Deciphering Peripheral Taste Neuron Diversity: Using Genetic Identity to Bridge Taste Bud Innervation Patterns and Functional Responses.

Peripheral taste neurons exhibit functional, genetic, and morphological diversity, yet understanding how or if these attributes combine into taste neuron types remains unclear. In this study, we used male and female mice to relate taste bud innervation patterns to the function of a subset of proenkephalin-expressing (Penk+) taste neurons. We found that taste arbors (the portion of the axon within the taste bud) stemming from Penk+ neurons displayed diverse branching patterns and lacked stereotypical endings. The range in complexity observed for individual taste arbors from Penk+ neurons mirrored the entire population, suggesting that taste arbor morphologies are not primarily regulated by neuron type. Notably, the distinguishing feature of arbors from Penk+ neurons was their propensity to come within 110 nm (in apposition with) different types of taste-transducing cells within the taste bud. This finding is contrary to the expectation of genetically defined taste neuron types that functionally represent a single stimulus. Consistently, further investigation of Penk+ neuron function revealed that they are more likely to respond to innately aversive stimuli -sour, bitter and high salt concentrations - as compared to the full taste population. Penk+ neurons are less likely to respond to non-aversive stimuli -sucrose, umami, and low salt- compared to the full population. Our data support the presence of a genetically defined neuron type in the geniculate ganglion that is responsive to innately aversive stimuli. This implies that genetic expression might categorize peripheral taste neurons into hedonic groups, rather than simply identifying neurons that respond to a single stimulus.Significance Statement Peripheral taste neuron coding has been heavily debated. Our study delves into this issue by leveraging genetic expression in a specific neuron subset to relate peripheral innervation patterns to functional taste responses. We examined a taste neuron type that appears to be in apposition with multiple taste-transducing cell types and responds to innately aversive concentrations of sour, bitter, and high NaCl stimuli. These collective observations suggest that genetic markers can delineate groups of neurons sharing similar hedonic responses rather than categorizing neurons solely based on individual taste qualities.

Nuclear dualism without extensive DNA elimination in the ciliate Loxodes magnus.

Most eukaryotes have one nucleus and nuclear genome per cell. Ciliates have instead evolved distinct nuclei that coexist in each cell: a silent germline vs. transcriptionally active somatic nuclei. In the best-studied model species, both nuclei can divide asexually, but only germline nuclei undergo meiosis and karyogamy during sex. Thereafter, thousands of DNA segments, called internally eliminated sequences (IESs), are excised from copies of the germline genomes to produce the streamlined somatic genome. In Loxodes, however, somatic nuclei cannot divide but instead develop from germline copies even during asexual cell division, which would incur a huge overhead cost if genome editing was required. Here, we purified and sequenced both genomes in Loxodes magnus to see whether their nondividing somatic nuclei are associated with differences in genome architecture. Unlike in other ciliates studied to date, we did not find canonical germline-limited IESs, implying Loxodes does not extensively edit its genomes. Instead, both genomes appear large and equivalent, replete with retrotransposons and repetitive sequences, unlike the compact, gene-rich somatic genomes of other ciliates. Two other hallmarks of nuclear development in ciliates-domesticated DDE-family transposases and editing-associated small RNAs-were also not found. Thus, among the ciliates, Loxodes genomes most resemble those of conventional eukaryotes. Nonetheless, base modifications, histone marks, and nucleosome positioning of vegetative Loxodes nuclei are consistent with functional differentiation between actively transcribed somatic vs. inactive germline nuclei. Given their phylogenetic position, it is likely that editing was present in the ancestral ciliate but secondarily lost in the Loxodes lineage.

Role of meteorology and air pollution on fog conditions over Delhi during the peak winter 2024.

