First Report on the Occurrence of Tomato Yellow Leaf Curl Virus in Tennessee.

In the summer of 2021, a field survey of several tomato-growing counties in Tennessee (TN) was conducted for plants exhibiting virus-like symptoms. While scouting in September in Grainger County, one of the largest areas under tomato (Solanum lycopersicum) production in TN, leaves from six tomato plants (cv. BHN 589) growing on a farm located near Rutledge were collected and subsequently stored at -80˚C. Only one of the plants exhibited symptoms typical of tomato yellow leaf curl virus (TYLCV) infection, which included chlorosis, leaf curling, downward cupping, thickening, and mottling. Total DNA was isolated using the DNeasy Plant Mini Kit (Qiagen, Santa Clara, CA) and subjected to PCR using primers TYv2337F (5'-ACGTAGGTCTTGACATCTGTTGAGCTC-3') and TYc138-R: (5'-AAGTGGGTCCCACAATTGCAAGAC-3') and Ex-Taq polymerase (Takara Bio, Mountain View, CA) to amplify a 634-bp genomic fragment of TYLCV (Alkowni et al. 2019). Primers against tomato elongation factor-1 served as internal PCR control (Dias et al. 2023). Each primer set amplified amplicons of expected sizes; however, the TYLCV fragment was detected only from the plant exhibiting typical symptoms of infection. Amplicons were purified with the QIAquick PCR purification kit (Qiagen) and sequenced directly bi-directionally by Eurofins USA using the above primers. The resultant sequences were edited and analyzed with CLC Genomic Workbench v. 24.0.1. Blast analysis of the sequences (606 nts) against those available in GenBank showed 93 TYLCV isolates with over 95% nucleotide sequence identity. Subsequently, the full-length genome was PCR amplified using primers TYBamHIv (5'- GGATCCACTTCTAAATGAATTTCCTG-3') and TYBamHI2c (5'-GGATCCCACATAGTGCAAGACAAAC-3') (Rojas et al. 2007), ligated into pGEM-T (Promega, Madison, WI) and cloned. Plasmids were purified using QIAprep Spin Miniprep kit (Qiagen) and five independent plasmids clones were sequenced using Oxford Nanopore sequencing (v14 library chemistry & R10.4.1 flow cell) by Eurofins USA. The resultant sequences were edited and analyzed with CLC Genomic Workbench and a consensus sequence representing the full-length genome (2,781 nts) was generated and submitted to GenBank (Accession No. PP505780). Blast analysis showed over 98% nucleotide sequence identity with 100 TYLCV isolates from GenBank. The highest sequence identity of 98.6% was with the sequence of an isolate from Florida (AY530931). To the best of our knowledge, this is the first report of the occurrence of TYLCV in TN. The virus was detected in a tomato plant grown from seed. The seed transmissibility of TYLCV remains controversial (Perry 2018; and references therein); thus, the most likely source of infection in this report is transmission by rare viruliferous vectors (Bemisia tabaci). It remains unknown, however, whether TYLCV is endemic in TN, or recently introduced by mobile vectors from neighboring states. The presence of TYLCV has been reported in Alabama (Akad et al. 2007), Kentucky (de Sá et al. 2008), Mississippi (Ingram and Henn 2001), Georgia (Momol et al. 1999) and North Carolina (Polston et al. 2002). The B. tabaci vector of the virus has sporadic occurrences in crops within TN (Li et al. 2021). Tennessee is one of the leading tomato producers exporting globally with production covering over 1,300 hectares and over 430 producers (Dias et al. 2023). Because of the potential threat of TYLCV to tomato industry in the state, additional surveillance measures need to be put in place to determine TYLCV incidence.

Effects of isolation stress and voluntary ethanol exposure during adolescence on ethanol and nicotine co-use in adulthood using male rats.

Background: Alcohol use in adolescence may increase susceptibility to substance use disorders (SUDs) in adulthood. This study determined if voluntary ethanol (EtOH) consumption during adolescence, combined with social isolation, alters the trajectory of EtOH and nicotine intake during adulthood, as well as activating brain neuroinflammation. Methods: Adolescent male isolate- and group-housed rats were given 0.2 % saccharin/20 % EtOH (Sacc/EtOH) or water using intermittent 2-bottle choice; controls were given water in both bottles (n=17-20 per group). Some rats from each group (n=5-6) were euthanized one week later to measure autoradiographic [3H]PK-11195 binding, an indicator of microglial reactivity, and the remainder (n=11-14 per group) were tested in adulthood in 2-bottle choice, followed by nicotine self-administration using an incremental fixed ratio (FR) schedule with Sacc/EtOH and water concurrently available. Results: Isolation housing increased adolescent intake of Sacc/EtOH, but the increase did not produce an observable neuroimmunological response in brain. Adolescent EtOH exposure decreased adult intake of both Sacc/EtOH and unsweetened EtOH, with isolate-housed rats showing a greater effect than group-housed rats. In the co-use model, a cross-price economic demand analysis revealed a substitutional relationship between Sacc/EtOH and nicotine, but no effect of adolescent Sacc/EtOH exposure. Compared to group-housed rats, isolate-housed rats were more sensitive to the changing price of nicotine and showed greater substitutability of Sacc/EtOH for nicotine. Conclusion: The current results suggest that adolescent EtOH exposure per se, with or without isolation stress, does not likely explain the enhanced risk for either alcohol or nicotine use later in life.

