Due to anticipated postoperative neuropsychological sequelae, patients with gliomas infiltrating the corpus callosum rarely undergo tumor resection and mostly present in a poor neurological state. We aimed at investigating the benefit of glioma resection in the corpus callosum, hypothesizing neuropsychological deficits were mainly caused by tumor presence. Between 01/2017 and 1/2020, 21 patients who underwent glioma resection in the corpus callosum were prospectively enrolled into this study. Neuropsychological function was assessed preoperatively, before discharge and after 6 months. Gross total tumor resection was possible in 15 patients, and in 6 patients subtotal tumor resection with a tumor reduction of 97.7% could be achieved. During a median observation time of 12.6 months 9 patients died from glioblastoma after a median of 17 months. Preoperatively, all cognitive domains were affected in up to two thirds of patients, who presented a median KPS of 100% (range 60–100%). After surgery, the proportion of impaired patients increased in all neurocognitive domains. Most interestingly, after 6 months, significantly fewer patients showed impairments in attention, executive functioning, memory and depression, which are domains considered crucial for everyday functionality. Thus, the results of our study strongly support our hypothesis that in patients with gliomas infiltrating the corpus callosum the benefit of tumor resection might outweigh morbidity. Despite recent advances in molecular diagnostics and modern individual treatment, most patients suffering from glioma still face limited survival. Broad evidence exists that besides age, the preoperative Karnofsky performance score and adjuvant radiochemotherapy, the extent of surgical tumor resection (EoR) has a significant impact on patients’ survival. Nevertheless, patients suffering from gliomas that invade the corpus callosum rarely undergo surgical tumor resection. On the one hand, these tumors are considered more aggressive due to corpus callosum invasion and thus, to dissemination to both hemispheres, on the other hand, many neurosurgeons refrain from tumor resection within the corpus callosum in order to spare patients’ neurological or neurocognitive functions.1. Thus, enforced integration of cerebral processing between the two hemispheres is attributed to the corpus callosum, supported by the observation of increased corpus callosum size in persons capable of completing complex tasks and in persons with less behavioral laterality3. Only recently, left-brain oriented persons, being thought to be more lateralized due to the frequent ipsilateral location of language, have been shown to have a significantly smaller corpus callosum than right-brain oriented persons4.The corpus callosum is the largest interhemispheric commissure providing a connection between homologous cortical areas. There is ongoing debate whether it exerts an excitatory or inhibitory function, although evidence substantiating the theory of excitation predominates6. Left hand tactile agnosia, alexia in the left visual field and all above impairment of behavior are among the most common symptoms. Alexithymia, difficulty of attention, impaired verbal and working memory and difficulties in learning and coordinating new bimanual tasks can be detected applying neuropsychological tests in patients with damaged corpus callosum.Lesioning the corpus callosum may produce various symptoms subsumed under the callosal disconnection syndrome8.We observed many patients with huge frontal glioma and corpus callosum invasion who presented with avolition, aboulia or impaired consciousness already at the time of diagnosis, and many of these patients died within a few months after tumor biopsy and despite radiochemotherapy. This led us to hypothesize that tumor resection might not harm patients more than refraining from it. Likewise, removal of tumor tissue invading the corpus callosum could even improve patients’ neurological condition, assuming that reducing the mass effect and modifying the microenvironment of the surrounding neurons would translate into better neurocognitive and neurological function9. However, median survival of patients with butterfly glioblastoma was markedly improved by tumor resection, doubling a patient’s remaining life time in comparison to tumor biopsy only; a resection of ≥ 65% of the tumor volume was found to be associated with longer overall survival. Another analysis on the impact of EoR in butterfly glioblastoma was provided by Dayani et al., and they found out that the amount of total tumor reduction, but not EoR within the corpus callosum influenced patients’ overall survival (OS)10. Chen et al. equally observed EoR to be independently associated with longer OS in both, low- and high-grade glioma, whereas no such association was found for corpus callosum involvement which had no significant impact on OS11.Interestingly, only recently some publications focused on the resection of butterfly glioblastomas or tumors involving the corpus callosum. Chaichana et al. reported on significant shorter overall survival for patients suffering from butterfly glioblastoma compared to patients with glioblastoma in other regions11, only one publication by Dziurzynski et al. reported on the doubtful benefit of the resection of butterfly glioblastomas12. However, adjuvant treatment had been administered to barely half of their patients, probably confounding their results.While these three publications provided evidence that the resection of tumors involving the corpus callosum improves patients’ overall survivalAs a consequence, we decided to perform tumor resection in a cohort of patients suffering from glioma invading the corpus callosum and to evaluate prospectively the impact of surgery on patients’ clinical and neuropsychological function and OS. We hypothesized that removal of tumors with corpus callosum invasion might improve patients’ prognosis while maintaining or even ameliorating their neurological function, thereby breaking a passed-on dogma of refraining from tumor resection within the corpus callosum.We performed a prospective single-center study in patients who underwent surgical resection of tumors invading the corpus callosum. Patients underwent neuropsychological evaluation as part of their pre-surgical work-up, before their hospital discharge as well as after a follow up period of at least 3 months between January 2017 and January 2020.Study approval was granted by the ethics committee of Frankfurt University Hospital . All procedures performed were in accordance with the ethical standards of the institutional research committee and with the standards laid down in the Declaration of Helsinki. All patients gave written informed consent prior to data collection.Between 01/ 2017 and 01/ 2020, all patients meeting the criteria for study inclusion were identified. Inclusion criteria comprised (1) adult patients aged ≥ 18 years, (2) radiological suspicion of glioma with corpus callosum invasion, (3) indication for tumor resection and (4) fluent knowledge of German. The indication for surgical treatment was evaluated in a multidisciplinary tumor-board for each patient. Study-specific exclusion criteria were (1) any previous brain tumor treatment except tumor biopsy, (2) tumor spread into basal ganglia precluding tumor removal at a great extent, (3) lack of adequate social or family support needed for adherence to the further postoperative therapeutic regimen, and (4) any medical contra-indication for brain tumor surgery.Clinical characteristics, including the Karnofsky-Performance Score, results of magnetic resonance imaging and data on tumor characteristics including molecular analysis of tumor tissue were recorded prospectively for every patient.An additional review of tumor location, extent of lesion resection and response assessment in neuro-oncology (RANO) criteria was conducted by a trained neuro-radiologist before data analysis. In detail, structural MRI including standard sequences (T1-weighted (w), T2-w, T2*-w, FLAIR, diffusion-weighted imaging (DWI), T1-w with contrast agent) and a 3-dimensional T1-w sequence with contrast agent was performed prior to surgery, early postoperatively  as well as thereafter every 3 months. Tumor volume was assessed on 3D-T1-w sequences using Brainlab software  by manual segmentation. EoR was calculated as the difference of pre- and early postoperative tumor volumes, expressed as percentage. Gross tumor resection was defined as complete tumor resection, and subtotal and partial tumor resection were defined as 90–99% and < 90% EoR, respectively.Neurocognitive assessment was performed at three different time points; as part of the preoperative work-up (t1), at the end of hospital stay (t2) and after a median follow-up-period of 5.3 (range 3.1–12.8) months (t3).All patients underwent neurocognitive testing before surgery. Data on postoperative assessment had to remain incomplete either due to patients’ non-compliance, due to refusal to undergo further evaluation or because of death in one patient. Thus, follow-up evaluation at time points t2 and t3 was possible in a subset of 16 patients and 11 patients, respectively. All neurocognitive evaluations were performed by the same trained clinical neuropsychologist. Each assessment took place under optimal testing conditions and took patients approximately 1 h to complete. The applied elaborated test-battery included tests for attention, language, executive functioning, memory, visuospatial functioning, object recognition and bimanual coordination, the mini-mental state examination (MMSE) for assessing orientation, as well as the assessment of emotion such as anxiety and depression by the Hospital Anxiety and Depression Scale (HADS). A detailed list of all tests is provided in Table 14. Orientation, visuospatial functioning, object recognition and bimanual coordination were considered impaired as soon as one error per test occurred. Thereafter, both, the Z-score for each domain and the percentage of patients impaired per domain were calculated for each time point.Patients’ performances for the domains attention, language, executive functioning and memory were compared to published normative data of healthy controls accounting for age, gender, and educational level. The according scores of each test were then transformed into Z-scores, and cognitive decline was defined as a Z-score of less than − 1.5 SDp value of ≤ 0.05 was considered statistically significant.For analyzing the statistical effect of surgery on neurocognition (i.e. t2 vs. t1 and t3 vs. t1) we applied a Chi-Square test for each neurocognitive domain. In all evaluations, a The ethics committee of Frankfurt University Hospital approved the protocol and conduction of this study (SNO-09–2017).All patients gave written informed consent on the evaluation of their clinical and neurocognitive data.3. Tumor resection was complete in 15 patients, and subtotal in 6 patients, with median residual tumor volume of 2.1 cm3 and median EoR reaching 97.7% in these 6 patients . Most importantly, after the median follow-up period of 5.3 months, at t3, neurocognitive dysfunction was observed in a