Severe air pollution and foggy conditions during winter are persistent challenges, pose significant health hazards, and disrupt daily routines worldwide. In this study, we have investigated the conditions favoring the prolonged fog events in Delhi during January 2024 using observations, back trajectories, and reanalysis datasets. Analysis of visibility observations reveals that foggy (54, 121, 139, and 372 half-hours of very dense, dense, moderate, and shallow fog, respectively) conditions persisted in Delhi for 46 % of the time during the study period. The existence of 3-4 days of cold wave to severe cold wave conditions and the lack of passage of strong western disturbances across north and northwest India have also favored the prolonged fog formation. In addition, high relative humidity (>80 %), shallow boundary layer (216 m), stable weather conditions such as the absence of significant surface winds, the existence of cold wave to severe cold wave, temperature inversion (up to 4 °C), poor ventilation, and presence of high particulate matter (PM10: 298 µg/m3 and PM2.5: 182 µg/m3) facilitated the fog formation. Further, analyses reveal a spurt in daily particulate matter (PM10: 603 µg/m3 and PM2.5: 420 µg/m3; 13.4 and 28 times, respectively, exceeded the WHO air quality guideline levels) along with 4.5 h of zero visibility on 14th January. The analysis of particulate matter reveals the dominance of fine particles from nearby regions, which could have originated from the large-scale anthropogenic open biomass burning used for heating activities. The results derived from this study indicate the need for an accurate representation of the local anthropogenic emissions in the atmospheric models to improve the predictability of air quality and fog and provide insights into the need for their control, particularly during such extreme events.

The Impact of the Critical Care Resuscitation Unit on Quaternary Care Accessibility for Rural Patients: A Comparative Analysis.

Background: Previous research suggests that patients from rural areas who are critically ill with complex medical needs or require time-sensitive subspecialty interventions face worse healthcare outcomes and delays in care when compared to those from urban areas. The critical care resuscitation unit (CCRU) at our quaternary care center was established to expedite the transfer of critically ill patients or those who need time-sensitive intervention. This study investigates if disparities exist in treatments and outcomes among patients transferred to the CCRU from rural versus urban hospitals. Methods: This is a retrospective study of adult, nontrauma patients admitted to the CCRU via interhospital transfer from outside facilities from January 1 to December 31, 2018. Patients transferred from within our institution or with missing clinical data were excluded. Multivariable logistic regressions were performed to measure the association between patients' demographic and clinical factors with in-hospital mortality. Results: We analyzed 1381 nontrauma patients, and 484 (35%) were from rural areas. Median age was 59 [47-69], and 629 (46%) were female. Median sequential organ failure assessment was 3 ([1-6], p=0.062) for both patients transferred from urban and rural hospitals. There was no significant difference between groups with respect to most demographic and clinical factors, as well as types of interventions after CCRU arrival, including emergent surgical interventions within 12 hours of arrival at the CCRU. Rural patients were more likely to be transferred for care by the acute care emergency surgery service than were patients from urban areas and were transferred over a significantly greater distance (difference of 53 kilometers (km), 95% CI: -58.9-51.7 km, P < 0.001). Transfer from rural areas was not associated with increased odds of in-hospital mortality (OR: 0.90, 95% CI: 0.60, 1.36; P=0.63). Conclusion: Thirty-five percent of patients transferred to the CCRU came from rural areas, which house 25% of the state population of Maryland. Patients transferred from rural counties to the CCRU faced greater transport distances, but they received the same level of care upon arrival at the CCRU and had the same odds of in-hospital mortality as patients transferred from urban hospitals.

Re-Envisioning Electronic Health Records to Optimize Patient-Centered Cancer Care, Quality, Surveillance, and Research.

Electronic health records (EHRs) are a significant advancement over paper records. However, the full potential of EHRs for improving care quality, patient outcomes, surveillance, and research in cancer care is yet to be realized. The organic evolution of EHRs has resulted in a number of unanticipated consequences including increased time spent by clinicians interfacing with the EHR for daily workflows. Patient access to clinicians and their records has been an important advancement in patient-centered care; however, this has brought to light additional gaps and challenges in EHRs meeting these needs. A significant challenge for EHR design and physician workflows is how best to meet the complex goals and priorities of various stakeholders including providers, researchers, patients, health systems, payors, and regulatory agencies. The National Cancer Policy Forum convened a 2022 workshop, "Innovations in Electronic Health Records for Oncology Care, Research and Surveillance," to address these challenges and to facilitate collaboration across all user groups with the goal of re-envisioning EHRs that will better support shared goals of improving patient outcomes and advancing cancer care and research without overburdening clinicians with administrative tasks. Here, we summarize the current EHR ecosystem as discussed at the workshop and highlight opportunities to improve EHR contributions to oncology evidence and care.

Overall Survival, Treatment Duration, and Rechallenge Outcomes With ICI Therapy for Recurrent or Metastatic HNSCC.

