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This paper presents results on multiplicity fluctuations of positively and negatively charged hadrons as well as net-electric charge fluctuations measured in central Ar+Sc interactions at beam momenta 13A, 19A, 30A, 40A, 75A, and 150 A GeV/c. The fluctuation analysis is one of the tools to search for the predicted critical point of strongly interacting matter. Results are corrected for the experimental biases and quantified using cumulant ratios. In most instances, multiplicity and net-charge distributions appear narrower than the corresponding Poisson or Skellam distributions. Cumulant ratios are compared with the EPOS1.99 model predictions, which provide a qualitative description that aligns with observations for positively and negatively charged particles. The obtained results are also compared to earlier NA61/SHINE results from inelastic p+p interactions in the same analysis acceptance.

In the mammalian auditory system, sensory cell loss resulting from aging, ototoxic drugs, infections, overstimulation and other causes is irreversible and leads to permanent sensorineural hearing loss. To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1 , a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal. The data suggest a new therapeutic approach based on expressing crucial developmental genes for cellular and functional restoration in the damaged auditory epithelium and other sensory systems.

Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low and variable efficiency of HC production. Gfi1 is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of Atoh1 and Gfi1 over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of Atoh1 and Gfi1 in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in Atoh1  +  Gfi1 cultures than Atoh1 alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3 DTR mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of Atoh1 or Atoh1  +  Gfi1 in cochlear supporting cells induced appearance of HCLCs, with Atoh1  +  Gfi1 expression leading to 6.2-fold increase of new HCLCs after 4 weeks compared to Atoh1 alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8 weeks. Combinatorial Atoh1 and Gfi1 induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.

The cochlear implant (CI) is widely considered to be one of the most innovative and successful neuroprosthetic treatments developed to date. Although outcomes vary, CIs are able to effectively improve hearing in nearly all recipients and can substantially improve speech understanding and quality of life for patients with significant hearing loss. A wealth of research has focused on underlying factors that contribute to success with a CI, and recent evidence suggests that the overall health of the cochlea could potentially play a larger role than previously recognized. This article defines and reviews attributes of cochlear health and describes procedures to evaluate cochlear health in humans and animal models in order to examine the effects of cochlear health on performance with a CI. Lastly, we describe how future biologic approaches can be used to preserve and/or enhance cochlear health in order to maximize performance for individual CI recipients.

Inappropriate activation of the tumour-suppressor protein p53 during development can promote phenotypes similar to those of CHARGE syndrome, suggesting that p53 activation not only has a beneficial function in suppressing cancer but also a deleterious function in promoting developmental syndromes. CHARGE syndrome promoted by activated p53 The complex congenital disorder known as CHARGE syndrome results in many phenotypes, including heart defects, retarded growth and development, genital hypoplasia and ear abnormalities. Most CHARGE syndrome patients have mutations in the gene for the chromatin remodeller protein CHD7, but in mouse the Chd7 mutation is embryonically lethal, and not all CHARGE syndrome phenotypes are evident. Laura Attardi and colleagues now demonstrate that inappropriate activation of the p53 tumour suppressor gene during development can promote CHARGE phenotypes in mice, including ocular coloboma and defects of both the outer and inner ear, which are typical of CHARGE syndrome and rare in other conditions. The findings that p53 mutations can drive both cancer and developmental diseases throws a new light on the function of p53 in vivo . CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities 1 . Despite 70–90% of CHARGE syndrome cases resulting from mutations in the gene CHD7 , which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood 2 . Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53 25,26,53,54 ) 3 , along with a wild-type allele of p53 (also known as Trp53 ), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53 25,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53 25,26,53,54 /− embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7 -null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV. BDNF and AAV. Ntf3 , on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV. BDNF or AAV. Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term.