Increased risk of cardiac arrhythmia in Hailey-Hailey disease patients.

BACKGROUND: Hailey-Hailey disease (HHD) is a rare autosomal dominant skin disease caused by mutations in the ATP2C1 gene, which encodes the secretory Ca2+/Mn2+-ATPase (SPCA1) pump in the Golgi apparatus. Although ATP2C1 is ubiquitously expressed in the body, possible extracutaneous manifestations of HHD are unknown. However, dysfunction of the Golgi apparatus not specifically coupled to ATP2C1 has been associated with heart disease. OBJECTIVE: To investigate the association between HHD and common heart disease in a Swedish, population-based cohort. METHODS: We conducted a population-based cohort study based on a linkage of Swedish nationwide registers to investigate the relationship between HHD and heart disease. We have been granted ethical approval from the Swedish Ethical Review Authority to conduct this study. The patients in this manuscript have given written informed consent to the publication of their case details. A total of 342 individuals with an ICD-10 diagnosis of HHD (Q82.8E) were identified and matched with randomly selected comparison individuals without HHD on a 1:100 ratio. Furthermore, in a separate clinical cohort we matched 23 HHD patients for age, sex, and BMI with control subjects to examine electrocardiogram parameters, electrolytes, and cardiovascular biomarkers. RESULTS: Compared with individuals without HHD, individuals with HHD had an excess risk of arrhythmia (RR 1.4, CI 1.0-2.0), whereas no increased risks of myocardial infarction (RR 1.1, CI 0.6-1.7) or heart failure (RR 1.0, CI 0.6-1.6; Table 1) were found. We found no difference in ECG parameters, cardiovascular biomarkers, and electrolytes in the clinical subset. CONCLUSION: This study reveals that HHD is associated with an increased risk of arrhythmia and represents the first data of any extracutaneous comorbidity in HHD. Thus, HHD may be a systemic disease. Our findings also shed light on the importance of the Golgi apparatus' Ca2+/Mn2+ homeostasis in common heart disease.

Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression.

This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3-1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.

Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.

Continuous and differential improvement in worldwide access to hematopoietic cell transplantation: activity has doubled in a decade with a notable increase in unrelated and non-identical related donors.

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (6 World Health Organization regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT numbers increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA-identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/10 million population was observed for autologous HCT (correlation coefficient [r]=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation was detected from related donors (r=0.48 for HLA-identical sibling; r=0.45 for other). The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

The efficacy of sacituzumab govitecan and trastuzumab deruxtecan on stable and active brain metastases in metastatic breast cancer patients-a multicenter real-world analysis.

BACKGROUND: Fifteen to thirty percent of all patients with metastatic breast cancer (MBC) develop brain metastases (BCBMs). Recently, the antibody-drug conjugates (ADCs) sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have shown to be highly effective in the treatment of MBC. However, there are only limited data whether these macromolecules are also effective in patients with BCBMs. We therefore aimed to examine the efficacy of SG and T-DXd in patients with stable and active BCBMs in a multicenter real-world analysis. PATIENTS AND METHODS: Female patients with stable or active BCBMs who were treated with either SG or T-DXd at three breast centers in Germany before 30 June 2023 were included. As per local clinical praxis, chemotherapy efficacy was evaluated by whole-body computed tomography and cranial magnetic resonance imaging at baseline and at least every 3 months according to local standards. Growth dynamics of BCBMs were assessed by board-certified neuroradiologists. RESULTS: Of 26 patients, with a median of 2.5 prior therapy lines in the metastatic setting (range 2-15), 12 (43%) and 16 (57%) patients received SG and T-DXd, respectively. Out of the 12 patients who received SG, 2 (17%) were subsequently treated with T-DXd. Five out of 12 (42%) and 5 out of 16 (31%) patients treated with SG and T-DXd, respectively, had active BCBMs at treatment initiation. The intracranial disease control rate was 42% [95% confidence interval (CI) 13% to 71%] for patients treated with SG and 88% (95% CI 72% to 100%) for patients treated with T-DXd. After a median follow-up of 12.7 months, median intracranial progression-free survival was 2.7 months (95% CI 1.6-10.5 months) for SG and 11.2 months (95% CI 7.5-23.7 months) for T-DXd. CONCLUSIONS: SG and T-DXd showed promising clinical activity in both stable and active BCBMs. Further prospective clinical studies designed to investigate the efficacy of modern ADCs on active and stable BCBMs are urgently needed.