Importance: Immune checkpoint inhibition (ICI) is a frontline treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but questions remain surrounding optimal duration of therapy, benefits and risks of ICI rechallenge, and efficacy in first vs subsequent lines of therapy. Objectives: To estimate survival in US patients receiving ICI-based treatment for R/M HNSCC, compare outcomes associated with treatment discontinuation vs continuation at 1 or 2 years, and assess outcomes after immunotherapy rechallenge. Design, Setting, and Participants: This retrospective, population-based cohort study included adult patients in the Flatiron Health nationwide oncology database treated with immunotherapy for R/M HNSCC from 2015 to 2023. Data cutoff was August 31, 2023; data analysis was conducted from December 2023 to February 2024. Exposures: Treatment continuation vs discontinuation at 1 and 2 years; rechallenge with ICI after at least a 60-day period off ICI therapy without intervening systemic treatment (immediate rechallenge), or with intervening systemic treatment (delayed rechallenge). Main Outcomes and Measures: Overall survival (OS) from ICI initiation was analyzed using the Kaplan-Meier method. Cox multivariable regression was used to examine associations of key variables (line of therapy, human papillomavirus [HPV] status, Eastern Cooperative Oncology Group [ECOG] performance status) with survival. Results: The cohort included 4549 patients with R/M HNSCC who received ICI-containing therapy (median [IQR] age, 66 [59-72] years; 3551 [78.1%] male; 56 [1.2%] Asian, 260 [5.7%] Black or African American, 3020 [66.4%] White, 1213 [26.7%] other or unknown race; 3226 [70.9%] ECOG performance status 0 or 1). There were 3000 patients (65.9%) who received ICI in frontline and 1207 (26.5%) in second line; 3478 patients (76.5%) received ICI monotherapy. Median (IQR) OS was 10.9 (4.1-29.1) months and was longer in patients who received ICI in frontline therapy (12.2 [4.8-32.0] vs 8.7 [3.2-22.4] months), had HPV-positive cancer (16.6 [6.5-43.9] vs 8.8 [3.5-24.0] months), and had ECOG performance status 0 or 1 (13.5 [5.2-33.9] vs 5.5 [2.0-13.7] months). There were no survival differences on adjusted analysis between patients who stopped vs those who continued ICI at 1 or 2 years. Median (IQR) OS after ICI rechallenge was 15.7 (13.7-21.9) months in the immediate rechallenge group and 9.9 (3.7-18.1) months in the delayed rechallenge group. Conclusions and Relevance: In this large cohort study of patients with R/M HNSCC receiving ICI-based therapy, survival estimates closely mirrored clinical trial results, both in frontline and later-line settings. Discontinuation of ICI in long-term responders at 1 or 2 years may be a reasonable strategy that does not appear to compromise survival. ICI rechallenge was associated with clinical benefit in a subset of patients.

Association between measures of resuscitation in the critical care resuscitation unit and in-hospital mortality among patients with sepsis.

Objectives: We hypothesized that lactate clearance and reduction of the Sequential Organ Failure Assessment (SOFA) score during patients' critical care resuscitation unit (CCRU) stay would be associated with lower in-hospital mortality. Methods: This was a retrospective study of adult patients who had sepsis diagnoses and were admitted to the CCRU in 2018. Multivariable logistic regression analysis was performed to assess the association of clinical factors, lactate clearance, and SOFA reduction with hospital mortality. Results: A total of 401 patients with lactate clearance data and 455 patients with SOFA score data were included in the study. The mean (SD) lactate and SOFA score on admission were 2.2 (1.8) mmol/L and 4.4 (4.3), respectively. Average lactate clearance was 0.1 (2.6) mmol/L, and average SOFA score reduction was 0.65 (5.9). Patients with a one point reduction in SOFA score during their CCRU stay had a 31% reduction of mortality (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.62-0.77, p < 0.001). SOFA score reduction was associated with lower hospital mortality for both surgical patients (OR 0.69, 95% CI 0.58-0.81, p < 0.001) and non-surgical patients (OR 0.71 95% CI 0.06-0.83, p < 0.001). Conclusion: SOFA score reduction, but not lactate clearance during the CCRU stay, was associated with lower odds of in-hospital mortality. These findings suggest that resuscitative efforts leading to an early improvement in SOFA score may benefit patients with sepsis.

Real-world outcomes of atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC)treated with osimertinib (osi) vs. Afatinib or erlotinib.

OBJECTIVES: Limited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20. METHODS: We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression. RESULTS: Among 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004). CONCLUSIONS: In a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC.

Two paralogous PHD finger proteins participate in natural genome editing in Paramecium tetraurelia.

The unicellular eukaryote Paramecium tetraurelia contains functionally distinct nuclei: germline micronuclei (MICs) and a somatic macronucleus (MAC). During sex, the MIC genome is reorganized into a new MAC genome and the old MAC is lost. Almost 45,000 unique internal eliminated sequences (IESs) distributed throughout the genome require precise excision to guarantee a functional new MAC genome. Here, we characterize a pair of paralogous PHD finger proteins involved in DNA elimination. DevPF1, the early-expressed paralog, is present in only some of the gametic and post-zygotic nuclei during meiosis. Both DevPF1 and DevPF2 localize in the new developing MACs, where IES excision occurs. Upon DevPF2 knockdown (KD), long IESs are preferentially retained and late-expressed small RNAs decrease; no length preference for retained IESs was observed in DevPF1-KD and development-specific small RNAs were abolished. The expression of at least two genes from the new MAC with roles in genome reorganization seems to be influenced by DevPF1- and DevPF2-KD. Thus, both PHD fingers are crucial for new MAC genome development, with distinct functions, potentially via regulation of non-coding and coding transcription in the MICs and new MACs.

Electronic Medical Record-Based Nudge Intervention to Increase Comprehensive Molecular Genotyping in Patients With Metastatic Non-Small Cell Lung Cancer: Results From a Prospective Clinical Trial.

PURPOSE: Less than half of the patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) undergo comprehensive molecular testing. We designed an electronic medical record (EMR)-based "nudge intervention" to prompt plasma-based molecular testing at the time of initial medical oncology consultation. METHODS: A nonrandomized prospective trial was conducted at the University of Pennsylvania's academic practice and two affiliated community practices. Molecular genotyping was performed by tissue- and/or plasma-based next generation sequencing methods. Comprehensive testing was defined as testing for EGFR, ALK, BRAF, ROS1, MET, RET, KRAS, and NTRK. Guideline-concordant treatment was defined as the use of the appropriate first-line (1L) therapy as per the National Comprehensive Cancer Network (NCCN) guidelines. Proportion of patients with comprehensive molecular genotyping results available at any time, molecular results available before 1L therapy, and guideline-concordant 1L treatment were compared between the preintervention and postintervention cohorts using Fisher's exact test or Pearson's chi-squared test. RESULTS: Five hundred and thirty-three patients were included, 376 in the preintervention cohort and 157 in the postintervention cohort. After implementation of the EMR-based nudge, a higher proportion of patients underwent comprehensive molecular testing in the postintervention versus the preintervention cohort (100% v 88%, P = <.001), had results of comprehensive molecular testing available before initiating 1L treatment (97.3% v 91.6%, P = .026), and received NCCN guideline-concordant care (89.8% v 78.2%, P = .035). CONCLUSION: Across three practice sites in a large health system, implementation of a provider team-focused EMR-based nudge intervention was feasible, and led to a higher number of patients with NSCLC undergoing comprehensive molecular genotyping. These findings demonstrate that behavioral nudges can promote molecular testing and should be studied further as a tool to improve guideline-concordant care in both community and academic sites.

Role of the Critical Care Resuscitation Unit in a Comprehensive Stroke Center: Operations for Mechanical Thrombectomy During the Pandemic.