smaller number of patients in any domain, reaching significance in the domains attention, executive functioning and memory .Considering a decrease in a Z-score of more than 1.5 SD as cognitive decline, the percentage of patients impaired per domain at the different time points is depicted in Fig. p = 0.040).Those neurocognitive tests, for which no normative data were available, provided similar results Fig. ; the numTo our knowledge, this is the first study investigating neurocognition in patients who underwent brain tumor resection within the corpus callosum. The key findings of this investigation are that (1) tumor invasion of the corpus callosum did not result in shortened OS compared to the according literature on tumors not invading the corpus callosum, if tumor resection was performed; (2) after resection of tumors with corpus callosum invasion neurocognition only declined within the first postoperative days, whereas (3) after at least 3.1 months, patients’ performances had improved dramatically in every neurocognitive domain.15. However, a correlation of OS and EoR was not provided until 2015, when Chen et al. investigated the impact of corpus callosum involvement on EoR, progression-free survival and OS11. Analyzing data of 22 high grade glioma patients among 33 patients with corpus callosum invasion, they observed longer median progression-free survival (ranging from 3.8 to 10.0 months) and longer median OS, (ranging from 7.1 to 20.9 months) in patients who underwent higher EoR, with an EoR > 85% being of statistical significance.The number of reports on tumor resection within the corpus callosum is scarce. One of the first retrospective studies was provided by Steltzer et al. in 1997, comparing OS in patients resected for high grade glioma with and without corpus callosum involvement and showing that median OS decreased from 105 to 57 weeks, if the corpus callosum was involved3. Estimated median OS was 19.4 months for both, the entire cohort as well as the cohort of exclusively glioblastoma patients, being in line with results of key trials on high grade glioma patients. Thus, in glioblastoma patients, the combination of radiotherapy and temozolomide was reported to result in OS of 14.6 months in the EORTC 26981/22981 trial16, in OS of 16.6 months in the RTOG 0525 trial17, and, by adding tumor-treating fields in the EF-14 trial, in OS of 20.5 months18. Of note, no stratification according to MGMT promotor methylation and IDH mutation status was performed in these trials, allowing for a comparison with the hereby presented data on patients with tumors of different molecular features. However, recent literature on the resection of butterfly glioblastoma reported on shorter median OS; the largest according series of patients was published by Chaichana et al. in 2014, and they observed median OS of 6.4 months in 29 patients who underwent surgical resection of butterfly glioblastoma9. The difference in OS to the present study might not only be explained by the fact, that we included both, butterfly glioblastoma and tumors invading the corpus callosum, but also by the administration of adjuvant radiotherapy and/ or chemotherapy to only 66% and 55% of their patients compared to radiochemotherapy to 81% of our patients. Another series by Burks et al. reported on longer median OS in 27 butterfly high grade glioma patients, with median OS coming up to 15 months19, whereas in a series published by Dayani et al., median OS was 14.1 months10. Most importantly, patients who underwent biopsy of butterfly glioma experienced significantly shortened OS, ranging from 1.5 to 4.2 months20. Among our presented study cohort only one patient experienced similar short OS: the patient was 76 years old, suffered from huge left frontal glioblastoma and was the only one presenting slight aboulia, that temporary worsened after subtotal tumor resection and improved until hospital discharge. Rapid early tumor progression hampered further adjuvant treatment, and she died 3.8 months after surgery. Another 8 patients, all undergoing operation for glioblastoma, died after a median of 17.5 months.In the present study complete tumor resection could be achieved in 15 patients, and in 6 patients median EoR was 97.7%, with median residual tumor volume of 2.1 cm19. In the present study, all surgical procedures were conducted in patients under general anesthesia using subcortical motor mapping and continuous somatosensory evoked potential monitoring. In 3 patients with strictly callosal situated lesions we chose an interhemispheric approach, while in all other patients a transcortical frontal approach along the axis of the tumor was performed. In case of tumor invasion surgical resection comprised the cingulate gyrus accordingly, otherwise, the cingulum was spared. Interestingly, none of the 11 patients who underwent tumor resection within the cingulate gyrus presented aboulia or akinetic mutism, but slight SMA-syndrome with transient contralateral weakness was observed in 5 of these patients due to tumor resection extending into the posterior superior frontal gyrus. Although the small number of patients does not allow for a meaningful conclusion, we presume that (1) the selection of patients with a preoperative relatively high KPS score, (2) with tumors mainly situated in the frontal lobe, and (3) the conduction of surgery with intraoperative neurophysiological monitoring and mapping might have been responsible for the relatively low number of postoperative neurological deficits observed in our cohort of patients.Whether aboulia might be associated with shortened OS is speculative. However, none of the other 21 patients experienced aboulia or postoperative callosal disconnection syndrome. Burks et al. reported on immediate postoperative aboulia in 11 (44%) of 25 patients who underwent standard tumor resection and in 1 (7%) of 15 patients who underwent a cingulum-sparing technique with awake subcortical mapping24. However, data on neurocognitive outcome after glioma surgery are less frequent and provide heterogeneous results. An effort to summarize these data has been made only recently by Ng et al., including 11 studies on a total of 313 patients, of whom 45% suffered from high grade and 55% of low grade glioma25. In sum, and despite the heterogeneity of data, an improvement of patients’ performances was observed as early as within the first days after surgery in all cognitive domains, except for executive function that sustainably declined after surgery.Neurocognitive impairment is frequent in brain tumor patients. Depending on tumor aggressiveness, tumor size, location, and genetic characteristics impairments in neurocognitive function have been observed in up to 83% of treatment-naïve glioma patients27, being affected in only two and one patient, respectively, in the present study cohort by surgical tumor resection. Sustained impairment on figurative memory, on the other hand, seems more consistent with lesions in anterior parts of the corpus callosum. Since successful visual memory encoding engages both, episodic and semantic memory, an interhemispheric transfer between the right occipito-temporal connections responsible for pure visual information and mostly left-lateralized frontal and temporal semantic hub areas is required29. This might explain the relatively high percentage of sustained impairment of visual memory following the disconnection of left lateralized semantic areas and right lateralized areas needed for visuo-construction, whereas at the same time verbal memory and language, both less depending on interhemispheric communication, improved over time. In order to investigate whether ongoing impairments of visual memory depend on interhemispheric connections future studies might use tests applying non-semantic coding items like abstract signs. However, with exception of these functions critically depending on interhemispheric transfer, in total, patients’ neurocognitive abilities dramatically improved within several weeks after surgery, consequently improving patients’ everyday functioning and their quality of life.Data of the present study contrast with these results. Prior to surgery neurocognitive dysfunction was observed in no more than 63.2% of our patients, although all but one patient suffered from high grade glioma of large volume. During the postoperative course, all cognitive functions worsened and the proportion of impaired patients increased in every domain, whereas at long-term follow-up evaluation, a clear improvement of neurocognitive dysfunction was observed. At this time point, language was impaired in none of the patients, and less than a fifth of patients were impaired in attention, executive functioning, memory, orientation or visuospatial functioning. Only the rate of impairment on figurative memory, bimanual coordination and object recognition remained elevated, affecting 50%, 41.7% and 58% of patients, respectively. Indeed, postoperative white matter integrity through corpus callosum might explain these sustained cognitive impairments. Nevertheless, the interhemispheric information transfer necessary for bimanual coordination and tactile recognition has been attributed to the posterior body and the splenium of the corpus callosumThe major limitation of our study is the incompleteness of follow-up neurocognitive data sets. Due to patients’ refusal to undergo further postoperative cognitive evaluation (n = 5), death (n = 3) or study inclusion within the 6 months preceding the final evaluation (n = 1) a longitudinal follow-up was only possible in 12 patients. Thus, the heterogeneity of patient cohorts at different time points may have biased presented results. Moreover, it is likely that only patients with relatively good clinical performance biased our results. On the one hand, only patients with tumors that were amenable to a great extent of tumor resection were included into our study; on the other hand, patients who were willing and able to undergo long-term follow-up cognitive evaluation might have possibly caused an overestimation of clinical and neurocognitive results. Nonetheless, surgery-related outcome measures such as EoR and OS were assessed in all patients, enabling unbiased comparison to the relevant literature and strengthening the concept of surgical resection of tumors with corpus callosum invasion.Further evaluations in a bigger cohort of patients is mandatory, in order to allow for further meaningful correlations of clinical, surgical, histopathological and cognitive data. Future findings may encourage surgeons to perform resection rather than biopsy in patients with huge corpus callosum invading lesions, positively impacting both, OS and quality of life in these patients.The results of the present study suggest benefit from complete or subtotal resection of huge tumors invading the corpus callosum. No long-term decline but dramatic improvements in patients’ OS and neurocognitive functioning was observed, providing evidence that in patients with gliomas infiltrating the corpus callosum, who preoperatively present in rather good neurological state, the benefit of tumor resection might outweigh morbidity.Supplementary information.


