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Inherited retinal dystrophies and late-stage age-related macular degeneration, for which treatments remain limited, are among the most prevalent causes of legal blindness. Retinal prostheses have been developed to stimulate the inner retinal network; however, lack of sensitivity and resolution, and the need for wiring or external cameras, have limited their application. Here we show that conjugated polymer nanoparticles (P3HT NPs) mediate light-evoked stimulation of retinal neurons and persistently rescue visual functions when subretinally injected in a rat model of retinitis pigmentosa. P3HT NPs spread out over the entire subretinal space and promote light-dependent activation of spared inner retinal neurons, recovering subcortical, cortical and behavioural visual responses in the absence of trophic effects or retinal inflammation. By conferring sustained light sensitivity to degenerate retinas after a single injection, and with the potential for high spatial resolution, P3HT NPs provide a new avenue in retinal prosthetics with potential applications not only in retinitis pigmentosa, but also in age-related macular degeneration.Semiconducting polymer nanoparticles can act as light-sensitive interfaces with retinal neurons, and on microinjection in the eye, rescue vision in retinas affected by photoreceptor degeneration, offering a potential new treatment option for inherited retinal dystrophies and late-stage age-related macular degeneration.

To investigate the three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia and mantle cell lymphoma patients, here we integrate in situ Hi-C and nine additional omics layers. Beyond conventional active (A) and inactive (B) compartments, we uncover a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, 28% of the compartments change, mostly involving a widespread chromatin activation from naive to germinal center B cells and a reversal to the naive state upon further maturation into memory B cells. B cell neoplasms are characterized by both entity and subtype-specific alterations in 3D genome organization, including large chromatin blocks spanning key disease-specific genes. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture. The dynamics of genome architecture during human cell differentiation and upon neoplastic transformation remain poorly characterized. Here, the authors integrate in situ Hi-C and nine additional omic layers to characterize the dynamic changes in 3D genome architecture during normal B cell differentiation and in neoplastic cells from chronic lymphocytic leukemia and mantle cell lymphoma patients.

Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Chromosome conformation capture (3C)-based experiments combined with computational modelling are pivotal for unveiling 3D chromosome structure. Here, we introduce TADdyn, a tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci in a completely data-driven way. We apply TADdyn on in situ Hi-C time-course experiments studying the reprogramming of murine B cells to pluripotent cells, and characterize the structural rearrangements that take place upon changes in the transcriptional state of 21 genomic loci of diverse expression dynamics. By measuring various structural and dynamical properties, we find that during gene activation, the transcription starting site contacts with open and active regions in 3D chromatin domains. We propose that these 3D hubs of open and active chromatin may constitute a general feature to trigger and maintain gene transcription. Regulation of chromosome structure plays essential roles in many nuclear processes. Here, the authors present TADdyn, a tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci and find that during gene activation, transcription starting sites contact with open chromatin regions into active physical domains.

The ongoing effort to detect and characterize physical entanglement in biopolymers has so far established that knots are present in many globular proteins and also, abound in viral DNA packaged inside bacteriophages. RNA molecules, however, have not yet been systematically screened for the occurrence of physical knots. We have accordingly undertaken the systematic profiling of the several thousand RNA structures present in the Protein Data Bank (PDB). The search identified no more than three deeply knotted RNA molecules. These entries are rRNAs of about 3,000 nt solved by cryo-EM. Their genuine knotted state is, however, doubtful based on the detailed structural comparison with homologs of higher resolution, which are all unknotted. Compared with the case of proteins and viral DNA, the observed incidence of knots in available RNA structures is, therefore, practically negligible. This fact suggests that either evolutionary selection or thermodynamic and kinetic folding mechanisms act toward minimizing the entanglement of RNA to an extent that is unparalleled by other types of biomolecules. A possible general strategy for designing synthetic RNA sequences capable of self-tying in a twist-knot fold is finally proposed. Significance Biopolymers have arguably evolved to be free of entanglements that could impair their folding or function. This selection mechanism is, however, opposed by the general physical principle that sufficiently long and densely packed polymers are inevitably entangled. This competition is nowadays well-documented for proteins and viral DNA, which can be knotted and yet, functionally viable. By contrast, the incidence of knots in RNA is still virtually unexplored. To fill this gap, we topologically profiled thousands of RNA structures, finding only three deeply knotted chains. Comparison with higher-resolution homologs further suggests that these instances may actually be unknotted as well. The practical absence of knots indicates that thermodynamic or kinetic mechanisms are likely at play for minimizing the entanglement of biologically viable structured RNAs.

Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget disease of bone (PDB), but recent data regarding their prevalence in PDB patients are lacking. Study 1: To compare the prevalence of primary HPTH and NL in 708 patients with PDB and in 1803 controls. Study 2: To evaluate the prevalence of NL-metabolic risk factors in 97 patients with PDB and NL, 219 PDB patients without NL, 364 NL patients without PDB, and 219 controls, all of them without HPTH. Cross-sectional multicentric study. Italian referral centers for metabolic bone disorders. Patients with PDB from the Associazione Italiana malati di osteodistrofia di Paget registry. Participants in the Olivetti Heart and the Siena Osteoporosis studies. HPTH; NL; NL-metabolic risk factors. Patients with PDB showed higher prevalence of primary HPTH and NL compared with controls (P < 0.01). The NL recurrence occurs more frequently in patients with polyostotic PDB. About one-half of patients with PDB but without NL showed 1 or more NL-related metabolic risk factors. The hyperoxaluria (HyperOx) prevalence was higher in patients with PDB and NL compared with patients with NL but without PDB and in patients with PDB without NL compared with controls (P = 0.01). Patients with PDB and HyperOx showed a longer lapse of time from the last aminobisphosphonate treatment. NL and HPTH are frequent metabolic complication of PDB. The NL occurrence should be evaluated in patients with PDB, particularly in those with polyostotic disease and/or after aminobisphosphonate treatment to apply an adequate prevention strategy.

Teriparatide is a bone-forming therapy for osteoporosis that increases bone quantity and texture, with uncertain action on bone geometry. No data are available regarding its influence on bone strain. To investigate teriparatide action on parameters of bone quantity and quality and on Bone Strain Index (BSI), also derived from DXA lumbar scan, based on the mathematical model finite element method. Forty osteoporotic patients with fractures were studied before and after two years of daily subcutaneous 20 mcg of teriparatide with dual X-ray photon absorptiometry to assess bone mineral density (BMD), hip structural analysis (HSA), trabecular bone score (TBS), BSI. Spine deformity index (SDI) was calculated from spine X-ray. Shapiro-Wilks, Wilcoxon and Student's t test were used for classical statistical analysis. Auto Contractive Map was used for Artificial Neural Network Analysis (ANNs). In the entire population, the ameliorations after therapy regarded BSI (-13.9%), TBS (5.08%), BMD (8.36%). HSA parameters of femoral shaft showed a worsening. Dividing patients into responders (BMD increase >10%) and non-responders, the first presented TBS and BSI ameliorations (11.87% and -25.46%, respectively). Non-responders presented an amelioration of BSI only, but less than in the other subgroup (-6.57%). ANNs maps reflect the mentioned bone quality improvements. Teriparatide appears to ameliorate not only BMD and TBS, but also BSI, suggesting an increase of bone strength that may explain the known reduction in fracture risk, not simply justified by BMD increase. BSI appears to be a sensitive index of TPD effect. ANNs appears to be a valid tool to investigate complex clinical systems.

Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1) or type-2 (CB2) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.

