A latent pool of neurons silenced by sensory-evoked inhibition can be recruited to enhance perception.

To investigate which activity patterns in sensory cortex are relevant for perceptual decision-making, we combined two-photon calcium imaging and targeted two-photon optogenetics to interrogate barrel cortex activity during perceptual discrimination. We trained mice to discriminate bilateral whisker deflections and report decisions by licking left or right. Two-photon calcium imaging revealed sparse coding of contralateral and ipsilateral whisker input in layer 2/3, with most neurons remaining silent during the task. Activating pyramidal neurons using two-photon holographic photostimulation evoked a perceptual bias that scaled with the number of neurons photostimulated. This effect was dominated by optogenetic activation of non-coding neurons, which did not show sensory or motor-related activity during task performance. Photostimulation also revealed potent recruitment of cortical inhibition during sensory processing, which strongly and preferentially suppressed non-coding neurons. Our results suggest that a pool of non-coding neurons, selectively suppressed by network inhibition during sensory processing, can be recruited to enhance perception.

Epiretinal Membrane Formation Following Rhegmatogenous Retinal Detachment Repair: A Retrospective Cohort Study.

INTRODUCTION: This study aimed to investigate the incidence of and risk factors for epiretinal membrane (ERM) formation following primary rhegmatogenous retinal detachment (RRD) repair. METHODS: This comparative, retrospective, single center cohort study included eyes with primary RRD treated between 2011 and 2023 at Massachusetts Eye and Ear, Boston, Massachusetts, with pars plana vitrectomy (PPV), scleral buckle (SB), PPV+SB, or pneumatic retinopexy (PnR). Demographic, clinical, and surgical parameters were collected from medical records. The primary outcome was the risk of ERM formation, while the secondary outcome was the risk of ERM requiring surgery. Univariable and multivariable Cox regression was performed, and a hazard ratio (HR) and 95% confidence interval (95%CI) were reported. RESULTS: Overall, 394 eyes were included. The mean age was 58.49±12.8 years and most patients were male. There was a significantly lower risk of ERM formation following SB compared to PPV in the univariable analysis (HR=0.22, 95%CI=0.08-0.60, p=0.003); however, there was no significant association between treatment modality and ERM formation on multivariable Cox regression controlling for confounding factors (p=0.24). ERM formation was found more commonly in patients who were older (HR=1.03 per 1 year increase in age, 95%CI=1.01-1.04, p=0.001), those with worse baseline visual acuity (HR=1.36, 95%CI=1.09-1.71, p=0.008), and those with macula-off RRDs (HR=2.16, 95%CI=1.41-3.32, p<0.001). CONCLUSION: Surgical modality does not have a significant impact on the risk of ERM following retinal detachment repair. However, age, baseline visual acuity, and macular status are important predictors of ERM formation after RRD repair.

Exploring the impact of solar radiation on skin microbiome to develop improved photoprotection strategies.

The skin microbiome undergoes constant exposure to solar radiation (SR), with its effects on health well-documented. However, understanding SR's influence on host-associated skin commensals remains nascent. This review surveys existing knowledge on SR's impact on the skin microbiome and proposes innovative sun protection methods that safeguard both skin integrity and microbiome balance. A team of skin photodamage specialists conducted a comprehensive review of 122 articles sourced from PubMed and Research Gateway. Key terms included skin microbiome, photoprotection, photodamage, skin cancer, ultraviolet radiation, solar radiation, skin commensals, skin protection, and pre/probiotics. Experts offered insights into novel sun protection products designed not only to shield the skin but also to mitigate SR's effects on the skin microbiome. Existing literature on SR's influence on the skin microbiome is limited. SR exposure can alter microbiome composition, potentially leading to dysbiosis, compromised skin barrier function, and immune system activation. Current sun protection methods generally overlook microbiome considerations. Tailored sun protection products that prioritize both skin and microbiome health may offer enhanced defense against SR-induced skin conditions. By safeguarding both skin and microbiota, these specialized products could mitigate dysbiosis risks associated with SR exposure, bolstering skin defense mechanisms and reducing the likelihood of SR-mediated skin issues.

Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation.

Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and cis-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct ASCL1+ and HES6hi cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind cis-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.

Visualization of the nervus intermedius during microvascular decompression in hemifacial spasm: anatomical study.