Aspergillus fumigatus, in regard to how these fungi cope with host environmental stressors. Fungal UPR consists of a transmembrane kinase sensor (Ire1/IreA) and a downstream target Hac1/HacA. The active form of Hac is achieved via non-spliceosomal intron removal promoted by endonuclease activity of Ire1/IreA. Here, we assessed features of HacA and its involvement in virulence and susceptibility in Trichophyton rubrum. Our results showed that exposure to antifungals and ER-stressing agents initiated the activation of HacA from T. rubrum. Interestingly, the activation occurs when a 20 nt fragment is removed from part of the exon-2 and part of intron-2, which in turn promotes the arisen of the DNA binding site motif and a dimer interface domain. Further, we found changes in the cell wall and cellular membrane composition in the ΔhacA mutant as well as an increase in susceptibility toward azole and cell wall disturbing agents. Moreover, the ΔhacA mutant presented significant defects in important virulence traits like thermotolerance and growth on keratin substrates. For instance, the development of the ΔhacA mutant was impaired in co-culture with keratinocytes or human nail fragments. Changes in the pro-inflammatory cytokine release were verified for the ΔhacA mutant during the co-culture assay, which might be related to differences in pathogen-associated molecular patterns (PAMPs) in the cell wall. Together, these results suggested that HacA is an integral part of T. rubrum physiology and virulence, implying that it is an important molecular target for antidermatophytic therapy.The ability of fungi to sense environmental stressors and appropriately respond is linked to secretory system functions. The dermatophyte infection process depends on an orchestrated signaling regulation that triggers the transcription of genes responsible for adherence and penetration of the pathogen into host-tissue. A high secretion system is activated to support the host-pathogen interaction and assures maintenance of the dermatophyte infection. The gateway of secretion machinery is the endoplasmic reticulum (ER), which is the primary site for protein folding and transport. Current studies have shown that ER stress that affects adaptive responses is primarily regulated by UPR and supports fungal pathogenicity; this has been assessed for yeasts and  Trichophyton rubrum followed by Trichophyton interdigitale have been described as the predominant species isolated in dermatophytosis cases worldwide  represents the gateway of the secretory pathway, where most of the plasma membrane and secreted proteins undergo proper folding and post-translation modifications . The secWhen the ER capacity is overwhelmed by high concentrations of proteins inside the milieu, which exceed the ER folding competence, there is an accumulation of misfolded proteins that compromise cellular physiology. In order to mitigate this ensuing status of ER stress, a series of adaptive responses collectively termed unfolded protein responses (UPR) is initiated . The UPRAspergillus fumigatus pathogenicity  was cultivated in malt extract at 28°C, as previously described , caspofungin (CASP), griseofulvin (GRS), terbinafine (TRB), or undecanoic acid (UDA), and in the absence of drugs (control), followed by incubation at 28°C with shaking (120 rpm) for 12 h. The concentrations used for each drug were 70% of their minimum inhibitory concentration values, and obtained in accordance with the CLSI (M-38A2) (escribed . Conidia(M-38A2)  with theThe mycelia were ground by mechanical pulverization with a pestle and mortar in liquid nitrogen, and total RNA isolation was carried out using TRIzol  following the manufacturer’s instructions. RNA samples were treated with RNase-free DNAse I (Sigma-Aldrich). Complementary DNA was synthesized from each condition containing 1000 ng of total RNA in a 20 μL reaction volume using a High Capacity cDNA Synthesis kit (Thermo Fisher Scientific #4368814).hacA excision region (T. rubrum (TERG_05396). For the PCR reaction, approximately 140 ng of cDNA and 0.2 pmol/μL of each oligonucleotide were used. Thermocycler conditions were 95°C for 2 min, followed by 35 cycles at 95°C for 30 s, 53°C for 45 s, and 72°C for 1 min, and the last cycle at 72°C for 10 min.For qualitative expression analysis, primer pairs that yielded PCR products around the predicted n region  were userpb2 gene was used as a reference control, and all the analyses were carried out as previously described (The qPCR assays were performed using SYBR green PCR master mix (Applied Biosystems), 70 ng cDNA, forward and reverse primers used in concentrations previously determined  in a 12.escribed . A set oS. cerevisiae hac1 sequence as a query identified TERG_05396 as a putative ortholog for this gene. Thereafter, the prediction of the non-canonical intron excision site was determined by Infernal software  from pCSN43. The Overlap PCR was used to join the PCR products. Sets of primers were used for the split-marker approach, as described in The inactivation gene cassette was obtained using a split-marker approach . The 5′ hacA gene. Thereafter, the loss of hacA gene and integration of hph gene were confirmed by PCR and Southern blot analysis . The mycelia were then harvested and transferred to 20 mL fresh liquid Sabouraud medium and incubated for an extra 48 h under the same conditions described above. Further, the biomass was harvested through vacuum filtration and dried under sterile filter papers. The dried mycelium was weighed prior to saponification. Ergosterol was extracted as previously described (The quantification of ergosterol content was carried out as previously described  with modescribed  and quan5) of each strain, wild type and ΔhacA was inoculated into 25 mL of water that contained keratin (2.5 g/L) at pH 5.0, as the sole carbon and nitrogen sources, and incubated at 28°C for 7 days under shaking conditions (120 rpm). The mycelia were then harvested, and the supernatant was collected. The mycelial dry weight was obtained, and the pH of the supernatant was determined. Thereafter, the keratinolytic activity was estimated and expressed as units per gram of dry weight.The keratinolytic activity was determined, as previously described . KeratinThe analysis of growth rates was performed in different culture media: (i) agar malt extract (MEA), pH 5.7, (ii) potato dextrose agar (PDA), pH 5.7, (iii) Sabouraud, pH 5.7, (iv) MM (Cove’s) containing nitrate (70 mM) and glucose (55 mM) pH 5.0 , and (v)A microculture of strains was also carried out to assess differences in hyphal formation. The microculture was performed in Sabouraud agar and incubated for 6 days at 28°C.6–102 cell/mL. After 7 days of incubation at 28°C, images were taken using Image J software (T. rubrum (data not shown).A serial drop dilution assay was performed to analyze the susceptibility of strains toward antifungals and an ER stress compound DTT. Plates were inoculated with different concentrations of a conidia suspension in the range of 10software . The com5) was inoculated into the center of each well of a multi-well plate containing Sabouraud agar supplemented with concentrations of calcofluor white – CFW (in the range of 0–80 μg/mL) or CASP (in the range of 0–200 μg/mL) and incubated for 7 days at 28°C.In order to evaluate the susceptibility toward compounds that act on cell wall, a conidia suspension (approximately 1 × 104 cells and 103 cells) at different temperatures (37 and 42°C) for 30 and 60 min were determined.The tolerance to thermal stress conditions was also evaluated. In this sense, the number of colonies grown (CFU) after exposure to conidia (102) were sterilized by autoclaving. Nail fragments were then soaked with conidia (1 × 104/mL) from T. rubrum strains for 1 h, followed by the addition of 200 μL of distilled water. The plates were incubated at 28°C for 72 h, and fungal growth was assessed by light microscopy (Leica DMI3000B). The human keratinocytes (HaCaT) cell line was cultured, as previously described  according to the manufacturer’s recommendation. Committee of Ethics in Human Research of the Ribeirão Preto Medical School at the University of São Paulo approved all experiments involving the use of human nail fragments provided by healthy adults (protocol No.8330/2009).Nail interaction assay was performed as previously described  with minescribed . The cochac-1 from Saccharomyces cerevisiae as a query revealed TERG_05396 as a putative ortholog for this gene in T. rubrum. The predicted hac-1/hacA gene from T. rubrum contains 1281 nucleotides. The comparison among mRNA secondary structures of hac-1/hacA sequences from different fungal species evidenced a region of intron excision for prompt hac-1/hacA activation. Following sequencing of the hacA amplified products from T. rubrum, we showed that under ER stress, a fragment of 20 nt was removed from hacA mRNA. We also demonstrated that some antifungal compounds (griseofulvin and terbinafine) were responsible for hacA activation through the 20 nt fragment removal as well as the positive controls DTT and tunicamycin  using a split-marker approach  also made the expected fragments of 452 and 2159 bp (5′UTR fragment), and 684, 1283, and 1766 bp (3′ UTR fragment). The PCR confirmed the loss of the hacA gene, and homologous integration was identified by genomic Southern blot analysis , compared to the wild-type strain , or Cove’s medium . As ergosterol is the principal sterol within the cellular membrane with roles in fluidity, membrane protein assembly , and their activation triggers intracellular signaling that leads to the production of pro-inflammatory mediators, like cytokines. In this work, we assessed the levels of IL-1β, IL-8, and TNFα after 24 h of co-culture of the human keratinocyte line (HaCaT) with conidia from both strains, the or IL-1β . This reTo assess genes that are directly or indirectly regulated by HacA, we evaluated the modulation of genes related to cell wall synthesis, ergosterol biosynthesis, pigmentation, heat shock proteins, and the genes coding for mannosyltransferase enzymes , 12.fks1 and chsD, and we observed marked differences in control (0 h) between the wild type and mutant, with a significant decrease in transcript levels for the mutant strain. Further, over time , the mutant strain exhibited reduced transcription levels of fks1, compared to the wild type, whereas no differences in transcript levels were shown for chsD among the strains at the same time point. We also demonstrated that in response to terbinafine exposure, an increase in chsD transcriptional levels was assessed for the wild type, probably as an adaptive response leading to cell wall remodeling. Several lines of evidence point to the UPR impact on the fungal wall and cell membrane, suggesting potential connections between cell wall integrity (CWI) pathway and UPR . Chemical treatment with DTT promoted an up-regulation of erg1 from the wild type strain, while no significant differences were observed for the mutant. DTT induces an ER stress and as this organelle is linked to lipid synthesis; thus, could be possible that induction on the erg1 transcript levels was an attempt to cope with the ER perturbation. Conversely, no differences were found in the transcript levels of erg1 were verified for the TRB treatment at this time point.The hsp90 levels, whereas at this same time point the mutant strain prompted a rise in the hsp75-like levels. These results might reflect a compensatory modulation in the ΔhacA strain. However, when exposed to terbinafine, only the wild type maintained elevated transcript levels for both Hsp encoding genes. It is already known that Hsp is involved in the sensing and adaptation of pathogens to thermal conditions as well as diverse conditions. In this context, previous reports have suggested Hsp90 as a potential therapeutic target as it is an abundant Hsp (corresponding to approximately 2% of the protein repertoire) which contributes to cell wall integrity, germination, pigmentation of conidia, drug resistance, and virulence  between strains. Notwithstanding, the DHN-melanin pathway consists of other genes that could be directly or indirectly regulated by HacA like pksP, arp1, and arp2. Another study has also reported that differences in the melanin of A. fumigatus within the conidial cell wall was found to be related to both stress tolerance and virulence  is the gateway for the secretory pathway and is the center for post-translational modification, accurate folding, and assembly of up to 30% of the cellular proteome . Fungi ahacA mRNA mediates the activated form of HacA through IreA, The RNase domain of IreA is responsible for catalyzing the intron removal from hacA in a spliceosome independent manner, which in turn leads to a shift in the open reading frame, and the arisen of bZIP domain in activated HacA , an increase in azole susceptibility was also assessed . The patients/participants provided their written informed consent to participate in this study.NM-R, TB, and AR conceived the study and wrote the manuscript. TB performed the experimental design and laboratory experiments. AF and EL contributed with deletion cassette construction. PS performed the bioinformatics analysis. NP assisted in the immunological assays. VO assisted in the microbiological assays.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