Allometry has been a paradigm of constraints, including intrinsic constraints on the evolvability of allometry, as a source of developmental and genetic constraints on the evolution of form, and of functional constraints, maintaining functional equivalence as body size evolves. Yet, allometry may be the simplest case of varied constraints, and of morphological integration, even though allometry itself is not simple. Evolutionary allometry may be especially complex because it depends not only on developmental origins of allometry and determinants of allometric variation but also on the evolutionary dynamics of size and shape. It should also depend on the ecological opportunity for size-dependent ecomorphological specialization. We predict that lineages that converge in those would exhibit similar evolutionary allometries but otherwise, evolutionary allometries would be heterogeneous. Countering this expectation are familiar craniofacial evolutionary allometries, often ascribed to developmental bias. To test both those hypotheses, we compare evolutionary allometries of mandibles across lineages of squirrels and evolutionary to growth allometries. As expected, lineages that converge on size-dependent specializations exhibit similar evolutionary allometries, but otherwise their allometries are no more similar than expected by chance. Growth allometries of squirrels (and a cricetid rodent) slightly resemble the evolutionary allometry of one lineage, but growth allometries of species from other lineages are orthogonal to their own lineages’ evolutionary allometry. We would expect that craniofacial allometries that are not brain-driven would, like mandibular evolutionary allometries, be predictable only from size-dependent ecological specializations.

Hair cells in the mature cochlea cannot spontaneously regenerate. One potential approach for restoring hair cells is stem cell therapy. However, when cells are transplanted into scala media (SM) of the cochlea, they promptly die due to the high potassium concentration. We previously described a method for conditioning the SM to make it more hospitable to implanted cells and showed that HeLa cells could survive for up to a week using this method. Here, we evaluated the survival of human embryonic stem cells (hESC) constitutively expressing GFP (H9 Cre-LoxP) in deaf guinea pig cochleae that were pre-conditioned to reduce potassium levels. GFP-positive cells could be detected in the cochlea for at least 7 days after the injection. The cells appeared spherical or irregularly shaped, and some were aggregated. Flushing SM with sodium caprate prior to transplantation resulted in a lower proportion of stem cells expressing the pluripotency marker Oct3/4 and increased cell survival. The data demonstrate that conditioning procedures aimed at transiently reducing the concentration of potassium in the SM facilitate survival of hESCs for at least one week. During this time window, additional procedures can be applied to initiate the differentiation of the implanted hESCs into new hair cells.

Modularity and integration are fundamental properties of organisms and central to theories of complex adaptation. Modularity and integration of shape can provide valuable information about the geometry and spatial structure of modules, but a recent study contends that Procrustes superimposition yields alarmingly high frequencies of statistically significant modularity and integration. We reexamine those claims, using data simulated with biologically realistic parameter values, extending the analyses to consider the impact of simulation procedure, model complexity, and landmark sampling scheme, as well as the impact of superimposition on the strength of modularity and integration and on model comparisons. We further extend analyses to evolutionary modularity and integration. We find that superimposition, followed by sliding semilandmarks to minimize bending energy almost invariably induces significant modularity and integration but sliding to minimize the Procrustes Distance, rarely does (no more than 11% of simulated populations are significantly modular) and even more rarely strengthens it. Integration is more often significant in simulated populations, and is more strongly affected by model complexity, density of semi-landmarks, simulation procedure and sample size. The frequency of significant modularity and integration can reach 17% of simulated lineages but neither evolutionary modularity nor integration are significantly strengthened by superimposition followed by sliding. The most alarming results are the extremely high frequency of significant integration in large samples (N = 500) and the non-normal distribution of effect sizes (Z-scores). Even so, the effect of superimposition is slight compared to the strength of variational or evolutionary modularity and integration found in empirical cases.

Convergence is widely regarded as compelling evidence for adaptation, often being portrayed as evidence that phenotypic outcomes are predictable from ecology, overriding contingencies of history. However, repeated outcomes may be very rare unless adaptive landscapes are simple, structured by strong ecological and functional constraints. One such constraint may be a limitation on body size because performance often scales with size, allowing species to adapt to challenging functions by modifying only size. When size is constrained, species might adapt by changing shape; convergent shapes may therefore be common when size is limiting and functions are challenging. We examine the roles of size and diet as determinants of jaw shape in Sciuridae. As expected, size and diet have significant interdependent effects on jaw shape and ecomorphological convergence is rare, typically involving demanding diets and limiting sizes. More surprising is morphological without ecological convergence, which is equally common between and within dietary classes. Those cases, like rare ecomorphological convergence, may be consequences of evolving on an adaptive landscape shaped by many-to-many relationships between ecology and function, many-to-one relationships between form and performance, and one-to-many relationships between functionally versatile morphologies and ecology. On complex adaptive landscapes, ecological selection can yield different outcomes.