OBJECTIVE: The surgical anatomy of the nervus intermedius (NI) is highly variable. The aim of this study was to describe the anatomy of the NI during endoscope-assisted microvascular decompression (MVD) in hemifacial spasm (HFS), and the involvement of the nerve in the vascular conflict. METHODS: The authors reviewed a prospectively maintained database for MVDs performed between 2002 and 2022 and extracted clinical data including patient demographics, symptoms, and offending vessel(s). Operative videos and photographs were analyzed retrospectively in an attempt to identify the NI. RESULTS: Endoscopic identification of the NI was possible in 139 of 435 MVDs. The anatomy is very variable. In 79 (56.8%) patients, a single-bundle pattern was detected, whereas a multiple-bundle pattern was identified in 60 (43.2%) patients. Overall the most common pattern was a single-bundle type A (49.7%). In 20.1%, a multiple-bundles type A was identified. In 4.3%, a single-bundle type B was detected. In 2.9% a single-bundle type C was found, and in just 0.7% a multiple-bundles type C was detected. A multiple-origin pattern (type D) was found in 31 patients (22.3%). The NI was frequently involved in the neurovascular conflict (approximately 85%). The type of NI or vascular compression pattern did not affect the results regarding the outcome or recurrence of HFS. CONCLUSIONS: The anatomy of the NI is for the first time evaluated endoscopically in MVD for HFS. The nerve had various anatomical patterns that were clearly identified. Further studies to evaluate the compression patterns in relation to NI neuralgia are warranted.

Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx-mediated resistance to HER2-targeting therapies.

Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer-associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2-targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top-up-regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma-contact and no-contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx-induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2-targeting therapies in breast cancer brain metastases.

Comparison of target agent treatment strategies for platinum-resistant recurrent ovarian cancer: A Bayesian network meta-analysis.

BACKGROUND: We aimed to compare 7 newer immunotherapies and targeted therapies for platinum-resistant relapsed ovarian cancer. METHODS: We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library electronic databases for phase III trials involving platinum-resistant recurrent ovarian cancer (PRrOC) patients treated with immunotherapy or targeted therapy in combination with chemotherapy. The quality of the included trials was assessed using the GRADE method. The primary outcome of comparison was progression-free survival, and secondary outcomes included overall survival and safety. RESULTS: This analysis included 7 randomized phase III controlled trials, encompassing 2485 PRrOC patients. Combining bevacizumab plus chemotherapy and lurbinectedin demonstrated statistically significant differences in progression-free survival compared to all other regimens of interest. However, no statistically significant differences were observed in the overall survival. Nivolumab and mirvetuximab exhibited fewer serious adverse events than the other regimens of interest. CONCLUSIONS: Our findings indicate that bevacizumab combined with chemotherapy and lurbinectedin monotherapy has significant efficacy in patients with PRrOC. For patients with PRrOC who have exhausted treatment options, nivolumab and mirvetuximab may be considered as alternatives because of their better safety profiles.

Endoscope-assisted microvascular decompression in hemifacial spasm with a teflon bridge.

BACKGROUND: Microvascular conflicts in hemifacial spasm typically occur at the facial nerve's root exit zone. While a pure microsurgical approach offers only limited orientation, added endoscopy enhances visibility of the relevant structures without the necessity of cerebellar retraction. METHODS: After a retrosigmoid craniotomy, a microsurgical decompression of the facial nerve is performed with a Teflon bridge. Endoscopic inspection prior and after decompression facilitates optimal Teflon bridge positioning. CONCLUSIONS: Endoscope-assisted microsurgery allows a clear visualization and safe manipulation on the facial nerve at its root exit zone.

Targetable leukaemia dependency on noncanonical PI3Kγ signalling.

Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.

Skin cancers are the most frequent cancers in fair-skinned populations, but we can prevent them.

Cancers of the skin are the most commonly occurring cancers in humans. In fair-skinned populations, up to 95% of keratinocyte skin cancers and 70-95% of cutaneous melanomas are caused by ultraviolet radiation and are thus theoretically preventable. Currently, however, there is no comprehensive global advice on practical steps to be taken to reduce the toll of skin cancer. To address this gap, an expert working group comprising clinicians and researchers from Africa, America, Asia, Australia, and Europe, together with learned societies (European Association of Dermato-Oncology, Euromelanoma, Euroskin, European Union of Medical Specialists, and the Melanoma World Society) reviewed the extant evidence and issued the following evidence-based recommendations for photoprotection as a strategy to prevent skin cancer. Fair skinned people, especially children, should minimise their exposure to ultraviolet radiation, and are advised to use protective measures when the UV index is forecast to reach 3 or higher. Protective measures include a combination of seeking shade, physical protection (e.g. clothing, hat, sunglasses), and applying broad-spectrum, SPF 30 + sunscreens to uncovered skin. Intentional exposure to solar ultraviolet radiation for the purpose of sunbathing and tanning is considered an unhealthy behaviour and should be avoided. Similarly, use of solaria and other artificial sources of ultraviolet radiation to encourage tanning should be strongly discouraged, through regulation if necessary. Primary prevention of skin cancer has a positive return on investment. We encourage policymakers to communicate these messages to the general public and promote their wider implementation.

Novel Measurement of the Neutron Magnetic Form Factor from A=3 Mirror Nuclei.