UC samples were more abundant in Proteobacteria (8.42%), Actinobacteria (6.89%) and Candidate Division TM7 (2.88%) than those of healthy volunteers . On the other hand, Bacteroidetes and Verrucomicrobia were presented at a lower level in UC relative to the controls . In conclusion, our results show a reduced gut microbial diversity in Polish UC patients, a reduction of taxa with an anti-inflammatory impact and an increased abundance of potentially pathogenic bacteria.Ulcerative colitis (UC) is a chronic immune-mediated disorder, whose etiology is not fully understood and for which no effective treatment is available. Recently, research has focused on the dysbiosis of gut microbiome in UC. However, the results so far remain inconsistent and insufficient to understand the microbial component in UC pathogenesis. In this study, we determine specific changes in the gut microbial profile in Polish UC patients compared to healthy subjects for the first time. Using 16S rRNA gene-based analysis we have described the intestinal microbial community in a group of 20 individuals (10 UC patients and 10 controls). Our results after multiple hypothesis testing correction demonstrated substantially lower gut microbiome diversity in UC cases compared to the controls and considerable differences at the phylum level, as well as among 13 bacterial families and 20 bacterial genera ( Over the past few years, the morbidity of UC has constantly increased, affecting millions of people worldwide. Therefore, it has become a global public health challenge4. Unfortunately, the available treatment involving immunosuppressants, corticosteroids, aminosalicylates, biological agents, diet or surgery only relieves the symptoms8. The lack of effective treatment is certainly a consequence of the as yet not fully understood etiology of the disease. However, it is known that UC has a multifactorial background based on a defective intestinal barrier and an impaired immune response against luminal antigens, which is modified by environmental factors in genetically predisposed people12.Ulcerative colitis (UC) belonging to inflammatory bowel diseases (IBD) is characterized by chronic inflammation of the colorectal mucosa and systematic biochemical abnormalitiesloci have been indicated. Studies have shown that these candidate loci are mostly involved in regulating the immune response13. On the other hand, current research reports changes in gut microbiota balance in UC patients, underlying the possible role of microbial flora in UC pathogenesis. Although it still remains unclear whether dysbiosis is a cause or consequence of intestinal inflammation, much research has shown that gut microbiota constitute a crucial element of the host immune system, gut-associated lymphoid tissue (GALT), and disturbances to it may affect various diseases15. Trillions of microbes forming a complex ecosystem in the human gut influence the functioning of host organism due to microbial metabolites, such as short-chain fatty acids (SCFAs), carbohydrates, vitamins and gases16. SCFAs  activate the G protein-coupled receptors, which are located on macrophages, dendritic cells and mast cells. They regulate, among other things, the expression of multiple genes, such as anti- and pro-inflammatory cytokines, hormones release, claudin-5 and occluding production influencing the integrity of the blood–brain barrier19. There is evidence that specific bacterial species (from Clostridia and Bacteroides genera) of gut microbiota play a role in mucosal immune homeostasis and inflammation, particularly in the regulation of T helper 1, 2, 17  and T-reg cells release, which are responsible for the induction and inhibition of colonic inflammation20.Up to now, more than 100 UC-associated genetic Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria23. Indeed, the implementation of the Human Microbiome Project allowed first standards to be set for each bacterial phyla abundance in healthy subjects21. However, later studies on healthy populations have verified this data and showed that Firmicutes dominate among bacterial phylas, and together with Bacteroidetes constitute almost 90% of intestinal microbiota24. Studies also revealed, that abundance values of each phyla are characterized by large variability, within the population, as well as between them23. In the Polish population gut microbial composition has been characterized only in men with obesity and cardiometabolic disorders, so far26. There is no data available for healthy individuals.In healthy conditions, human gut microbiota is composed of around 400–500 bacterial species, of which over 90% belong to four major phyla, i.e. 28. Studies revealed that over 50 genera displayed a positive correlation with a given primer pair-mediated amplification efficiency, thereby indicating that the analysed region of 16S rRNA gene plays an important role in the generation of a bias in the determination of gut microbiota composition27.Research have proved that factors, such as the way of sample preparation, analysed region (V1-V9) of 16S rRNA gene or applied sequencing technology, may affect abundance of each microbial taxaFirmicutes and Bacteroidetes phyla, and an increase in pathogenic species from the Enterobacteriaceae family32. However, there is great variability of results across studies, with contradictory findings, hence an in-depth analysis of gut microbiota in UC patients is still needed28. A fully explained pathogenesis of UC could be a milestone in the development of effective targeted therapy, as faecal microbiota transplantation (FMT) has recently promised to be33. Our recent pilot investigation concerning FMT in UC patients has proved a strong correlation between specific gut bacteria and clinical parameters in the FMT procedure determining its effectiveness34. Thus detailed knowledge about the microbiome of a healthy population is needed and our analysis of UC microbiota in Polish patients will constitute an important basis for therapeutic options and further research on UC.In UC patients, changes concerning the diversity and composition of gut microbiota on different taxonomic levels compared to healthy subjects have been observed. The dysbiosis associated with UC often relies on a decrease in beneficial, commensal bacteria, particularly those belonging to The purpose of the current work was to investigate the gut microbial composition for the first time in Polish UC patients relative to healthy subjects. In particular, we wanted to discover specific quantitative and qualitative changes occurring on different taxonomic levels in the gut microbiota compared to healthy volunteers. Description of intestinal microbial diversity in patients with UC aims at a better understanding of the disease's mechanism and it is necessary in order to improve FMT efficacy as an encouraging treatment approach. Our results we have verified performing a meta-analysis with the similar publicly available data.In the present study, we investigated gut microbial composition in a group of 10 Polish UC cases and 10 healthy subjects. All patients had active UC disease, wherein 4 (40%) presented a moderate and 6 (60%) a severe form of the disease  and Actinobacteria (6.89%) than those of healthy volunteers   relative to the controls (27.97%). In both groups, most of the bacteria identified belonged to Firmicutes phylum and constituted 67.24% in patients and 58.85% in control subjects. These four main phyla including Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria comprised over 90% of the total microbial community in analysed guts, although the observed differences were not statistically significant. Among the other things, less common phyla, Verrucomicrobia, Candidate Division TM7, Euryarchaeota, Cyanobacteria and Synergistetes were detected in the samples analysed. An abundance of Verrucomicrobia was observed to be significantly higher in healthy subjects relative to UC patients , but after multiple correction, the statistical significance was not high  was also eradicated after correction  Fig. . Bacterocteria 8.2% and Acigh Fig. . Furthercteria 8.2% and Acion Fig. .Figure 3p < 0.05) in both groups of samples  and Bacteroidaceae (21.9%) were found to be most abundant.At the family level, we observed that 13 bacterial taxa displayed significantly different abundance  abundance level in patients with UC compared to healthy volunteers  in two dimensions (dim.) was performed. This analysis demonstrated that in UC patient group nts Fig. .Figure 539. Two of these studies did not report all quantitative data  about microbial abundance, as well as raw sequencing data were not available, even on request, which made it impossible to include them in the meta-analysis39.Our electronic search identified 1445 potentially eligible entries Fig. . Five ad37. The studies achieved relatively high scores in the quality assessment (NOS score) (seven to eight). Included studies are characterized in Table Finally, we were able to include 3 studies in meta-analysis to verify our significant differences in microbiota composition between UC and control groupPerformed by us meta-analysis showed a significant difference in the content of several bacterial families and genera between the studied group of patients with UC and the controls.Streptococcaceae than healthy controls  and heterogeneity (I2 = 10.07%)  Fig. .Figure 8Phascolarctobacterium in patients with UC compared to healthy controls. Phascolarctobacterium was reduced in UC patients compared to controls  and heterogeneity (I2 = 17.94%)  Fig. .Figure 1Ruminococcus compared to controls with a SMD of − 0.261 (95% CI − 0.397 to -0.125) and heterogeneity (I2 = 0%) , as well as Shannon’s entropy (even p > 0.05) compared to the control samples. We have identified on average 225 OTUs in healthy controls and 144 in UC subjects. These results confirm previous findings about dysbiosis observed in UC40.We revealed that the diversity of microbiota in UC patients was reduced, which was manifested by the lower amount of total OTUs   compared to the controls (27.97%). Most research performed so far in UC proves a decrease in Bacteroidetes in UC cases46. However, there are also studies leading to the opposite conclusions, e.g. Fuentes et al. observed significantly higher levels of Bacteroidetes in UC patients at baseline (before FMT) compared with donors, where differences ranged from 1.2 up to 15 times as much depending on the species47. We also have shown that samples from patients with UC are more abundant in Proteobacteria (8.42%) and Actinobacteria (6.89%) relative to healthy volunteers , which correlates with the results of American scientists for 61 UC patients and 61 controls43. Furthermore, in our research, Verrucomicrobia was found to be more abundant in healthy subjects compared to UC. Despite the lack of statistically significant quantitative variations in the gut microbiota at the phylum level between both groups, considerable qualitative and quantitative differences in microbial compositions within phylas were identified.This study shows that four basic bacterial phyla, including Firmicutes concerned a considerable increase in Bacillaceae, Clostridiaceae 1, Enterococcaceae, Staphylococcaceae, Streptococcaceae and Veillonellaceae, as well as a decrease in the Christensenellaceae family in UC patients in relation to healthy controls  is characteristic for IBD, including UC, because of its role. F. prausnitzii produces a 15 kDa anti-inflammatory protein that inhibits the NF-κB pathway in intestinal epithelial cells and was shown to prevent UC in a mouse model48. On the other hand, an increase of Steptococcus, Staphylococcus and Veillonella was proved in our UC patients group, which was also the case in some other studies45. Moreover, some research indicates a decrease in Clostridium cluster XIVa and an upward trend in the Clostridium cluster IX in UC49. In our UC patient group, an increase in Clostridium was observed, albeit not a statistically significant one. We revealed that a characteristic decrease in Bacteroidetes