Using narratives to correct politically charged health misinformation and address affective belief echoes.

BACKGROUND: In May 2020, news outlets reported misinformation about the Centers for Disease Control (CDC) related to COVID-19. Correcting misinformation about outbreaks and politics is particularly challenging. Affective belief echoes continue to influence audiences even after successful correction. Narrative and emotional flow scholarship suggest that a narrative corrective with a positive ending could reduce belief echoes. Therefore, this study investigated the efficacy of a narrative corrective with a relief ending for correcting misinformation about the CDC. METHODS: Between 29 May and 4 June 2020, we tested the effectiveness of a narrative to correct this misinformation. Participants in the United States (N = 469) were enrolled via Qualtrics panels in an online message experiment and randomized to receive a narrative corrective, a didactic corrective or no corrective. RESULTS: The narrative corrective resulted in lower endorsement of the misinformation compared with the control and the didactic corrective. The narrative corrective had a positive indirect effect on perceived CDC competence and mask wearing intentions for politically moderate and conservative participants via relief. CONCLUSIONS: Public health institutions, such as the CDC, should consider utilizing narrative messaging with positive emotion endings to correct misinformation. Narratives better address affective belief echoes, particularly for counter-attitudinal audiences.

Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen secretion.

Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation has been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired reepithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, while its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif-KO mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.

Darier disease is associated with neurodegenerative disorders and epilepsy.

Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.

Protocol for a cluster-randomized trial of a school-based skin cancer preventive intervention for adolescents.

BACKGROUND: Adolescents infrequently use sun protection and engage in intentional tanning more frequently compared to other age groups, leading to increased ultraviolet radiation (UVR) exposure that heightens skin cancer risk across the lifespan. High schools are therefore an ideal setting for offering skin cancer preventive interventions. Yet, there are limited UVR protection interventions for high school students, especially those that are personalized, tested using randomized designs, and include long-term outcome assessment to determine the durability of intervention effects. METHOD: The Sun-safe Habits Intervention and Education (SHINE) cluster-randomized trial will test a novel, personalized intervention that targets high school adolescents' sun protection and tanning behaviors, and tracks their outcomes for up to one year following intervention. Enrolled high schools will be randomized to receive either the personalized SHINE intervention, which includes facial UVR photographs and sun protection action planning, or standard education using publicly available materials. Students in both conditions will receive information about skin cancer, sun protection, and skin self-examination. Outcome variables will include students' sun protection and tanning behaviors and sunburn occurrence. Potential moderators (e.g., race/ethnicity) and mediators (e.g., self-efficacy) will also be assessed and tested. CONCLUSIONS: This trial examines the efficacy of a personalized intervention targeting sun protection and tanning of high school students. The project will lead to new scientific understanding of the theoretical mechanisms underlying outcomes and moderators of the intervention effects, which will inform future intervention tailoring to meet the needs of vulnerable subgroups.

Political Party Collective Norms, Perceived Norms, and Mask Wearing Behavior: A Test of the Theory of Normative Social Behavior.

The theory of normative social behavior (TNSB) postulates that people are influenced by others' behaviors, which they observe from messages and experience. In addition to focusing on perceived (i.e., descriptive and injunctive) norms, the TNSB was expanded to include collective norms, which represent what people actually do. Testing this expanded theoretical model, the current study examined whether two types of collective norms - collective political norms and collective regional norms - interacted with descriptive norms to influence pandemic mask wearing behavior expectations among U.S. adults (N = 444). The interaction was statistically significant for collective political norms (ß = -.74, p = .009) but not collective regional norms (ß = -.16, p = .85). Specifically, descriptive norms were related to increased mask wearing expectation for all values of political party collective norms, but the effects were stronger when political party collective norms were low (i.e., low mask wearing behavior was normative). The findings support the inclusion of collective norms in the TNSB, clarify the relationships among different types of norms, and provide insights for norms-based interventions.

Framing COVID-19 Preprint Research as Uncertain: A Mixed-Method Study of Public Reactions.

