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Within-situation disengagement – the mental withdrawal during conversations in acoustically challenging environments – is a common experience of older people with hearing difficulties. Yet, most research on the neural mechanisms of attentional disengagement from speech listening has focused on the distraction by one competing speaker, whereas within-situation disengagement is often characterized by distraction towards external visual stimuli or internal thoughts and occurs in situations with ambient, multi-talker background masking. Across three electroencephalography (EEG) experiments, the current study examined how disengagement due to external and internal distractions affect the neural tracking of speech masked by different levels of multi-talker babble (speech in quiet, +6 dB, and −3 dB SNR). We observed early (<200 ms), enhanced neural responses to the speech envelope for speech masked by background babble compared to speech in quiet (Experiments 1-3), suggesting stochastic facilitation. Importantly, neural tracking of the speech envelope was reduced when individuals were distracted by a visual-stimulus stream (Experiment 2) and by internal thought and imagination (Experiment 3). There were some indices suggesting the greatest disengagement-related decline in neural speech tracking occurs for the most difficult speech-masking condition, but this was not consistent across all measures. The current data show that disengagement due to external and internal distractions yield decreases in neural speech tracking, potentially suggesting a common neural pathway through which gain is downregulated in auditory cortex. These results indicate that disengagement from listening can be identified through non-invasive neural measures. Many older adults with hearing difficulties mentally “tune out” during conversations in noisy environments, yet the neural mechanisms underlying this within-situation disengagement remain poorly understood. Across three electroencephalography experiments, we examined how external (visual) and internal (thought-based) distractions influence neural tracking of speech masked by multi-talker babble. We observed that attentional disengagement – whether induced by external stimuli or internal thoughts – reduced the brain’s tracking of the speech envelope. These findings demonstrate that listening disengagement can be objectively identified through neural measures and suggest a shared neural pathway through which both external and internal distractions down-regulate auditory gain, providing new insight into attentional control in challenging listening conditions.

Pupillometry is the most used objective tool to assess listening effort but has several disadvantages. The current study explores a new, objective way to assess listening effort through eye movements. Building on cognitive and neurophysiological work, we examine the hypothesis that eye movements decrease when speech listening becomes challenging. In three experiments with human participants from both sexes, we demonstrate, consistent with this hypothesis, that fixation duration increases and spatial gaze dispersion decreases with increasing speech masking. Eye movements decreased during effortful speech listening for different visual scenes (free viewing; object tracking) and speech materials (simple sentences; naturalistic stories). In contrast, pupillometry was insensitive to speech masking during story listening, highlighting the challenges with pupillometric measures for the assessments of listening effort in naturalistic speech-listening paradigms. Our results reveal a critical link between eye movements and cognitive load, and provide the foundation for a novel measure of listening effort applicable in a wide range of contexts.Competing Interest StatementThe authors have declared no competing interest.

To extend the assessment of listening effort beyond a sound booth, we validated mobile eye-tracking glasses (Pupil Labs Neon) by comparing them to a stationary system (Eyelink DUO) in a controlled environment. We recorded eye movements, pupil size, and head movements from 26 young adults during a speech-in-noise task. When listening conditions became challenging, we observed reduced gaze dispersion and increased pupil sizes of similar magnitude from both devices, in addition to reduced head movements recorded solely by the mobile device. These findings suggest that mobile eye-trackers reliably capture listening effort, paving the path towards assessments in daily settings.

Magnetic domain walls are boundaries between regions with different configurations of the same magnetic order. In a magnetic insulator, where the magnetic order is tied to its bulk insulating property, it has been postulated that electrical properties are drastically different along the domain walls, where the order is inevitably disturbed. Here we report the discovery of highly conductive magnetic domain walls in a magnetic insulator, Nd₂Ir₂O₇, that has an unusual all-in-all-out magnetic order, via transport and spatially resolved microwave impedance microscopy. The domain walls have a virtually temperature-independent sheet resistance of ∼1 kilohm per square, show smooth morphology with no preferred orientation, are free from pinning by disorders, and have strong thermal and magnetic field responses that agree with expectations for all-in-all-out magnetic order.

Approximately 7% of pancreatic cancers occur in patients with a germline mutation in BRCA1 or BRCA2 , an alteration that compromises DNA repair. In a randomized trial in patients with metastatic pancreatic cancer that had responded to platinum-based chemotherapy, progression-free survival was nearly twice as long with olaparib than with placebo (7.4 months vs. 3.8 months).