in the case of UC mainly concerns a reduction in Bacteroidaceae (genus Bacteroides) and Prevotellaceae . These results also confirm those obtained by Nemoto et al.46. However, in another investigation, Bacteroidetes significantly increased in UC47. The growth in Proteobacteria in the intestinal microbiota of UC patients observed in our study was caused generally by an increased level of Enterobacteriaceae (genus Escherichia-Shigella). It is therefore worth highlighting the evidence that Escherichia-Shigella is correlated with inflammation and in healthy humans should not exceed 0.5% of the gut microbiota32. In our data, it constituted 3.9% in UC patients and 0.3% in the controls. Furthermore, we observed a substantial decrease in beneficial Bifidobacterium in Polish UC patients. A considerable decrease in Akkermansia (phylum Verrucomicrobia) was also found in our research as associated with UC, which is consistent with major findings. Previous studies demonstrated the anti-inflammatory effect of Akkermansia derived vesicles, which could reduce the substance triggering colitis50. The Akkermansia level could be decreased due to reduced mucins in patients with UC, which constitute an energy source for this bacteria51. These relationships indicate important genus that should be focused on in the search for microbiota markers of active UC, its course and the effect of FMT treatment.We demonstrated that diversity in bacterial composition among ols Fig.   in 16S rRNA geneStreptococcaceae, Christensenellaceae, Ruminococcus, Streptococcus, Anaerostipes and Phascolarctobacterium37.Secondly, the limitation of our pilot study is small groups size. Thus, we performed a meta-analysis to verify our findings with other similar studies applying exactly the same methodology pipeline in the comparative analysis of UC cases versus controls, which are only few. After re-analysis of raw sequencing data from finally 3 studies and our results  and random-effects meta-analysis we revealed significant differences between both studied groups in the abundance of In conclusion, our study conducted on Polish patients allowed us to point out alterations specific for UC in the gut microbial community compared to healthy controls. These results indicate that gut microbiota in UC is less diverse and considerable abundance differences are observed at the phylum, family and genus level compared to a healthy intestine. We reveal that dysbiosis in UC is generally based on a reduction in beneficial bacteria and an increase in undesirable groups of them. However, it should be taken into account that a number of factors may influence the specific structure of gut microbiota, including host genetic factors, like the expression of relevant inflammatory proteins. In the future, studies on bacterial species, their function and correlation with host genetic factors will be more desirable in discovering UC etiology.2) with active UC and under the care of the H. Swiecicki Clinical Hospital at Poznan University of Medical Sciences and the Department of Gastroenterology, Dietetics and Internal Diseases at Poznan University of Medical Sciences in Poland were enrolled in this study. All participants provided written informed consent. This study was approved by the local Ethics Committee of Poznan University of Medical Sciences (resolution no. 1106/17 approved on 9 November 2017). All experiments were performed in accordance with the principles of the 1964 Declaration of Helsinki with its later amendments. Patients were recruited from January 2018 to December 2019. UC diagnosis was made based on clinical, endoscopic and histological data. Detailed characteristics for all patients including age, BMI, treatment, range of disease, disease severity (based on Truelove-Witts score) and duration of disease are presented in Table Clostridium difficile infection, diabetes, cancers), pregnancy and intake of antibiotics or probiotics during the last 3 months.Ten Polish patients  from Polish population. Exclusion criteria were antibiotics or probiotics intake and alcohol abuse during the last 6 months. The first morning faecal sample was taken from each participant and stored until analysis at -80ºC.The control group consisted of 10 healthy subjects  control library was added to the concentration of 20%. Sequencing was performed on an Illumina MiSeq platform using a MiSeq Reagent Kit v3 (600 cycles).Bacterial DNA was isolated from the faecal samples collected from each individuals using a Genomic Mini AX Bacteria + Kit , according to the manufacturer's protocol. The sequences of region V3-V4 of the 16S rRNA bacterial gene were amplified using barcoded primers with Illumina adapters and KAPA HiFi HotStart ReadyMix PCR Kit . Bacterial libraries were prepared according to 16S Metagenomic Sequencing Library Preparation protocol . The final concentration of library was 8 pM. Bacteriophage 52. Alpha diversity was determined using OTU richness and Shannon’s entropy. Raw demultiplexed sequencing data with sample annotations were deposited in the Short Read Archive database (SRA) (http://www.ncbi.nlm.nih.gov/bioproject/PRJNA679275).16S rRNA gene sequences were obtained and processed using a CLC Genomic Workbench 8.5 and CLC Microbial Genomics Module 1.2. . The average number of reads per sample was 217,819. Reads were demultiplexed and trimmed. Chimeric sequences were removed and operational taxonomic units (OTUs) were clustered against the SILVA v119 97% 16S rDNA gene databaset-test for independent measures. The assumption of whether the data follow the normal distribution was evaluated using the Shapiro–Wilk test. Levene’s test was used to check the equality of variances. In case the data did not confirm the assumptions, the non-parametric Mann–Whitney test was used. Furthermore, a correction with respect to multiple hypothesis testing was performed. The adjusted p-values were calculated according to the Benjamini–Hochberg procedure. In order to investigate the relationship between particular microbial phylas, principal component analysis (PCA) was performed.The differences in demographic data between the groups were analysed by the p < 0.05. GraphPad Prism 8.0.1  and CLC Genomics Workbench software  was applied to prepare graphs.The statistical analysis was performed using STATA software . All tests were considered significant at We conducted a systematic search of studies in PubMed, Embase, The Cochrane Library and Web of Science database included the keywords (‘Inflammatory Bowel Disease’ [Mesh] OR ‘IBD’ [Mesh] OR ‘Colitis’ [Mesh]) AND  with the following filters: last 10 years, Clinical Trial, Controlled Clinical Trial, Randomized Controlled Trial, Humans, Adult. We also performed manual searches. The last search update was November 2020.Including criteria were: case–control studies with adult patients diagnosed for active UC based on endoscopy and histology, where healthy individuals without history of disease were used as controls; assessments of microbiota composition based on stool samples using NGS technology covering V3 and V4 regions of 16S rRNA gene; studies with publicly available raw 16S data for each case and control samples . The raw sequencing data have been re-analysed by us according to the same pipeline as our data.2, statistics based on Q-Cochran test was used. The Publication bias was assessed by Egger’s test. The calculations were performed by MedCalc statistical software version 19.6 .The methodological quality of randomized studies was assessed using the Newcastle—Ottawa quality assessment scale case–control studies Table . The higSupplementary Information


Clinical trials of these products in India, Ghana, and Niger suggest similar efficacy to Rotarix and RotaTeq in low-income settings.9 All these vaccines are live human-attenuated or animal-human reassortants administered orally. Like other live oral vaccines such as oral polio, cholera, and typhoid, they are less immunogenic and efficacious in children in low-income settings, probably because of a combination of factors that underpins the infant’s immune response, including maternal antibodies, chronic enteropathy, the microbiota, and interference from other infections. Additionally, a low-level risk for intussusception (in the range of one to seven cases per 100 000 vaccinated infants) has been observed for Rotarix and RotaTeq;10 this finding might be due to a class effect of replicating rotavirus vaccines.The Rotarix and RotaTeq vaccines are currently used in national immunisation programmes of over 80 countries and subnationally or in the private sector of many others. Their use has led to impressive reductions in incidence of severe rotavirus diarrhoea by more than 80% in high-income and 50% in low-income settings.11 report the first phase 1/2 study of a novel parenteral rotavirus vaccine for use in infants. The vaccine includes a truncated VP8 subunit protein of the human Wa strain (VP7 serotype 1 and VP4 serotype 8) and a tetanus toxoid P2 protein. Infants were randomly assigned to receive 10, 30, or 60 μg of vaccine with aluminium hydroxide or a saline placebo, coadministered with routine vaccines at ages 6, 10, and 14 weeks. Frequency and severity of adverse events were similar between groups. Adjusted and unadjusted IgG seroresponses against VP8 strains were 98–100%; unadjusted IgA seroresponses were in the range of 58–81% against the P8 protein, but only 9–27% when whole lysate was used. Adjusted neutralising antibody responses were over 80% for P8 strains, 30–50% for P4 strains and 17–23% for P6 strains.In this context, Michelle Groome and colleagues12 infants received the human attenuated Rotarix vaccine after the last parenteral vaccine dose, and vaccine virus excretion at day 5, 7, and 9 after the first dose was measured by stool ELISA.11 Encouragingly, vaccine shedding (any positive sample) was 57% (95% CI 23–76%) lower in vaccinated children (30 μg and 60 μg dose groups combined) than in the children who received placebo. Taking these results together, the authors conclude that the vaccine is immunogenic, and that reduced Rotarix vaccine virus shedding suggests intestinal immunity, which might be a proxy for vaccine efficacy. The authors also acknowledge the absence of significant heterotypic immunity, indicating that studies with vaccines with different P serotypes are needed.Using similar methodology to that used to assess polio vaccines,The study is the first phase 2 human trial of an inactivated rotavirus vaccine, and shows the potential of such a strategy, as well as the challenges it faces. First, a non-replicating vaccine approach could possibly circumvent the lower efficacy of live oral vaccines observed in less developed regions, although that remains a conjecture until a study with clinical endpoints is done. Second, a more predictable advantage is that a parenteral vaccine is not expected to cause intussusception. Third, an inactivated vaccine could have some effect on reducing rotavirus shedding but, as for polio, it might be better at preventing disease while less effective at preventing shedding than live oral vaccines.11 indicate that a phase 2 trial with a formulation with additional rotavirus antigens is planned, with the hopes of broadening what appears to be a predominantly homotypic response. Hopefully when the phase 3 trial is designed, this vaccine will be compared with an established vaccine in a non-inferiority trial, rather than to placebo. Such a study will be more difficult and will require substantially more infant participants, but would provide more definitive answers regarding comparative efficacy, and might be the only ethical choice with widespread vaccine use. Finally, implementation of a new parenteral vaccine in a crowded vaccine calendar might require antigen combinations, with old and possibly new targets such as norovirus, which is another major cause of childhood diarrhoeal disease.13Groome and colleagues