During the COVID-19 pandemic, journalists were encouraged to convey uncertainty surrounding preliminary scientific evidence, including mentioning when research is unpublished or unverified by peer review. To understand how public audiences interpret this information, we conducted a mixed method study with U.S. adults. Participants read a news article about preprint COVID-19 vaccine research in early April 2021, just as the vaccine was becoming widely available to the U.S. public. We modified the article to test two ways of conveying uncertainty (hedging of scientific claims and mention of preprint status) in a 2 × 2 between-participants factorial design. To complement this, we collected open-ended data to assess participants' understanding of the concept of a scientific preprint. In all, participants who read hedged (vs. unhedged) versions of the article reported less favorable vaccine attitudes and intentions and found the scientists and news reporting less trustworthy. These effects were moderated by participants' epistemic beliefs and their preference for information about scientific uncertainty. However, there was no impact of describing the study as a preprint, and participants' qualitative responses indicated a limited understanding of the concept. We discuss implications of these findings for communicating initial scientific evidence to the public and we outline important next steps for research and theory-building.

Mass Spectrometry Analysis of Shark Skin Proteins.

The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage in which proteins play a key role. While proteins in the skin mucus layer of various common bony fish species have been explored, the proteins of shark skin mucus remain unexplored. In this pilot study, we examine the protein composition of the skin mucus in spiny dogfish sharks and chain catsharks through mass spectrometry (NanoLC-MS/MS). Overall, we identified 206 and 72 proteins in spiny dogfish (Squalus acanthias) and chain catsharks (Scyliorhinus retifer), respectively. Categorization showed that the proteins belonged to diverse biological processes and that most proteins were cellular albeit a significant minority were secreted, indicative of mucosal immune roles. The secreted proteins are reviewed in detail with emphasis on their immune potentials. Moreover, STRING protein-protein association network analysis showed that proteins of closely related shark species were more similar as compared to a more distantly related shark and a bony fish, although there were also significant overlaps. This study contributes to the growing field of molecular shark studies and provides a foundation for further research into the functional roles and potential human biomedical implications of shark skin mucus proteins.

Communicating scientific uncertainty in the early stages of the COVID-19 pandemic: A message experiment.

The World Health Organization (WHO) officially declared COVID-19 a pandemic on March 11, 2020. It was a time of significant uncertainty as experts were not yet certain whether social distancing behaviors were necessary to slow the spread of the virus. Some public communicators opted to acknowledge uncertainty based on the limited evidence, whereas others downplayed uncertainty. This situation provided researchers with an opportunity to advance theory by explicating and testing cognitive responses to message uncertainty. Immediately following the WHO declaration (March 13-19, 2020), U.S. adults (N = 1186) were randomly assigned to one of six conditions in a 2 (message uncertainty: low, high) × 3 (argument support: expert, threat, precedent) between-participants experiment. Overall, perceived uncertainty negatively mediated the impact of message uncertainty on intentions. However, participant education was a key moderator. For those with more than a high school education, uncertain messages were related to higher intentions to social distance through increased critical reflection. For those with a high school education or less, uncertain messages were related to lower intentions through decreased message credibility.

Hailey-Hailey Disease is Associated with Diabetes: A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis.

Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey  disease was performed to assess the risks of type 1  diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no  excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.

Secondary ionization of pyrimidine nucleobases and their microhydrated derivatives in helium nanodroplets.

Radiation damage in biological systems by ionizing radiation is predominantly caused by secondary processes such as charge and energy transfer leading to the breaking of bonds in DNA. Here, we study the fragmentation of cytosine (Cyt) and thymine (Thy) molecules, clusters and microhydrated derivatives induced by direct and indirect ionization initiated by extreme-ultraviolet (XUV) irradiation. Photofragmentation mass spectra and photoelectron spectra of free Cyt and Thy molecules are compared with mass and electron spectra of Cyt/Thy clusters and microhydrated Cyt/Thy molecules formed by aggregation in superfluid helium (He) nanodroplets. Penning ionization after resonant excitation of the He droplets is generally found to cause less fragmentation compared to direct photoionization and charge-transfer ionization after photoionization of the He droplets. When Cyt/Thy molecules and oligomers are complexed with water molecules, their fragmentation is efficiently suppressed. However, a similar suppression of fragmentation is observed when homogeneous Cyt/Thy clusters are formed in He nanodroplets, indicating a general trend. Penning ionization electron spectra (PIES) of Cyt/Thy are broad and nearly featureless but PIES of their microhydrated derivatives point at a sequential ionization process ending in unfragmented microsolvated Cyt/Thy cations.