Introduction: Standard of care for patients with acute ischemic stroke from large vessel occlusion (AIS-LVO) includes prompt evaluation for urgent mechanical thrombectomy (MT) at a comprehensive stroke center (CSC). During the start of the coronavirus 2019 pandemic (COVID-19), there were reports about disruption to emergency department (ED) operations and delays in management of patients with AIS-LVO. In this study we investigate the outcome and operations for patients who were transferred from different EDs to an academic CSC's critical care resuscitation unit (CCRU), which specializes in expeditious transfer of time-sensitive disease. Methods: This was a pre-post retrospective study using prospectively collected clinical data from our CSC's stroke registry. Adult patients who were transferred from any ED to the CCRU and underwent MT were eligible. We compared time intervals in the pre-pandemic (PP) period between January 2018- February 2020, such as ED in-out and CCRU arrival-angiography, to those during the pandemic (DP) between March 2020-May 31, 2021. We used classification and regression tree (CART) analysis to identify which time intervals, besides clinical factors, were associated with good neurological outcome (90-day modified Rankin scale 0-2). Results: We analyzed 203 patients: 135 (66.5%) in the PP group and 68 (33.5%) in the DP group. Time from ED triage to computed tomography (difference 7 minutes, 95% confidence interval [CI] -12 to -1, P < 0.01) for the DP group was statistically longer, but ED in-out was similar for both groups. Time from CCRU arrival to angiography (difference 9 minutes, 95% CI 4-13, P < 0.01) for the DP group was shorter. Forty-nine percent of the DP group achieved mRS ≤ 2 vs 32% for the PP group (difference -17%, 95% CI -0.32 to -0.03, P < 0.01). The CART identified initial National Institutes of Health Stroke Scale, age, ED in-and-out time, and CCRU arrival-to-angiography time as important predictors of good outcome. Conclusion: Overall, the care process in EDs and at this single CSC for patients requiring MT were not heavily affected by the pandemic, as certain time metrics during the pandemic were statistically shorter than pre-pandemic intervals. Time intervals such as ED in-and-out and CCRU arrival-to-angiography were important factors in achieving good neurologic outcomes. Further study is necessary to confirm our observation and improve operational efficiency in the future.

The Drosophila tumor necrosis factor Eiger promotes Myc supercompetition independent of canonical Jun N-terminal kinase signaling.

Numerous factors have been implicated in the cell-cell interactions that lead to elimination of cells via cell competition, a context-dependent process of cell selection in somatic tissues that is based on comparisons of cellular fitness. Here, we use a series of genetic tests in Drosophila to explore the relative contribution of the pleiotropic cytokine tumor necrosis factor α (TNFα) in Myc-mediated cell competition (also known as Myc supercompetition or Myc cell competition). We find that the sole Drosophila TNF, Eiger (Egr), its receptor Grindelwald (Grnd/TNF receptor), and the adaptor proteins Traf4 and Traf6 are required to eliminate wild-type "loser" cells during Myc cell competition. Although typically the interaction between Egr and Grnd leads to cell death by activating the intracellular Jun N-terminal kinase (JNK) stress signaling pathway, our experiments reveal that many components of canonical JNK signaling are dispensable for cell death in Myc cell competition, including the JNKKK Tak1, the JNKK Hemipterous and the JNK Basket. Our results suggest that Egr/Grnd signaling participates in Myc cell competition but functions in a role that is largely independent of the JNK signaling pathway.

Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation.

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. METHODS: Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. RESULTS: Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. CONCLUSIONS/INTERPRETATION: These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR.

Experimental models of Parkinson's disease: Challenges and Opportunities.

Parkinson's disease (PD) is a widespread neurodegenerative disorder occurs due to the degradation of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Millions of people are affected by this devastating disorder globally, and the frequency of the condition increases with the increase in the elderly population. A significant amount of progress has been made in acquiring more knowledge about the etiology and the pathogenesis of PD over the past decades. Animal models have been regarded to be a vital tool for the exploration of complex molecular mechanisms involved in PD. Various animals used as models for disease monitoring include vertebrates (zebrafish, rats, mice, guinea pigs, rabbits and monkeys) and invertebrate models (Drosophila, Caenorhabditis elegans). The animal models most relevant for study of PD are neurotoxin induction-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-Hydroxydopamine (6-OHDA) and agricultural pesticides (rotenone, paraquat), pharmacological models (reserpine or haloperidol treated rats), genetic models (α-synuclein, Leucine-rich repeat kinase 2 (LRRK2), DJ-1, PINK-1 and Parkin). Several non-mammalian genetic models such as zebrafish, Drosophila and Caenorhabditis elegance have also gained popularity in recent years due to easy genetic manipulation, presence of genes homologous to human PD, and rapid screening of novel therapeutic molecules. In addition, in vitro models (SH-SY5Y, PC12, Lund human mesencephalic (LUHMES) cells, Human induced pluripotent stem cell (iPSC), Neural organoids, organ-on-chip) are also currently in trend providing edge in investigating molecular mechanisms involved in PD as they are derived from PD patients. In this review, we explain the current situation and merits and demerits of the various animal models.

Impact of veterinary pharmaceuticals on environment and their mitigation through microbial bioremediation.

Veterinary medications are constantly being used for the diagnosis, treatment, and prevention of diseases in livestock. However, untreated veterinary drug active compounds are interminably discharged into numerous water bodies and terrestrial ecosystems, during production procedures, improper disposal of empty containers, unused medication or animal feed, and treatment procedures. This exhaustive review describes the different pathways through which veterinary medications enter the environment, discussing the role of agricultural practices and improper disposal methods. The detrimental effects of veterinary drug compounds on aquatic and terrestrial ecosystems are elaborated with examples of specific veterinary drugs and their known impacts. This review also aims to detail the mechanisms by which microbes degrade veterinary drug compounds as well as highlighting successful case studies and recent advancements in microbe-based bioremediation. It also elaborates on microbial electrochemical technologies as an eco-friendly solution for removing pharmaceutical pollutants from wastewater. Lastly, we have summarized potential innovations and challenges in implementing bioremediation on a large scale under the section prospects and advancements in this field.

Gene regulatory landscape of cerebral cortex folding.

Folding of the cerebral cortex is a key aspect of mammalian brain development and evolution, and defects are linked to severe neurological disorders. Primary folding occurs in highly stereotyped patterns that are predefined in the cortical germinal zones by a transcriptomic protomap. The gene regulatory landscape governing the emergence of this folding protomap remains unknown. We characterized the spatiotemporal dynamics of gene expression and active epigenetic landscape (H3K27ac) across prospective folds and fissures in ferret. Our results show that the transcriptomic protomap begins to emerge at early embryonic stages, and it involves cell-fate signaling pathways. The H3K27ac landscape reveals developmental cell-fate restriction and engages known developmental regulators, including the transcription factor Cux2. Manipulating Cux2 expression in cortical progenitors changed their proliferation and the folding pattern in ferret, caused by selective transcriptional changes as revealed by single-cell RNA sequencing analyses. Our findings highlight the key relevance of epigenetic mechanisms in defining the patterns of cerebral cortex folding.

Fine Tuning between Radical versus Nonradical States of Azoheteroarenes on Selective Osmium Platforms.

The article highlights the cooperative impact of azoheteroarenes [abbt: 2,2'-azobis(benzothiazole), L1-L3; bmpd: (E)-1,2-bis(1-methyl-1H-pyrazole-3-yl) diazene, L4] and coligands [bpy: 2,2'-bipyridine; pap: 2-phenylazopyridine] in tuning radical (N-N•-) versus nonradical (N═N0) states of L on selective OsII-platforms in structurally/spectroscopically characterized monomeric [1]ClO4-[6]ClO4 and [1](ClO4)2-[2](ClO4)2/[7](ClO4)2-[8](ClO4)2, respectively. The preferred syn-configuration of L in the complexes prevented obtaining ligand bridged dimeric species. It revealed that {Os(bpy)2} facilitated the stabilization of both nonradical ([1](ClO4)2-[2](ClO4)2) and radical ([1]ClO4-[2]ClO4) states of L1/L2, while it delivered exclusively the radical form for L3 in [3]ClO4. In contrast, {Os(pap)2} generated radical states of L1-L3 in [4]ClO4-[6]ClO4, respectively, without any alteration of the redox state of OsII and azo (N═N0) function of the pap coligand. The neutral state of L4 was, however, ascertained in [7](ClO4)2 or [8](ClO4)2 irrespective of the nature of the metal fragment {Os(bpy)2} or {Os(pap)2}, respectively. Switching between radical and nonradical forms of L in the complexes as a function L and coligand could be addressed based on their relative FMO (frontier molecular orbital) energies. Multiple close redox steps of the complexes extended a competitive electron transfer scenario between the redox active components including metal/L/bpy/pap, leading to delicate electronic forms in each case.

A Rare Presentation of Systemic Lupus Erythematosus in a Patient With Fever of Unknown Origin.

This case presents a 23-year-old male with a rare presentation of lupus as fever of unknown origin (FUO). The patient's clinical symptoms, examination findings, and laboratory results painted a complex picture that necessitated considering macrophage activation syndrome and adult-onset Still's disease but ultimately led to the diagnosis of systemic lupus erythematosus. The case emphasizes the importance of including lupus in the differential diagnosis of FUO given the associated risks and higher mortality rates in this demographic, especially in males. Understanding lupus prevalence and classification criteria aids in diagnosis, highlighting the importance of a systematic approach for FUO and emphasizing timely intervention for improved patient outcomes.

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.