Background: Wrestling is a high-impact sport characterized by rapid, forceful movements, posing a considerable injury risk to athletes who are often evaluated in emergency departments (EDs) across the United States. This study examines the principal mechanics, distributions, and epidemiological trends of wrestling-related injuries. Hypothesis: (1) Upper extremity injuries would be the most common, (2) young men would be the most affected group, and (3) sprains/strains would be the most frequent diagnosis. Study Design: Descriptive epidemiology study. Methods: Patients evaluated at US EDs for wrestling-related injuries between January 1, 2015, and December 31, 2024, were identified using the National Electronic Injury Surveillance System database. Patient characteristics, injury location, diagnosis, disposition, and mechanisms of injury were recorded. Data analysis was calculated using national estimates (NEs) and linear regression to assess trends and associations. Results: From 2015 to 2024, US EDs reported approximately 10,508 cases (NE, 370,089) of wrestling-related visits. Of these, 88.4% involved males (NE, 326,985). Pediatric patients (≤18 years of age) accounted for the majority of injuries, accounting for 84.9% of all cases (NE, 314,166), with a mean age of 15.9 ± 6.2 years for the entire cohort. The lowest number of wrestling-related injuries occurred in 2020 (NE, 20,270), while the highest number was reported in 2024 (NE, 57,026). The most commonly injured body regions were the shoulder (15.2%; NE, 56,150) and head (13.1%; NE, 48,619). Sprains and strains represented the most frequent injury type at 27.6% (NE, 102,253). Conclusion: This study showed that males constituted the predominant majority of ED visits from wrestling injuries, with shoulder and neck strains being the most prevalent. The significant rise in injuries from 2020 to 2024 highlights the necessity for preventative measures and heightened awareness of wrestling safety, especially in recreational environments, where occurrences are notably elevated.

The connection between chromatin nuclear organization and gene activity is vividly illustrated by the observation that transcriptional coregulation of certain genes appears to be directly influenced by their spatial proximity. This fact poses the more general question of whether it is at all feasible that the numerous genes that are coregulated on a given chromosome, especially those at large genomic distances, might become proximate inside the nucleus. This problem is studied here using steered molecular dynamics simulations in order to enforce the colocalization of thousands of knowledge-based gene sequences on a model for the gene-rich human chromosome 19. Remarkably, it is found that most (≈ 88%) gene pairs can be brought simultaneously into contact. This is made possible by the low degree of intra-chromosome entanglement and the large number of cliques in the gene coregulatory network. A clique is a set of genes coregulated all together as a group. The constrained conformations for the model chromosome 19 are further shown to be organized in spatial macrodomains that are similar to those inferred from recent HiC measurements. The findings indicate that gene coregulation and colocalization are largely compatible and that this relationship can be exploited to draft the overall spatial organization of the chromosome in vivo. The more general validity and implications of these findings could be investigated by applying to other eukaryotic chromosomes the general and transferable computational strategy introduced here.

Esca disease, the most widespread grapevine trunk disease in Europe, is characterized by both chronic and acute forms. In both cases, alterations in the plant’s physiological processes are significant and lead to yield losses and/or plant death. Studies have highlighted the effects of a mixture of foliar fertilizers and seaweeds in reducing foliar symptoms and improving both the quantity and quality of yield. These effects have now been evaluated on additional cultivars and in other vineyard areas. Furthermore, for the first time, the activity of the fertilizer mixture in reducing apoplexy and the resulting vine mortality has been assessed. During the 2022–2023 biennium, in four vineyards of the Lambrusco cultivar in the Province of Reggio Emilia, Northern Italy, affected by both chronic and acute forms of the disease, foliar applications of the mixture were carried out at 10-day intervals starting from the “nine leaves unfolded” BBCH (Biologische Bundesanstalt, Bundessortenamt and Chemical industry) stage 19 up to the “berries developing color” BBCH stage 83. The results confirmed the activity of the fertilizer mixture in reducing chronic symptoms, which appeared particularly pronounced in 2022, when rainfall quantity and distribution allowed regular development of phenological stages. In that year, in all vineyards, a reduction of approximately 50% and 60% in the incidence and severity of chronic leaf symptoms was recorded. Under these optimal growth conditions, treated vines generally showed superior yield and quality. Conversely, in 2023, characterized by heavy rains, smaller effects on foliar symptoms and no improvements in yield were observed. Applications of the mixture resulted in a significant reduction in apoplexy and, consequently, vine mortality, as verified in 2024. This effect did not appear to be influenced by climatic conditions. This study confirms that applications of the mixture aimed at reducing symptom expression and yield damage are a valid addition to the few available control practices. The positive effects observed on the acute form for the first time require further investigation.