The electromagnetic form factors of the proton and neutron encode information on the spatial structure of their charge and magnetization distributions. While measurements of the proton are relatively straightforward, the lack of a free neutron target makes measurements of the neutron's electromagnetic structure more challenging and more sensitive to experimental or model-dependent uncertainties. Various experiments have attempted to extract the neutron form factors from scattering from the neutron in deuterium, with different techniques providing different, and sometimes large, systematic uncertainties. We present results from a novel measurement of the neutron magnetic form factor using quasielastic scattering from the mirror nuclei ^{3}H and ^{3}He, where the nuclear effects are larger than for deuterium but expected to largely cancel in the cross-section ratios. We extracted values of the neutron magnetic form factor for low-to-modest momentum transfer, 0.6

Sun exposure and protection habits: Self-reported attitudes, knowledge and behaviours.

BACKGROUND: As exposure to UV radiation is the primary modifiable environmental risk factor associated with skin cancer, it remains the principal focus of most prevention strategies. Numerous sun protection campaigns have been implemented worldwide; however, their impact on the actual incidence and mortality rates of skin cancer seems to be limited. To create successful skin cancer prevention campaigns, it is important to have a comprehensive understanding of individuals' attitudes and behaviours regarding sun protection. The aim of the current study was to determine and report on the prevalence of self-reported attitudes, knowledge and behaviours regarding two of the major sun protection recommendations-avoidance of sun exposure and use of sunscreens-in an international representative sample across five continents. METHODS: This cross-sectional study was conducted in 20 countries using a web-based online survey. FINDINGS: A total of 50,552 individuals, comprising 25,388 men (50.22%) and 25,164 women (49.78%), participated in the survey. Among them, 83.2% reported having been voluntarily exposed to the sun (for sun-basking reasons) at least once in the last 12 months, and 47.96% acknowledged being exposed to the sun between the hours of 10 AM and 4 PM. The primary reason for non-adherence was that these hours were the most convenient times (32.28%). Only 24.05% reported applying sunscreen every 2 h when outdoors. Forgetfulness was the primary reason as provided by 27.79% of participants. Males and older age groups were less likely to adopt sun-protective behaviours around the world. Forgetfulness and the challenges posed by time constraints seem to be the biggest barriers to proper adherence. INTERPRETATION: These findings should prompt the collaboration with health authorities and the manufacturers to enhance adherence by setting reasonable sunscreen prices and creating formulations that make their application less burdensome.

Venous Stasis Ulceration due to Massive Splenomegaly Causing Iliac Vein Compression From Secondary Myelofibrosis.

Venous stasis ulcers are nonhealing lesions due to venous hypertension secondary to valvular dysfunction or deep venous outflow obstruction. We describe a case of a 71-year-old male with a history of polycythemia vera, secondary myelofibrosis, and massive splenomegaly up to 38 cm who presented with chronic, perimalleolar venous stasis ulcers and pain on the left lower extremity. CT showed significant compression of the left common iliac vein due to mass effect from the spleen. He was managed medically while being evaluated for partial splenic artery embolization but expired due to other chronic conditions before any intervention could be performed. Partial splenic artery embolization may be considered as a treatment option for patients with symptomatic iliac vein compression due to massive splenomegaly secondary to myelofibrosis, as long as extramedullary hematopoiesis is not compromised.

FLT3 agonists and secondary hematopoietic malignancies: a potential class effect.

Expansion of cDC cells via FLT3 agonism has promising therapeutic potential in the treatment of advanced solid tumors. Here, we discuss the results of a clinical trial using GS-3583, an FLT3 agonist, that was stopped after a patient in the study developed acute myeloid leukemia.

New trends on personalized sunscreens.

BACKGROUND/PURPOSE: Nowadays, there are emerging trends in customized and personalized photoprotection, focusing on the innovative approaches to enhance sun protection efficacy tailored to individual needs. METHODS: We conducted an electronic search of the following databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Skin Group Specialised Skin Register, and TESEO. Specific search terms related to personalized photoprotection and the variables of age, genetic predisposition, skin phototype, photodermatosis, and physiological conditions such as pregnancy, as well as lifestyle habits were used. RESULTS/CONCLUSION: The article highlights the challenges and opportunities in adopting personalized photoprotection strategies, aiming to promote skin health and prevent the harmful effects of UV radiation in the era of precision medicine.

Arachnoid bands in hemifacial spasm: an overlooked etiology? Illustrative case.

BACKGROUND: Primary hemifacial spasm (HFS) is usually caused by arterial compression of the facial nerve at the root exit zone at the brainstem. Rarely, a purely venous compression is seen. However, arachnoid bands strangulating the facial nerve have not been recognized as a cause of hemifacial spasm. OBSERVATIONS: The authors present a case of a 24-year-old female who had experienced HFS for 9 years. Endoscopic inspection of the root exit zone revealed no vascular compression but an arachnoid band strangulating the facial nerve. After cutting the band, the lateral spread response disappeared, and the patient was immediately spasm free after the surgery. Two years later, she was still doing well without any spasms. LESSONS: This is the third patient in the authors' series of 535 patients who had no vascular conflict but rather a strangulation of the nerve by arachnoid bands. All patients have remained spasm free. To the authors' knowledge, no other group has reported arachnoid bands as an etiological factor of HFS so far.