyday speech sound could also be explained by oscillations passively following the low-level periodicities (e.g., in sound amplitude and spectral content) of auditory stimulation—and not by an adjustment to the speech rhythm per se. Recently, using novel speech/noise mixture stimuli, we have shown that behavioral performance can entrain to speech sound even when high-level features (including phonetic information) are not accompanied by fluctuations in sound amplitude and spectral content. In the present study, we report that neural phase entrainment might underlie our behavioral findings. We observed phase-locking between electroencephalogram (EEG) and speech sound in response not only to original (unprocessed) speech but also to our constructed “high-level” speech/noise mixture stimuli. Phase entrainment to original speech and speech/noise sound did not differ in the degree of entrainment, but rather in the actual phase difference between EEG signal and sound. Phase entrainment was not abolished when speech/noise stimuli were presented in reverse (which disrupts semantic processing), indicating that acoustic (rather than linguistic) high-level features play a major role in the observed neural entrainment. Our results provide further evidence for phase entrainment as a potential mechanism underlying speech processing and segmentation, and for the involvement of high-level processes in the adjustment to the rhythm of speech.
Learned and adaptive behaviors rely on neural circuits that flexibly couple the same sensory input to alternative output pathways. Here, we show that the Drosophila mushroom body functions like a switchboard in which neuromodulation reroutes the same odor signal to different behavioral circuits, depending on the state and experience of the fly. Using functional synaptic imaging and electrophysiology, we reveal that dopaminergic inputs to the mushroom body modulate synaptic transmission with exquisite spatial specificity, allowing individual neurons to differentially convey olfactory signals to each of their postsynaptic targets. Moreover, we show that the dopaminergic neurons function as an interconnected network, encoding information about both an animal’s external context and internal state to coordinate synaptic plasticity throughout the mushroom body. Our data suggest a general circuit mechanism for behavioral flexibility in which neuromodulatory networks act with synaptic precision to transform a single sensory input into different patterns of output activity.
Our vocal tone—the prosody—contributes a lot to the meaning of speech beyond the actual words. Indeed, the hesitant tone of a “yes” may be more telling than its affirmative lexical meaning . The human brain contains dorsal and ventral processing streams in the left hemisphere that underlie core linguistic abilities such as phonology, syntax, and semantics [2–4]. Whether or not prosody—a reportedly right-hemispheric faculty [5, 6]—involves analogous processing streams is a matter of debate. Functional connectivity studies on prosody leave no doubt about the existence of such streams [7, 8], but opinions diverge on whether information travels along dorsal  or ventral [10, 11] pathways. Here we show, with a novel paradigm using audio morphing combined with multimodal neuroimaging and brain stimulation, that prosody perception takes dual routes along dorsal and ventral pathways in the right hemisphere. In experiment 1, categorization of speech stimuli that gradually varied in their prosodic pitch contour (between statement and question) involved (1) an auditory ventral pathway along the superior temporal lobe and (2) auditory-motor dorsal pathways connecting posterior temporal and inferior frontal/premotor areas. In experiment 2, inhibitory stimulation of right premotor cortex as a key node of the dorsal stream decreased participants’ performance in prosody categorization, arguing for a motor involvement in prosody perception. These data draw a dual-stream picture of prosodic processing that parallels the established left-hemispheric multi-stream architecture of language, but with relative rightward asymmetry.
Contributors:Dimos Gaidatzis, Kehao Zhao, Liqing Geng, Michael H. Hauer, Li Wang, Xinghao Wang, Benjamin D. Towbin, Daphne S. Cabianca, Adriana Gonzalez-Sandoval, Susan M. Gasser, Teddy Yang, Veronique Kalck
Interphase chromatin is organized in distinct nuclear sub-compartments, reflecting its degree of compaction and transcriptional status. In Caenorhabditis elegans embryos, H3K9 methylation is necessary to silence and to anchor repeat-rich heterochromatin at the nuclear periphery. In a screen for perinuclear anchors of heterochromatin, we identified a previously uncharacterized C. elegans chromodomain protein, CEC-4. CEC-4 binds preferentially mono-, di-, or tri-methylated H3K9 and localizes at the nuclear envelope independently of H3K9 methylation and nuclear lamin. CEC-4 is necessary for endogenous heterochromatin anchoring, but not for transcriptional repression, in contrast to other known H3K9 methyl-binders in worms, which mediate gene repression but not perinuclear anchoring. When we ectopically induce a muscle differentiation program in embryos, cec-4 mutants fail to commit fully to muscle cell fate. This suggests that perinuclear sequestration of chromatin during development helps restrict cell differentiation programs by stabilizing commitment to a specific cell fate.
Contributors:Pawel Fedurek, Katie E. Slocombe, Klaus Zuberbühler
Conflict and aggressive interactions are common phenomena in group-living animals and vocal behaviour often plays an important role in determining their outcomes. In some species, vocal signals seem to provide bystanders with information about the nature of an ongoing aggressive interaction, which can be beneficial for the victims. For example, in chimpanzees and some other primates, victims adjust their screams depending on the composition of the by-standing audience, probably to solicit their support. Considerably less is known, however, about the role of other call types produced by victims of aggression. In this study, we focused on the fact that, immediately after screams, chimpanzee, Pan troglodytes schweinfurthii, victims often produce ‘waa’ barks, but little is known about their function. Our results showed that for screams, but not ‘waa’ barks, production was dependent on the audience composition with victims being more likely to scream when adult or late-adolescent males were in close proximity. We also found that after ‘waa’ barking, but not screaming, victims were more likely to retaliate against and less likely to reconcile with their aggressors, and that ‘waa’ barking was more common after victims had received support from other party members. These results suggest that, in chimpanzees, victims of aggression vocalize with a dual social strategy of attempting to recruit support from bystanders and to repel their attackers by signalling readiness to retaliate. We conclude that victim scream and ‘waa’ bark calls, although often produced during the same agonistic event, are directed at different audiences and fulfil different social functions, and that these calls can mediate both aggressive interactions and aggressor–victim relationships following aggression.
Contributors:Sergio Verjovski-Almeida, Natassia M. Vieira, Ingegerd Elvers, Kerstin Lindblad-Toh, Mayana Zatz, Yuri B. Moreira, Juliana P. Gomes, Jamie L. Marshall, Matthew S. Alexander, Louis M. Kunkel, Elinor K. Karlsson, Alal Eran
Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner.