Characterization of testicular embryonic-type neuroectodermal tumor and embryonic-type neuroectodermal tissue admixed with mature neuro-glial tissue using a broad immunohistochemical panel.

Embryonic-type neuroectodermal tumor (ENT) is a somatic-type malignancy characterized by overgrowth of embryonic-type neuroectodermal tissue (EtNT). In germ cell tumors, EtNT is frequently intermingled with other components that may exhibit significant morphologic overlap [mature neuro-glial tissue (MNGT), nephroblastomatous tissues, and primitive endodermal-type glands]. Therefore, the quantification of EtNT (crucial for the diagnosis of ENT) can be challenging. In this study, we investigated the immunohistochemical profile of ENT, EtNT, and MNGT using a broad immunohistochemical panel. We found that SOX2 was the most sensitive marker for EtNT (100%), but it also stained MNGT (28.6%). GFAP and S100 were relatively sensitive (71.4%) and highly specific (GFAP 100%, S100 85.8%) for MNGT, whereas synaptophysin stained both. Combining our results with those of previous studies, we propose that a combination of SOX11, SOX2, GFAP, S100, AFP, villin, CDX2, PAX8, and nuclear WT1 may help to identify and quantify EtNT in germ cell tumors.

Substantial contribution of transported emissions to organic aerosol in Beijing.

Haze in Beijing is linked to atmospherically formed secondary organic aerosol, which has been shown to be particularly harmful to human health. However, the sources and formation pathways of these secondary aerosols remain largely unknown, hindering effective pollution mitigation. Here we have quantified the sources of organic aerosol via direct near-molecular observations in central Beijing. In winter, organic aerosol pollution arises mainly from fresh solid-fuel emissions and secondary organic aerosols originating from both solid-fuel combustion and aqueous processes, probably involving multiphase chemistry with aromatic compounds. The most severe haze is linked to secondary organic aerosols originating from solid-fuel combustion, transported from the Beijing-Tianjing-Hebei Plain and rural mountainous areas west of Beijing. In summer, the increased fraction of secondary organic aerosol is dominated by aromatic emissions from the Xi'an-Shanghai-Beijing region, while the contribution of biogenic emissions remains relatively small. Overall, we identify the main sources of secondary organic aerosol affecting Beijing, which clearly extend beyond the local emissions in Beijing. Our results suggest that targeting key organic precursor emission sectors regionally may be needed to effectively mitigate organic aerosol pollution.

Fermentation Performances and Aroma Contributions of Selected Non-Saccharomyces Yeasts for Cherry Wine Production.

This study evaluates the fermentation performances of non-Saccharomyces strains in fermenting cherry must from Italian cherries unsuitable for selling and not intended to be consumed fresh, and their effects on the chemical composition of the resulting wine. Fermentation trials in 100 and 500 mL of must were carried out to select 21 strains belonging to 11 non-Saccharomyces species. Cherry wines obtained by six select strains were chemically analyzed for fixed and volatile compounds. Quantitative data were statistically analyzed by agglomerative hierarchical clustering, partial least squared discriminant analysis, and principal component analysis. Wines revealed significant differences in their composition. Lactic acid and phenylethyl acetate levels were very high in wines produced by Lachancea and Hanseniaspora, respectively. Compared to S. cerevisiae wine, non-Saccharomyces wines had a lower content of fatty acid ethyl esters 4-vinyl guaiacol and 4-vinyl phenol. The multivariate analysis discriminated between wines, demonstrating the different contributions of each strain to aroma components. Specifically, all wines from non-Saccharomyces strains were kept strictly separate from the control wine. This study provided comprehensive characterization traits for non-conventional strains that enhance the aroma complexity of cherry-based wine. The use of these yeasts in cherry wine production appears promising. Further investigation is required to ascertain their suitability for larger-scale fermentation.

The Impact of Selected Ingredients on the Predicted Glycemic Index and Technological Properties of Bread.

Bread, a staple food consumed worldwide, plays a pivotal role in nutrition. Nevertheless, it is to be underlined that white bread is classified as a high glycemic index food, and its frequent consumption can lead to rapid increases in blood glucose, potentially causing metabolic stress and contributing to insulin resistance and type 2 diabetes. So, there is a growing interest in bread formulations with ingredients that can lower its GI. With this view, bread was formulated, substituting wheat with chickpea flour, red chicory powder, and three distinct types of resistant starch. The results showed the different resistant starches' impacts on the glycemic index reduction. Specifically, chemically modified tapioca RS IV produced a bread formulation with a low predicted glycemic index (pGI < 55). Retrograded starch from tapioca (RS III) allows the bread to reach a pGI value of 55, the upper value for classifying a food as low pGI. The retrograded starch from corn (RS III) allows a decrease in the bread's glycemic index, but the product is still classified as 'high pGI' (>70). Moreover, the addition of by-products rich in polyphenols contributes to a lowering of the pGI. Concerning the technological parameters, the outcome revealed an increase in the moisture content across all the newly formulated samples compared to the control. At the same time, the volume and specific volume showed a decrease. The newly formulated samples exhibited a higher baking loss, particularly when incorporating resistant starch, which increased the hardness and chewiness with decreased cohesiveness. In conclusion, incorporating chickpea flour, red chicory powder, and tapioca-resistant starch (RS III and IV) offers a promising strategy for producing high-fiber bread with a low glycemic index, catering to health-conscious consumers.

Interactions of peroxy radicals from monoterpene and isoprene oxidation simulated in the radical volatility basis set.

Isoprene affects new particle formation rates in environments and experiments also containing monoterpenes. For the most part, isoprene reduces particle formation rates, but the reason is debated. It is proposed that due to its fast reaction with OH, isoprene may compete with larger monoterpenes for oxidants. However, by forming a large amount of peroxy-radicals (RO2), isoprene may also interfere with the formation of the nucleating species compared to a purely monoterpene system. We explore the RO2 cross reactions between monoterpene and isoprene oxidation products using the radical Volatility Basis Set (radical-VBS), a simplified reaction mechanism, comparing with observations from the CLOUD experiment at CERN. We find that isoprene interferes with covalently bound C20 dimers formed in the pure monoterpene system and consequently reduces the yields of the lowest volatility (Ultra Low Volatility Organic Carbon, ULVOC) VBS products. This in turn reduces nucleation rates, while having less of an effect on subsequent growth rates.

Surgery for pediatric low-grade gliomas within the vermis.

Pediatric low-grade gliomas (pLGGs) in the cerebellar vermis present unique challenges due to their intricate anatomical location and potential impact on critical neurological functions. Surgical intervention remains a cornerstone in the management of these tumors, aiming to achieve maximal tumor resection while preserving neurological function. In this review, the authors will discuss anatomical consideration and will explore current surgical techniques and strategies employed in the treatment of cerebellar vermis pLGGs such as the midline and lateral suboccipital approaches, as well as endoscopic-assisted technique. Additionally, we will emphasize the importance of intraoperative neurophysiological monitoring (IONM) in ensuring safe and effective tumor resection. Overall, this review provides insights into the neurosurgical approach of pLGGs in the cerebellar vermis.

Role of intraoperative ultrasound and MRI to aid grade of resection of pediatric low-grade gliomas: accumulated experience from 4 centers.

PURPOSE: Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children and achieving complete resection (CR) in pLGG is the most important prognostic factor. There are multiple intraoperative tools to optimize the extent of resection (EOR). This article investigates and discusses the role of intraoperative ultrasound (iUS) and intraoperative magnetic resonance imaging (iMRI) in the surgical treatment of pLGG. METHODS: The tumor registries at Tuebingen, Rome and Pretoria were searched for pLGG with the use of iUS and data on EOR. The tumor registries at Liverpool and Tuebingen were searched for pLGG with the use of iMRI where preoperative CR was the surgical intent. Different iUS and iMRI machines were used in the 4 centers. RESULTS: We included 111 operations which used iUS and 182 operations using iMRI. Both modalities facilitated intended CR in hemispheric supra- and infratentorial location in almost all cases. In more deep-seated tumor location like supratentorial midline tumors, iMRI has advantages over iUS to visualize residual tumor. Functional limitations limiting CR arising from eloquent involved or neighboring brain tissue apply to both modalities in the same way. In the long-term follow-up, both iUS and iMRI show that achieving a complete resection on intraoperative imaging significantly lowers recurrence of disease (chi-square test, p < 0.01). CONCLUSION: iUS and iMRI have specific pros and cons, but both have been proven to improve achieving CR in pLGG. Due to advances in image quality, cost- and time-efficiency, and efforts to improve the user interface, iUS has emerged as the most accessible surgical adjunct to date to aid and guide tumor resection. Since the EOR has the most important effect on long-term outcome and disease control of pLGG in most locations, we strongly recommend taking all possible efforts to use iUS in any surgery, independent of intended resection extent and iMRI if locally available.

Surgical and radiosurgical treatment of hypothalamic hamartoma: The Italian experience between 2011 and 2021.

OBJECTIVE: To investigate the Italian experience on the surgical and radiosurgical treatment of drug-resistant epilepsy due to hypothalamic hamartoma (HH) in the period 2011-2021 in six Italian epilepsy surgery centers, and to compare safety and efficacy profiles of the different techniques. METHODS: We collected pseudo-anonymized patient's data with at least 12 months of follow-up. Surgical outcome was defined according to Engel classification of seizure outcome. Univariate analysis was performed to assess the risk of post-operative seizures, categorized in dichotomous variable as favorable and unfavorable; explanatory variables were considered. Mann-Whitney or Chi-squared test were used to assess the presence of an association between variables (p < 0.05). RESULTS: Full presurgical and postoperative data about 42 patients from 6 epilepsy surgery centers were gathered. Engel class I was reached in the 65.8% and 66.6% of patients with gelastic and non-gelastic seizures, respectively. Other than daily non-gelastic seizures were associated with seizure freedom (p = 0.01), and the radiological type presented a trend toward significance (p = 0.12). SIGNIFICANCE: Endoscopic disconnection and laser interstitial thermal therapy are effective in the treatment of HH-related epilepsy, with a tolerable safety profile. Both gelastic and non-gelastic seizures can be treated, also in patients with a long history of seizures. PLAIN LANGUAGE SUMMARY: This study collected data about 42 patients with HH-related epilepsies. Endoscopic disconnection and laser therapy are both effective and safe in the treatment of hypothalamic hamartoma-related epilepsies.

Identifying Driving Factors of Atmospheric N2O5 with Machine Learning.

Dinitrogen pentoxide (N2O5) plays an essential role in tropospheric chemistry, serving as a nocturnal reservoir of reactive nitrogen and significantly promoting nitrate formations. However, identifying key environmental drivers of N2O5 formation remains challenging using traditional statistical methods, impeding effective emission control measures to mitigate NOx-induced air pollution. Here, we adopted machine learning assisted by steady-state analysis to elucidate the driving factors of N2O5 before and during the 2022 Winter Olympics (WO) in Beijing. Higher N2O5 concentrations were observed during the WO period compared to the Pre-Winter-Olympics (Pre-WO) period. The machine learning model accurately reproduced ambient N2O5 concentrations and showed that ozone (O3), nitrogen dioxide (NO2), and relative humidity (RH) were the most important driving factors of N2O5. Compared to the Pre-WO period, the variation in trace gases (i.e., NO2 and O3) along with the reduced N2O5 uptake coefficient was the main reason for higher N2O5 levels during the WO period. By predicting N2O5 under various control scenarios of NOx and calculating the nitrate formation potential from N2O5 uptake, we found that the progressive reduction of nitrogen oxides initially increases the nitrate formation potential before further decreasing it. The threshold of NOx was approximately 13 ppbv, below which NOx reduction effectively reduced the level of night-time nitrate formations. These results demonstrate the capacity of machine learning to provide insights into understanding atmospheric nitrogen chemistry and highlight the necessity of more stringent emission control of NOx to mitigate haze pollution.

Key drivers of the oxidative potential of PM2.5 in Beijing in the context of air quality improvement from 2018 to 2022.

The mass concentration of atmospheric particulate matter (PM) has been continuously decreasing in the Beijing-Tianjin-Hebei region. However, health endpoints do not exhibit a linear correlation with PM mass concentrations. Thus, it is urgent to clarify the prior toxicological components of PM to further improve air quality. In this study, we analyzed the long-term oxidative potential (OP) of water-soluble PM2.5, which is generally considered more effective in assessing hazardous exposure to PM in Beijing from 2018 to 2022 based on the dithiothreitol assay and identified the crucial drivers of the OP of PM2.5 based on online monitoring of air pollutants, receptor model, and random forest (RF) model. Our results indicate that dust, traffic, and biomass combustion are the main sources of the OP of PM2.5 in Beijing. The complex interactions of dust particles, black carbon, and gaseous pollutants (nitrogen dioxide and sulfur dioxide) are the main factors driving the OP evolution, in particular, leading to the abnormal rise of OP in Beijing in 2022. Our data shows that a higher OP is observed in winter and spring compared to summer and autumn. The diurnal variation of the OP is characterized by a declining trend from 0:00 to 14:00 and an increasing trend from 14:00 to 23:00. The spatial variation in OP of PM2.5 was observed as the OP in Beijing is lower than that in Shijiazhuang, while it is higher than that in Zhenjiang and Haikou, which is primarily influenced by the distribution of black carbon. Our results are of significance in identifying the key drivers influencing the OP of PM2.5 and provide new insights for advancing air quality improvement efforts with a focus on safeguarding human health in Beijing.

Diversity, integration, and variability of intergenerational relationships in old age: New insights from personal network research.

Relationships between family members from different generations have long been described as a source of solidarity and support in aging populations and, more recently, as a potential risk factor for COVID-19 contagion. Personal or egocentric network research offers a powerful kit of conceptual and methodological tools to study these relationships, but this has not yet been employed to its full potential in the literature. We investigate the heterogeneity, social integration, and individual correlates of intergenerational relationships in old age analyzing highly granular data on the personal networks of 230 older adults (2747 social ties) from a local survey in one of the areas of the world at the forefront of global aging trends (northern Italy). Using information on different layers in broad egocentric networks and on the structure of connectivity among the social contacts of aging people, we propose multiple conceptualizations and measures of intergenerational connectedness. Results show that intergenerational relationships are strongly integrated, but also highly diverse and variable, in older adults' social networks. Different types of intergenerational ties exist in different network layers, with various relational roles, degrees of tie strength, and patterns of association with individual and tie characteristics. We discuss how new and existing personal network data can be leveraged to consider novel questions and hypotheses about intergenerational relationships in contemporary aging families.

Potential pre-industrial-like new particle formation induced by pure biogenic organic vapors in Finnish peatland.

Pure biogenic new particle formation (NPF) induced by highly oxygenated organic molecules (HOMs) could be an important mechanism for pre-industrial aerosol formation. However, it has not been unambiguously confirmed in the ambient due to the scarcity of truly pristine continental locations in the present-day atmosphere or the lack of chemical characterization of NPF precursors. Here, we report ambient observations of pure biogenic HOM-driven NPF over a peatland in southern Finland. Meteorological decoupling processes formed an "air pocket" (i.e., a very shallow surface layer) at night and favored NPF initiated entirely by biogenic HOM from this peatland, whose atmospheric environment closely resembles that of the pre-industrial era. Our study sheds light on pre-industrial aerosol formation, which represents the baseline for estimating the impact of present and future aerosol on climate, as well as on future NPF, the features of which may revert toward pre-industrial-like conditions due to air pollution mitigation.

Do Minimally Invasive Approaches to Pediatric Orbital Tumors Provide an Advantage on Outcome and Efficiency?

OBJECTIVE: The present study evaluated whether minimally invasive approaches to orbital lesions could improve surgical, clinical, and aesthetic outcomes compared with more invasive ones. This is the first study specifically addressing this topic in children. METHODS: Children consecutively operated on from January 2010 to January 2020 were analyzed. Thirty patients matched the inclusion criteria and were divided into group A: 14 cases treated with traditional surgical approaches; and group B: 16 cases managed by minimally invasive approaches. RESULTS: There were no significant differences between the 2 groups in terms of demographic data and extent of tumor resection. Mean surgical time for the approach (40 minutes vs. 70 minutes, P < 0.0001), surgical complication such as periorbital edema (37% vs. 78%, P = 0.02) and dural tear (0 vs. 21%, P = 0.05), and procedures cost (P < 0.0001) were significantly reduced in group B. Regarding clinical outcomes, group B showed a significant reduction both in terms of postoperative pain (mean score based on visual pain scale was 2.9 vs. 4.1 P = 0.003) and mean hospitalization time (4.5 days vs. 5.5 days, P = 0.0004). The cosmetic outcome according to the Sloan classification was significantly better in group B as well (81% vs. 36% class I patients, P = 0.005). CONCLUSIONS: The use of mini-invasive approaches to orbital tumor has clear advantages in terms of surgical, clinical, and cosmetic outcomes in comparable patients; therefore, they should be preferred whenever feasible. Craniotomic approaches remain necessary for very large tumors.

Coexistence of Trigonocephaly and Sylvian Arachnoid Cysts: A Coincidence?

INTRODUCTION: The association between trigonocephaly and Sylvian fissure arachnoid cysts (ACs) has been occasionally reported in the literature. However, the real incidence of this association and its clinical relevance remain unknown. METHODS: The authors collected and retrospectively reviewed all clinical charts and CT scans of patients surgically treated for trigonocephaly at the Pediatric Neurosurgical Department of Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS from January 2014 to June 2023. RESULTS: During the study period, 136 patients with trigonocephaly underwent surgery. Analysis of the clinical charts revealed that in 39.7% of the cases (54/136), preoperative CT scan depicted the presence of a Sylvian fissure AC. Of these, AC was bilateral in 23 cases and unilateral in the remaining 31. All unilateral ACs were on the left side. The ACs were classified as Galassi grade I in 52 cases (96.3%) and Galassi grade II in 2 cases (3.7%). Interestingly, in 1 case we reported a Galassi grade I AC enlargement during follow-up, thereby necessitating surgical fenestration. CONCLUSION: ACs and trigonocephaly are well-known conditions for pediatric neurosurgeons; however, their association is poorly defined. Despite the lack of reports on the incidence and clinical significance of this association, it is worth knowing that radiological follow-up is essential in monitoring AC evolution.

Oxidized organic molecules in the tropical free troposphere over Amazonia.

New particle formation (NPF) in the tropical free troposphere (FT) is a globally important source of cloud condensation nuclei, affecting cloud properties and climate. Oxidized organic molecules (OOMs) produced from biogenic volatile organic compounds are believed to contribute to aerosol formation in the tropical FT, but without direct chemical observations. We performed in situ molecular-level OOMs measurements at the Bolivian station Chacaltaya at 5240 m above sea level, on the western edge of Amazonia. For the first time, we demonstrate the presence of OOMs, mainly with 4-5 carbon atoms, in both gas-phase and particle-phase (in terms of mass contribution) measurements in tropical FT air from Amazonia. These observations, combined with air mass history analyses, indicate that the observed OOMs are linked to isoprene emitted from the rainforests hundreds of kilometers away. Based on particle-phase measurements, we find that these compounds can contribute to NPF, at least the growth of newly formed nanoparticles, in the tropical FT on a continental scale. Thus, our study is a fundamental and significant step in understanding the aerosol formation process in the tropical FT.

Exploration of grape pomace peels and amaranth flours as functional ingredients in the elaboration of breads: phenolic composition, bioaccessibility, and antioxidant activity.

This study evaluated the incorporation of two ingredients as a source of bioactive compounds: amaranth flour (AF) and grape pomace peels flour (GP) to improve the nutritional qualities and functional properties of a wheat bread, emphasising the revalorisation of agricultural residues from grape winemaking as an ethical and economically viable source of bioactive compounds. Specifically, wheat flour (WF) substitutions were carried out for the individual ingredients, replacing 20% WF (A20 bread) or 5% GP (GP5 bread) and a mixture of both ingredients 20% WF and 5% GP (A20GP5 bread), and the antioxidant potential of the breads was analysed. The effect of simulated gastrointestinal digestion (SGID) on the phenolic profile and antioxidant activity of the fortified breads was also investigated. The substitution of WF by AF or GP introduced several phenolic compounds, digestion increased the bioaccessibility of phenolic compounds and reshaped their phenolic composition profiles. The combined presence of AF and GP in the breads modified the phenolic compounds composition and improved their antioxidant activity after SGID. Interactions between the phenolic compounds and other AF components (possibly proteins) were observed, which could protect the phenols from degradation during SGID, allowing them to be released after SGID.

Rollout of the 2022/2023 Seasonal Influenza Vaccination and Correlates of the Use of Enhanced Vaccines among Italian Adults.

In Italy, several types of seasonal influenza vaccines (SIVs) are available for older adults, but for the 2022/2023 season there were no guidelines on their specific use. This cross-sectional study assessed the frequency and determinants of the use of enhanced (adjuvanted and high-dose) SIVs in Italian older adults, as compared to standard-dose non-adjuvanted formulations. Of 1702 vaccines administered to a representative outpatient sample of adults aged ≥ 60 years and residing in Genoa, 69.5% were enhanced SIVs. Older age (adjusted odds ratio (aOR) for each 1-year increase 1.10; p < 0.001), and the presence of cardiovascular disease (aOR 1.40; p = 0.011) and diabetes (aOR 1.62; p = 0.005) were associated with the use of enhanced vaccines. Compared with the adjuvanted SIV, subjects immunized with the high-dose vaccine were older (aOR for each 1-year increase 1.05; p < 0.001) and had higher prevalence of respiratory diseases (aOR 1.85; p = 0.052). Moreover, usage of the enhanced SIVs was driven by the period of immunization campaign, place of vaccination and physician. Despite their superior immunogenicity and effectiveness, the adoption of enhanced SIVs in Italy is suboptimal, and should be increased. Enhanced formulations are mostly used in the oldest, and in subjects with some co-morbidities.

Evaluation of an institutional series of low-grade oncocytic tumor (LOT) of the kidney and review of the mutational landscape of LOT.

The 2022 WHO classification of urinary and male genital tumors introduced several novel kidney entities exhibiting eosinophilic/oncocytic features with specific mutational backgrounds. Thus, molecular techniques, such as next-generation sequencing (NGS), became more commonly used for their evaluation. We studied 12 low-grade oncocytic tumors (LOT) of the kidney (from 11 patients), identified in a cohort of 210 eosinophilic/oncocytic renal tumors, diagnosed in our institution between October 2019 and May 2023, which represented 5.7% (12/210) of all eosinophilic/oncocytic renal tumors during this period. We reviewed their clinicopathologic, histologic, and immunohistochemical features, as well as their mutational profiles. We also reviewed the literature on NGS-derived data of LOT, by selecting papers in which LOT diagnosis was rendered according to the criteria proposed initially. Median age was 65 years (mean: 63.5; range 43-79) and median tumor size was 2.0 cm (mean: 2.2; range: 0.9-3.1). All tumors were positive for PAX8, CK7, and GATA3, and negative or focally positive for CD117/KIT. We found the following gene mutations: MTOR ((6/11), 54.5%)), TSC1 ((2/11), 18.2%)), and 1 had both NOTCH1 and NOTCH4 ((1/11), 9.1%)). Wild-type status was found in 2/11 (18.2%) patients and one tumor was not analyzable. A review of 8 previous studies that included 79 LOTs revealed frequent mutations in the genes that regulate the mammalian target of rapamycin (mTOR) pathway: MTOR (32/79 (40.5%)), TSC1 (21/79 (26.6%)), and TSC2 (9/79 (11.4%)). Other mutated genes included PIK3CA, NF2, and PTEN, not typically known to affect the mTOR pathway, but potentially acting as upstream and downstream effectors. Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without "canonical" mutations.

Role of sesquiterpenes in biogenic new particle formation.

Biogenic vapors form new particles in the atmosphere, affecting global climate. The contributions of monoterpenes and isoprene to new particle formation (NPF) have been extensively studied. However, sesquiterpenes have received little attention despite a potentially important role due to their high molecular weight. Via chamber experiments performed under atmospheric conditions, we report biogenic NPF resulting from the oxidation of pure mixtures of ß-caryophyllene, α-pinene, and isoprene, which produces oxygenated compounds over a wide range of volatilities. We find that a class of vapors termed ultralow-volatility organic compounds (ULVOCs) are highly efficient nucleators and quantitatively determine NPF efficiency. When compared with a mixture of isoprene and monoterpene alone, adding only 2% sesquiterpene increases the ULVOC yield and doubles the formation rate. Thus, sesquiterpene emissions need to be included in assessments of global aerosol concentrations in pristine climates where biogenic NPF is expected to be a major source of cloud condensation nuclei.