Phospholipid scrambling (PLS) is a ubiquitous cellular mechanism involving the regulated bidirectional transport of phospholipids down their concentration gradient between membrane leaflets. ANO6/TMEM16F has been shown to be essential for Ca2+-dependent PLS, but controversy surrounds whether ANO6 is a phospholipid scramblase or an ion channel like other ANO/TMEM16 family members. Combining patch clamp recording with measurement of PLS, we show that ANO6 elicits robust Ca2+-dependent PLS coinciding with ionic currents that are explained by ionic leak during phospholipid translocation. By analyzing ANO1-ANO6 chimeric proteins, we identify a domain in ANO6 necessary for PLS and sufficient to confer this function on ANO1, which normally does not scramble. Homology modeling shows that the scramblase domain forms an unusual hydrophilic cleft that faces the lipid bilayer and may function to facilitate translocation of phospholipid between membrane leaflets. These findings provide a mechanistic framework for understanding PLS and how ANO6 functions in this process. Cell membranes are made of two layers of molecules called phospholipids. The types of phospholipid molecules in the outer layer are often different from those in the inner layer. This asymmetry is an important feature of most membranes, but cells also have proteins called ‘scramblases’ that can move (or scramble) the phospholipids between the two layers. This scrambling process often marks a cell for destruction but also plays a key role in many activities throughout the body including cell–cell fusion, blood clotting, autoimmune diseases and inflammation. Previous research revealed that a membrane protein called ANO6 is needed for some kinds of phospholipid scrambling. Other proteins that are most closely related to ANO6 are not phospholipid scramblases; instead they are channel proteins that allow ions to pass across cell membranes. ANO6 can also allow ions to flow across membranes, which raised the question: is ANO6 actually a scramblase itself, or does it control other proteins with scramblase activity? Yu, Whitlock et al. addressed this question by engineering human cells grown in the laboratory to produce the ANO6 protein, and found that these cells had high levels of phospholipid scrambling. Next, the scrambling of phospholipids in these cells was measured while the flow of ions through ANO6 was also recorded. These experiments revealed that these two processes happened almost simultaneously. Yu, Whitlock et al. suggest that this could mean that ANO6 allows ions to leak through when it shuttles phospholipids between layers of cell membranes. ANO1 is an ion channel that is related to ANO6 but it does not have scramblase activity. By designing and testing hybrid proteins that combined parts of ANO6 and ANO1, Yu, Whitlock et al. identified the part of ANO6 that is responsible for its scramblase activity. Furthermore, computer models of this ‘scrambling domain’ suggest that it forms an unusual groove that faces into the cell membrane, and that could help phospholipids to shuttle between the inner and outer layers of the membrane. Alternatively, this groove could interact with other proteins to regulate phospholipid scrambling; and if so, further work will be needed to identify these unknown proteins. Finally, swapping a relatively small number of features between ANO6 and ANO1 could confer scrambling activity on ANO1. This suggests that ANO1 may itself have a special relationship to membrane phospholipids. Uncovering the nature of this relationship, if it exists, as well as understanding how ANO6 scrambles phospholipids will challenge structural biologists to generate high-resolution images of these proteins in complex with phospholipids.

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1 , REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1 / REV3L -specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide- co glycolide)- b -poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1 / REV3L -specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.

The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and nonregenerative mouse hearts over a 7-d time period following myocardial infarction injury. By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration, and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and a retained embryonic cardiogenic gene program that is active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that can be modulated to promote heart regeneration.

The realization of quantum spin Hall effect in HgTe quantum wells is considered a milestone in the discovery of topological insulators. Quantum spin Hall states are predicted to allow current flow at the edges of an insulating bulk, as demonstrated in various experiments. A key prediction yet to be experimentally verified is the breakdown of the edge conduction under broken time-reversal symmetry. Here we first establish a systematic framework for the magnetic field dependence of electrostatically gated quantum spin Hall devices. We then study edge conduction of an inverted quantum well device under broken time-reversal symmetry using microwave impedance microscopy, and compare our findings to a non-inverted device. At zero magnetic field, only the inverted device shows clear edge conduction in its local conductivity profile, consistent with theory. Surprisingly, the edge conduction persists up to 9 T with little change. This indicates physics beyond simple quantum spin Hall model, including material-specific properties and possibly many-body effects. Quantum spin Hall edge states are protected by time-reversal symmetry and are expected to disappear in a strong magnetic field. Here, the authors use microwave impedance microscopy and find, surprisingly, edge conduction in mercury telluride quantum wells that survives up to 9 T with little change.

Asian HIV epidemics are concentrated among particular behavioural groups, but large variations exist in epidemic types, timing, and geographical spread between countries and within countries, especially in China. We aimed to understand the complexity of HIV epidemics in China by systematically analysing prevalence trends by data source, region, population group, and time period. We collected HIV prevalence data from official national sentinel surveillance sites at the provincial level from Jan 1, 1995, to Dec 31, 2010. We also searched PubMed, VIP Chinese Journal Database (VIP), China National Knowledge Infrastructure, and Wanfang Data from Jan 1, 1990, to Dec 31, 2012, for independent studies of HIV prevalence. We integrated both sets of data, and used an intraclass correlation coefficient test to assess the similarity of geographical pattern of HIV disease burden across 31 Chinese provinces in 2010. We investigated prevalence trends (and 95% CIs) to infer corresponding incidence by region, population group, and year. Of 6850 articles identified by the search strategy, 821 studies (384 583 drug users, 52 356 injecting drug users, 186 288 female sex workers, and 87 834 men who have sex with men) met the inclusion criteria. Official surveillance data and findings from independent studies showed a very similar geographical distribution and magnitude of HIV epidemics across China. We noted that HIV epidemics among injecting drug users are decreasing in all regions outside southwest China and have stabilised at a high level in northwest China. Compared with injecting drug users, HIV prevalence in female sex workers is much lower and has stabilised at low levels in all regions except in the southwest. In 2010, national HIV prevalence was 9·08% (95% CI 8·04–10·52) in injecting drug users and 0·36% (0·12–0·71) in female sex workers, whereas incidence in both populations stabilised at rates of 0·57 (0·43–0·72) and 0·02 (0·01–0·04) per 100 person-years, respectively. By comparison, HIV prevalence in men who have sex with men increased from 1·77% (1·26–2·57) in 2000, to 5·98% (4·43–8·18) in 2010, with a national incidence of 0·98 (0·70–1·25) per 100 person-years in 2010. We recorded strong associations between HIV prevalence among at-risk populations in each province, supporting the existence of overlap in risk behaviours and mixing among these populations. HIV epidemics in China remain concentrated in injecting drug users, female sex workers, and men who have sex with men. HIV prevalence is especially high in southwest China. Sex between men has clearly become the main route of HIV transmission. The World Bank Group, the Australian Research Council, the University of New South Wales, and Chinese Center for Disease Control and Prevention.