Background: Environmental changes are predicted to threaten human health, agricultural production and food security. Whilst their impact has been evaluated for major cereals, legumes and vegetables, no systematic evidence synthesis has been performed to date evaluating impact of environmental change on fruits, nuts and seeds (FN&S)—valuable sources of nutrients and pivotal in reducing risks of non-communicable disease. Methods: We systematically searched seven databases, identifying available published literature (1970–2018) evaluating impacts of water availability and salinity, temperature, carbon dioxide (CO2) and ozone (O3) on yields and nutritional quality of FN&S. Dose-response relationships were assessed and, where possible, mean yield changes relative to baseline conditions were calculated. Results: 81 papers on fruits and 24 papers on nuts and seeds were identified, detailing 582 and 167 experiments respectively. A 50% reduction in water availability and a 3–4dS m−1 increase in water salinity resulted in significant fruit yield reductions . A 75%–100% increase in CO2 concentrations resulted in positive yield impacts . Evidence on yield impacts of increased O3 concentrations and elevated temperatures (>25 °C) was scarce, but consistently negative. The positive effect of elevated CO2 levels appeared to attenuate with simultaneous exposure to elevated temperatures. Data on impacts of environmental change on nutritional quality of FN&S were sparse, with mixed results. Discussion: In the absence of adaptation strategies, predicted environmental changes will reduce yields of FN&S. With global intake already well-below WHO recommendations, declining FN&S yields may adversely affect population health. Adaptation strategies and careful agricultural and food system planning will be essential to optimise crop productivity in the context of future environmental changes, thereby supporting and safeguarding sustainable and resilient food systems. If not tackled by adequate adaptations strategies, these changes threaten to impact food security [There is now well established evidence that human-driven changes to our planet’s environment are accelerating at a pace that threatens human health through altered functioning of global systems . Changessecurity  and moresecurity , have deFruits are a major source of nutrients and bioactive compounds important for health and disease prevention. In the Global Burden of Disease 2017 models, inadequate intake of fruit is among the top three leading dietary risk factors for deaths and disability-adjusted life-years , and modGlobal healthy and sustainable reference diets now advise low amounts of animal products, based on a growing concern about the impact of animal source food production on environmental change, and encourage increased consumption of plant-based foods such as fruit and vegetables . Nuts anFN&Ss, like many other crops, are sensitive to changes in environmental exposures throughout the year. The number of hot days, the overall growing season climate and changes in minimum and maximum daily temperatures all substantially affect fruit development . For exaTo date there has been no systematic review of the impact of environmental changes on the availability and nutritional quality of FN&Ss. We here report the findings of a systematic review of available published studies examining the effect of changes in environmental exposures on yield of FN&Ss and the nutritional quality of fruits in field and greenhouse settings. We focus on studies that were conducted in standardised business-as-usual scenarios with no involvement of new technologies or changes in agricultural practices.2.2.1.6For the purposes of this review, fruit crops such as tomatoes, cucumbers, peppers, avocados, courgettes, pumpkins and aubergines that are typically consumed as vegetables were excluded.; and yields of the 15 most commonly consumed nuts7Including legumes commonly consumed as nuts. and seeds globally (appendix). The search for papers on nuts and seeds was performed in July 2018 and covered the papers published between 1 January 1970 and 30 June 2018, whilst the search for papers on fruits was performed in November 2018 and covered papers published between 1 January 1970 and 21 November 2018. Most commonly consumed varieties of each crop group were determined by studying the Food and Agriculture Organisation (FAO) food balance sheets [2 concentration, and elevated tropospheric O3 concentration. Specifically, we considered water salinity either through flooding, saline ground water or saline irrigation water, and did not include papers on soil salinity. The primary outcomes were the percentage change in yield of fruits, nuts or seeds (exposure versus baseline) and nutritional quality of fruit . All nutritionally-relevant substances reported in included papers were considered, namely: flavonoids, ascorbic acid (vitamin C), carotenoids, phenolic compounds, and antioxidants (including antioxidant activity).This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We perfe sheets . The evan = 4). Where full-texts were unavailable (n = 7), we contacted all authors and one author provided us with one additional paper.A search of seven databases was carried out in conjunction with a second systematic review evaluating the impact of environmental change on vegetables and legumes . Databas2.2.We included experimental studies conducted in field and greenhouse settings, written in English, French, Spanish, German or Dutch; modelling studies were excluded. Titles and abstracts were screened for relevance by four reviewers for fruits papers  and two reviewers for nuts and seeds papers . Full-texts were read by two reviewers , and any discrepancies were discussed and settled with a third reviewer (PS or HT). A single reviewer performed data extraction , of which a random 20% sample was checked by a second reviewer (CC). Extracted data included study location, publication year, study design (field or greenhouse study), environmental exposure considered , crop type and group, yields at baseline and under experimental conditions, and nutritional quality parameter concentration at baseline and under experimental conditions.2.3.stacks.iop.org/ERL/15/023002/mmedia). Parameters relating to randomisation, blinding and cost-effectiveness were excluded from the checklist. Papers were assigned a quality score ranging from 0 to a maximum of 5 relating to the following criteria: (1) clear description of the study design, (2) appropriate comparison group, (3) clear description of the methods, (4) rigorous and clearly described analysis, including critical examination of potential biases, and (5) precision estimate of the measure of effect CIs and/or standard deviations). Papers not reporting precision estimates were included in the review, however only papers that reported precision estimates of measured effects were to be included in pooled analysis. Papers not meeting a quality score of at least 4 were excluded.Papers identified for inclusion were assessed for quality using a modified version of the Critical Appraisal Skills Programme checklist for randomised controlled trials , adapted2.4.The absolute differences in outcome between baseline and exposure were used to derive percentage changes in yield or change in concentration of certain nutritional quality parameters for each individual experiment reported by the included studies. Results were grouped by environmental exposure (single or combination) and crop type (nuts and seeds) or crop group (fruits). Fruits were sub-divided into aggregates of similar dietary function. They were defined as: berries (including grapes and strawberries); pome (including apples and pears); cucurbits ; citrus ; and bromeliads (including pineapple). For the purposes of this analysis, field and greenhouse studies were combined due to the experiments having been conducted under a variety of ambient and soil conditions. Sensitivity analysis showed that the direction and scale of findings in the two study designs were similar.Scatter plots were used to visually display the relationship between changes in outcome and the evaluated range of the environmental exposures. Where measurement units for the exposures differed amongst the included studies, the percentage change in exposures were used. Crude summary estimates, here named ‘mean yield change’, along with their corresponding 95% confidence intervals (CIs), were calculated where a minimum of three different studies examining the same range of environmental exposure were identified. Due to the clustered nature of the data (i.e. multiple experiments in a single paper), the Huber (sandwich) estimate of variance  was used3.3.1.The initial database search identified 104 443 titles for fruits, and 3315 titles for nuts and seeds. After removal of duplicates and screening of titles and abstracts, 1337 potentially relevant papers for fruits (including one paper identified through consulting experts in the field and one paper identified by reference screening), and 99 potentially relevant papers for nuts and seeds remained for assessment of eligibility and quality. Of these, 1256 papers were excluded during full text screening for fruits, and 75 during nuts and seeds screening. A total of 81 papers (582 experiments) on fruits were included in the final analysis, of which 73 reported on yields and 27 reported on nutritional quality (19 reported on both). In the final analysis on yields of nuts and seeds, 24 papers (167 experiments) were included (figure Sixty-five papers on fruits reported on field studies and 16 papers on greenhouse studies (including one study in a rain shelter—supplement C). Of the 24 included nuts and seeds papers, 15 took place in field settings and 9 within greenhouses or related structures such as growth chambers, glasshouses and rain shelters. Experiments were conducted in 32 different countries, with the highest concentration in Spain (17 papers) and the United States , and peanuts were the most frequently studied of the nuts and seeds crops   that reported on the effect of reduced water availability on fruit yields  reported on the effect of reduced water availability on nutritional quality of fruits. The evaluated reduction in water availability ranged from 9.5% to 100%. Water stress largely resulted in increased nutrient concentrations in citrus and cucurbit crops, and decreased concentrations in pome crops. No consistent dose-response pattern in quality parameters could be observed in response to water stress figure . Eleven We identified 13 papers  examining the effect of restricted water availability on nut yields. The evaluated reduction in water availability ranged from 7.7% to 100%. The majority of experiments reported negative yield change across almonds, peanuts, and walnuts, with yields decreasing as water stress increased figure . Pecan y3.2.2.−1. The evaluated increase in water salinity ranged from 0.15 to 7.3 dS m−1, and was converted to a percentage increase from baseline salinity levels. Yield changes in response to increased water salinity were largely negative across berries, citrus, cucurbits and drupe crops, with yields decreasing as water salinity increased. Seven studies  evaluated yield changes in response to a 1–2 dS m−1 increase in water salinity. This resulted in a −4.9% non-significant mean yield change , while a 3 to 4 dS m−1 increase in water salinity resulted in a −28.2% mean yield change . Two studies reported uncertainty estimates; therefore, no pooled analysis was performed.We identified 12 papers  assessing the effect of water salinity on fruit yields (figure −1) resulted in increases in flavonoid, anti-oxidant and phenol concentrations.Two studies  assessed the effect of water salinity on three nutritional quality parameters in strawberries and nectarines. Across all experiments, an increase in salinity  assessing the effect of water salinity on peanuts, rapeseed and pistachio yields were identified. The evaluated increase in salinity ranged from 2.0 to 10.1 dS m3.2.3.2 levels; all but two studies reported on berries. The evaluated change in CO2 concentrations ranged from +37.0% to +200% and were not all relevant in terms of projected increases in atmospheric CO2 over coming decades. Yield changes were largely positive in response to exposure to increasing levels of CO2. A positive mean yield change was demonstrated from a 75% to 100% increase in CO2 concentration with all crop groups combined . Nutritional quality was reported in two papers  all reporting on berries. No consistent pattern of change in concentrations of flavonoids and phenols due to increased CO2 levels was observed.We included nine papers  reporting on the impact of changing atmospheric CO2 levels on production of nuts. All papers focused on peanuts. The evaluated increase in CO2 levels ranged from +46% to +200%. An increase in peanut yields in response to increasing changes in CO2 levels was observed . Only two papers reported uncertainty estimates and no pooled analysis was performed.We identified six studies  investigating the effect of elevated CO3.2.4.We identified six studies  assessing the impact of ambient temperature change on fruit yields. The evaluated increase in temperature ranged from +1 °C to +16 °C and a variety of baseline temperatures were considered (20 °C–33 °C). Considering experiments with a baseline temperature above 25 °C, a decrease in berry yields in response to increasing temperatures was observed. Three studies  assessed the impact of an increase in temperature on nutritional quality of fruits (berries and pome). Of these, two studies  reported a decrease in vitamin C concentrations, but no clear pattern of change in flavonoid concentrations was demonstrated.We included five studies  investigating the effect of temperature change on nut yields. All papers focussed on peanuts. The evaluated increase in temperature compared to baseline conditions ranged from +2.5 °C to +12 °C. Yield changes in response to increasing temperatures were positive in experiments where the baseline temperature was 20 °C or below and negative in experiments with higher baseline temperatures (28 °C–33 °C) figure . No stud3.2.5.3 concentration on fruit yields. Studies evaluated changes in O3 concentration ranging from +88% to +143% above baseline levels; in berries and drupe yield changes were negative, while in cucurbits yield changes were positive. None of the identified studies reported on the effect of O3 on nutritional quality of fruits.We identified three studies  that reported on the impact of O3 concentration on production of peanuts and linseed. All experiments resulted in negative yields.We included two papers  reporting the impact of O3.3.3.3.1.2 concentration on fruit yield (berry and pome). The combined environmental exposures had little impact on yields of fruits (range −7% to +12% yield change). The impact of the same combination of environmental exposures on nutritional quality of fruit  was assessed by three greenhouse studies (10 experiments), resulting in a non-significant reduction in mean flavonoid concentration, excluding the study reporting CO2 in μmol mol−1 .Three greenhouse studies (four experiments) examined the combined impact of a 4 °C–5 °C increase in temperature and a 300 to 360 ppm increase in CO2 concentration and 2.5 °C–12 °C temperature increase on peanut yield. Baseline temperatures ranged from 28 °C to 33 °C. The combined environmental exposures resulted largely in a decrease in peanut yields (range −92% to +3% yield change).We identified three studies  assessing the combined impact of a 300–350 ppm increase in CO3.3.2.−1 increase in salinity and between 10 and 50% reduction in water availability). All experiments reported negative yield changes.Two field studies (eleven experiments) evaluated the combined effects of reduced water availability and increased water salinity on pineapples and cantaloupe melons. The experiments assessed a broad range of increases in salinity and reductions in water availability  investigated the combined effect of salinity and water availability on peanut yield. Reductions in water availability ranged from −51.4 to −26.6%, and salinity increased from 3 to 7 dS m3.3.3.2 and O3 on peanut yield. The impacts on yield were inconclusive.One field study (two experiments) assessed the combined impact of elevated CO4.3 concentrations, elevated temperatures above 28 °C and increased water salinity have negative impacts on fruit, nut and seed yields. Positive effects on berry and peanut yields were seen under increased CO2 concentrations, however; the positive effect on yields of raised CO2 was found to be attenuated by elevated temperatures in experiments with combined environmental exposures.This systematic review summaries the current available experimental evidence of the impact of potential future environmental changes on yields of FN&Ss, and nutritional quality of fruits, under a business-as-usual scenario. While some experimental conditions were relatively heterogeneous, several consistent findings emerged. Our results suggest that reduced water availability, increased O4.1.Our findings relating to nuts and seeds are in line with a number of modelling studies predicting negative cereal yields in response to environmental change, in crops such as rice, maize and wheat , 4, 27. Precipitation is predicted to decrease in many arid sub-tropical areas  where ma−1 [−1 or over [The findings of potential negative impacts on fruit, nut and seed yields resulting from increased salinity and increased temperature are in line with our current understanding of the impact of salinity and temperature on staple crops , 34. The−1 . Increas−1 . Althoug−1 . It has  or over , undergo or over . However or over .Our results suggest that the sensitivity of peanuts to increased temperature depends upon the baseline temperature. Different stages of peanut growth require different temperatures: vegetative growth is optimal between 25 °C and 30 °C . This ma2 on berry and peanut yields, in keeping with a number of other studies evaluating the effect of CO2 on yields of rice [2 in C3 crops , which enhances productivity [2 on yields, a detrimental effect on nutritional quality has previously been found: elevated CO2 reduced concentrations of iron and zinc in C3 grains and legumes [2 on yields was attenuated by simultaneous exposure to increasing temperature. It has previously been suggested that certain climate change exposures, i.e. increased temperature and water stress, that have negative impacts on yields, may be attenuated by the positive yield impacts of increased atmospheric CO2 [2 enrichment (T-FACE) experiment on soybeans, in which the effect of a combined 200 ppm increase in CO2 and 3.5 °C elevation in temperature negated the negative effect of increased temperature alone; but also the positive effect of elevated CO2 alone [2 were shown with rice [2 and temperature, it is arguably of more practical relevance to consider environmental exposures in combination.We identified a potentially beneficial effect of CO of rice , potatoe of rice , peppers of rice , and let of rice , amongstuctivity . However legumes . Additioeric CO2 . This waO2 alone . Similarith rice , and beaA further effect of environmental change on the planet’s ecological systems is a global decline in pollinator populations that are essential for promoting yields and nutritional quality of many crops , includiThe health benefits of consuming not only (starchy) staples but also a wide variety of fruits, vegetables, legumes, nuts and seeds are now widely recognised, in prevention of both micronutrient deficiencies and NCDs . Maintai4.2.To our knowledge, this is the first systematic review assessing the impact of environmental changes on yields of nuts and seeds. We performed a thorough and systematic search of published literature to identify all relevant papers, and methodological and reporting quality of all eligible papers was assessed to minimise sources of bias in our synthesised summary of the evidence.There are however a number of limitations to our review. Firstly, only 17 of the 81 included papers (21%) provided uncertainty estimates for the outcome. As these were for different environmental exposures, our ability to perform quantitative analyses was limited. Secondly, the range of fruit groups assessed was limited for some environmental exposures; the overall nuts and seed varieties assessed was limited to eight nut and two seed types, with paucity of data for crops other than peanuts, and therefore our review does not provide a complete picture of the effect of environmental change on the diverse range of FN&Ss. Lastly, we did not account for differences in application of the environmental stressors under experimental conditions; studies used different strategies to ‘mimic’ drought, ranging from substantial but stable reduction in watering during all phenological stages of fruit growth, to specific intermittent water cuts. For example, the extent to which peanut yields are affected by decreased water availability depends on factors such as duration, intensity, and the timing of water stress . Althoug2, whilst others reported only yield components such as pod biomass or seed weight in grams. The effects of environmental stressors can affect plant growth at different stages, and therefore mediate their effect on different yield components such as seed or pod size, weight, branch number, plant biomass and total dry weight to differing extents [There are additional limitations to consider arising from the heterogeneity of methodologies used by the included papers. Firstly, yield measurements were inconsistent across the papers, for example some reported seed yield in tonnes/hectare or grams/nut/metre extents , 53. Whi4.3.−1 in 2017, and nuts and seeds consumption was well under a quarter of the recommended optimal intake level of 21 g per d the current mean global consumption is estimated at approximately 100 g d−1 for fruits, and 3 g d−1 for nuts and seeds [The agricultural sector now faces the challenge of producing enough nutritious food in a changing environment, while minimising the environmental footprint of food production. In addition to food security, livelihoods and health are likely to be affected, should the environment continue to change along current trajectories. Global consumption of fruits was under half the recommended intake level of 250 g dnd seeds . Reducti3 concentration increases visible bruising of fruits which reduces market value [The vast majority of global fruit production is based in tropical and sub-tropical parts of the world  that areet value , and thiet value . Most suWhat will become increasingly important in efforts to ensure the resilience of FN&Ss in our diets is a focus on sustainable production; as certain nut species are highly water demanding and relatively vulnerable to water stress, dietary shifts may be necessary towards the less water intensive nut types. Although the shift away from animal source foods towards more planted-based sources is estimated to substantially reduce greenhouse gas emissions , water uIn order to respond to changing environmental conditions and maintain the supply of nutritionally important crops, adaptation strategies will be required, such as cultivating resilient crop varieties, efficient irrigation systems, novel pollination techniques and agricultural innovations. It is likely to be the poorest economies and least climate resilient countries who will be most affected by environmental change, but as this will indirectly affect supply of crops to other regions, a global multi-sector response with development and implementation of locally-relevant strategies will be essential.4.4.Our study highlights two important gaps in the current evidence-base around the impact of environmental change on yields and nutritional quality of food crops, that could be addressed in future research. First, development of further standardisation and reporting guidelines for agricultural  studies, particularly concerning estimate uncertainties, would increase the validity and reliability of future evidence synthesis efforts in this area. Secondly, parameterisation of projection models for yields and nutritional quality of FN&Ss (as well as vegetables and legumes) under different environmental change scenarios will require detailed information on a large amount of different environmental exposure and crop impact combinations. In contrast, focussing on an evidence synthesis around the physiological drivers and mechanisms through which these environmental exposures affect certain fruits, vegetables, legumes, nuts and seeds, might allow construction of crop aggregates that could reduce the complexity of such models and enable robust yield and nutritional quality projections of nutritionally important crops globally.5.Our review identified a number of papers assessing the impact of environmental stressors on the yield of a small range of FN&Ss. Our findings suggest that under a business as usual scenario, yields of FN&Ss are likely to decrease in response to environmental change. Given the importance of FN&Ss to health, and contribution to adequate micronutrient and calorie intake, this will likely have negative implications for food security, nutrition, and NCD risk—especially in food insecure areas. Despite the inherent limitations of performing a systematic review in this field, these novel findings are of importance for research and policy in agricultural development, food security, and global public health. Our review highlights the need for further research using standardised methodologies, including reporting of uncertainty estimates, to assess environmental impacts on a more diverse range of nutritionally relevant crops, in order to fully understand the risk to dietary diversity and nutrition. Additionally, our review contributes to a growing number of inter-disciplinary systematic reviews bringing together the health, environmental and food systems sectors, further demonstrating the benefit of working across related fields to provide evidence for the urgent need to find solutions to improve the health of people and our planet.


The spatial mismatch of energy resources and electricity demand in China drives the large-scale construction of power transmission infrastructure, which consumes a large amount of carbon-intensive products. However, a systematic accounting framework for the carbon emissions of power transmission infrastructure has not yet been established. This study for the first time compiles an embodied carbon emissions inventory covering 191 typical power transmission infrastructure projects in China in 2015, including 145 types of alternating current (AC) transmission line projects, 37 typical AC substation projects, 8 typical direct current (DC) transmission line projects and 1 typical DC converter station project. The inventory also shows the detailed inputs of all the projects. These data not only enable a quantitative assessment of the embodied carbon emissions of power transmission infrastructure in China but also provide essential information for climate mitigation policy design in the power sector. Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12911645 In 2001, the Chinese government launched the West-East Power Transmission project3, which triggered the large-scale construction of transmission infrastructure. From 1990 to 2015, the total length of 220 kV and above transmission lines increased from 8.43 × 104 km to 6.83 × 105 km, making China the country with the largest transmission infrastructure in the world. Notably, in recent years, Chinese government attaches great importance to the construction of ultra-high voltage (UHV) power grids, which will lead to the acceleration of domestic power transmission infrastructure construction. In addition, the Global Energy Interconnection strategy proposed by the Global Energy Interconnection Development and Cooperation Organization (GEIDCO)4 has also received support from Chinese government and many other countries in the world, and will promote the construction of power transmission infrastructure worldwide6.The spatial mismatch between China’s energy centres and load centres has led to China’s large-scale power transmission infrastructure construction7, and can also indirectly lead to carbon emissions through the inputs of building materials  and electric equipment 11. Researchers have calculated greenhouse gas (GHG) emissions of transmission infrastructure in European regions12, countries14 and Northern Europe15 and verified that transmission infrastructure construction has a great impact on climate. However, the impact of the world’s largest power transmission infrastructure remains unknown. Moreover, there were limitations in the previous studies. First, in these studies, only data of raw materials were collected to calculate GHG emissions caused by construction processes16, and data of tools, vehicles, office equipment and other materials used in construction processes were not statistically complete. Second, these studies were based on the production and construction data of developed regions such as Europe and provide limited guidance for large-scale transmission infrastructure construction in developing countries.The construction of power transmission infrastructure can directly lead to carbon emissions from the consumption of gasoline, diesel, etc.figshare.com) for free download.To have a clear understanding of the carbon emissions caused by China’s transmission infrastructure construction, this study builds an embodied carbon emissions inventory of power transmission infrastructure in China in 2015 by combining process analysis and input-output (IO) analysis. The dataset described here includes more than 10,000 inputs and their emissions for 191 typical power transmission infrastructure projects in China, involving projects in six different terrains and six different voltage classes. All the data have been uploaded to the open-access online dataset figshare . This series of books reports the general cost of China’s power transmission infrastructure and can be used by all power system designers, as well as professionals engaged in power engineering planning, management, construction and installation, and can also be used as a reference for researchers and students of relevant majors in universities.The input inventory for transmission line, substation and converter station projects is derived from the General Cost of Power Transmission and Distribution Project of the State Grid Corporation of China (GCPT)28. We aggregate the same type inputs with different voltage class into a same classification. For example, 1000 kV power devices, 500 kV power devices, 110 kV power devices and other power devices were all integrated into the input of transmission and distribution equipment. To ensure the accuracy of data merging, a third member of the group checked the data again.All the input data were extracted by one member of our group and then confirmed by another member to ensure the accuracy of the extracted data30, and then adopted an environmentally extended input-output analysis (EEIOA)33 to calculate the embodied emissions intensities34, which are expressed as:e is a 1 × N matrix that represents sectoral embodied carbon emissions intensities; E is a 1 × N matrix of sectoral direct carbon emissions in year t; A represents the intermediate input matrix.First, we built a direct emission inventory from EXIOBASE35, as China’s energy structure and industrial technology vary significantly from those in other countries. By contrast, IO tables from EXIOBASE clearly differentiate domestic products and imports, thus enabling us to obtain a more accurate carbon intensity36.Input-output (IO) tables from EXIOBASE were used to calculate the embodied carbon emissions intensities. IO tables from EXIOBASE enable us to differentiate China’s domestic products and imports. It is worth noting that when using single regional IO tables to calculate embodied carbon intensities, there is an assumption that the embodied carbon emissions intensities of domestic products and imports are the same, and this assumption may lead to great uncertainty36. We followed these sector definitions to construct our emission inventories. It is worth noting that the monetary unit of the original input inventories is CNY, while the monetary unit of EXIOBASE is EUR. Therefore, the average exchange rate in 2015 was used for currency conversion37. Like the input data collection, one of our team members matched the inputs with IO table sectors, and another member verified the results. The emissions can be calculated as:CEa represents the embodied carbon emissions of Sector a, Va represents the input quantity of Sector a and ea represents the embodied emission intensity of Sector a.The EXIOBASE IO table includes 163 sectors and has a higher sector resolution than the China IO table, which contains 42 sectors. The higher the sector resolution that an IO table has, the more accurate the intensity data could be, as aggregation of sectors will lead to biased results38.The database is publicly available from FigshareOriginal data classification (column A): The classification of the original data in the book.Detailed input sectors (column B): When our team extracted the data, we aggregated some data according to the sector resolution used in this study.IO sector (column C): The sectors in the EXIOBASE IO table.(1) Part 1. 1 table of the corresponding relationship among the original data, initial classification of inputs and IO sectors.Detailed input sectors (column A): Same as the detailed input sectors introduced above.Monetary value of CNY (column B and column C): Value of each input in CNY.Exchange rate between EUR and CNY (column D): Average exchange rate of the year for converting CNY to EUR.Monetary value of EUR (column E and column F): Value of each input in EUR.Sectors and embodied emission intensities (column G and column H): The sectors in the EXIOBASE IO table and the embodied carbon emission intensities calculated by EEIOA.Embodied emissions (column I): The total embodied emissions and emissions of each input.(2) Part 2. 191 tables of the inventories of the inputs and embodied carbon emissions of 191 typical projects .Project code (column A): The codes of different typical projects.Terrain type (column B): The terrain of the project. The transmission line projects involve six different terrains .Voltage classes (column C): The voltage class of the project. Our research object is transmission infrastructure above 220 kV in China, including 220 kV, 330 kV, 500 kV, 750 kV, ± 800 kV and 1000 kV.Circuit style (column D): The circuit style of the transmission lines. There are two types of transmission lines for all voltage classes: single circuit and double circuit.Transmission length (column F): The distance of a typical project. The length of most typical projects is 50 kilometres. However, due to terrain limitations, the lengths of some typical projects are slightly different.Embodied emissions: The total embodied carbon emissions of the project.(3) Part 3. 1 table summarizing the embodied carbon emissions from transmission line projects.(4) Part 4. 1 table summarizing the embodied carbon emissions from substation and converter station projects. The details are the same as those in the tables above.We can see the differences in total embodied emissions between projects by analysing those emissions from transmission line, substation and converter station projects. Among the transmission line projects, projects 10GB4S, 10GB3H and 10GB4Q are the three typical projects with the highest embodied carbon emissions, which are 128 kt, 116 kt and 110 kt, respectively. It can be clearly seen that projects with a high voltage class and double circuit caused more emissions. The same features can also be found in substation projects. Projects 10A-2, 10B-1 and 7A-1 emit the most embodied carbon emissions of all substation projects, with values of 325 kt, 305 kt and 115 kt, respectively. Compared with the substations, the 800 kV converter station produces more embodied carbon emissions, 2.7 times that of project 10A-2. The main structure of a converter station includes a valve hall, converter transformer, AC switching plant, smoothing reactor, filter and reactive power compensation equipment. These structures need large amounts of metal and building materials, which are carbon-intensive products.The proportions of the inputs within each typical project show different characteristics. Here, we choose substation project 2A1 with the lowest emissions, substation project 10A2 with the highest emissions, transmission line project 2AP with the lowest emissions, transmission line project 10GB4S with the highest emissions, and the 800 kV converter station for analysis . The CEADs provide CVs for energy consumption and corresponding emission factors for various sectors44 , also known as the coefficient of variation (CV). Here, we assume a CV of 10% for the various input inventories. For the carbon emission intensities, our study is based on EXIOBASE 3.3. However, no official uncertainty information is available for EXIOBASE. Therefore, we use other CVs of the proxy data based on Hertwich and PetersThen, a Monte Carlo perturbation was adopted to conduct at least 10,000 simulations for the given source data, based on which the probability distributions of errors in individual source input parameters could be obtained.The results show that the maximum uncertainty range appears in typical project 10A-2 and is . The 10 projects with the largest uncertainty ranges among the transmission line and substation projects are shown in Table 45. The input inventory in the current study covers products such as temporary facilities, fixed machinery cost, construction tools and appliances, which are integral parts for transmission infrastructure construction. However, these inputs were not considered by the LCA based studies, thus inevitably leading to underestimation for embodied carbon emissions of transmission infrastructure. Moreover, the present study used IO to calculate the embodied carbon emission intensities, which can avoid the endless trace and truncation error problems inherent in LCA47. Therefore, our study provides a more comprehensive and accurate carbon emission accounting for China’s transmission infrastructure.In order to validate our dataset, we compared our study with existing studies using life cycle assessment (LCA)Supplementary tables