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Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson's disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was -0.46 (CI [95%] = -0.90 - -0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson's disease patients. Further clinical trials with larger patient populations are needed.

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ABSTRACT Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson´s disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson´s disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was −0.46 (CI [95%] = −0.90 - −0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson´s disease patients. Further clinical trials with larger patient populations are needed.

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MAIN CONCLUSION: An exonuclease V homologue from apomictic Brachiaria brizantha is expressed and localized in nucellar cells at key moments when these cells differentiate to give rise to unreduced gametophytes. Brachiaria is a genus of forage grasses with economical and agricultural importance to Brazil. Brachiaria reproduces by aposporic apomixis, in which unreduced embryo sacs, derived from nucellar cells, other than the megaspore mother cell (MMC), are formed. The unreduced embryo sacs produce an embryo without fertilization resulting in clones of the mother plant. Comparative gene expression analysis in ovaries of sexual and apomictic Brachiaria spp. revealed a sequence from B. brizantha that showed a distinct pattern of expression in ovaries of sexual and apomictic plants. In this work, we describe a gene named BbrizExoV with strong identity to exonuclease V (Exo V) genes from other grasses. Sequence analysis in signal prediction tools showed that BbrizExoV might have dual localization, depending on the translation point. A longer form to the nucleus and a shorter form which would be directed to the chloroplast. This is also the case for monocot sequences analyzed from other species. The long form of BbrizExoV protein localizes to the nucleus of onion epidermal cells. Analysis of ExoV proteins from dicot species, with exception of Arabidopsis thaliana ExoVL protein, showed only one localization. Using a template-based AlphaFold 2 modelling approach the structure of BbrizExoV in complex with metal and ssDNA was predicted based on the holo structure of the human counterpart. Features predicted to define ssDNA binding but a lack of sequence specificity are shared between the human enzyme and BbrizExoV. Expression analyses indicated the precise site and timing of transcript accumulation during ovule development, which coincides with the differentiation of nucelar cells to form the typical aposporic four-celled unreduced gametophyte. A putative function for this protein is proposed based on its homology and expression pattern.

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BACKGROUND: In Brachiaria sexual reproduction, during ovule development, a nucellar cell differentiates into a megaspore mother cell (MMC) that, through meiosis and mitosis, gives rise to a reduced embryo sac. In aposporic apomictic Brachiaria, next to the MMC, other nucellar cells differentiate into aposporic initials that enter mitosis directly forming an unreduced embryo sac. The IPT (isopentenyltransferase) family comprises key genes in the cytokinin (CK) pathway which are expressed in Arabidopsis during ovule development. BbrizIPT9, a B. brizantha (syn. Urochloa brizantha) IPT9 gene, highly similar to genes of other Poaceae plants, also shows similarity with Arabidopsis IPT9, AtIPT9. In this work, we aimed to investigate association of BbrizIPT9 with ovule development in sexual and apomictic plants. METHODS AND RESULTS: RT-qPCR showed higher BbrizIPT9 expression in the ovaries of sexual than in the apomictic B. brizantha. Results of in-situ hybridization showed strong signal of BbrizIPT9 in the MMC of both plants, at the onset of megasporogenesis. By analyzing AtIPT9 knockdown mutants, we verified enlarged nucellar cell, next to the MMC, in a percentage significantly higher than in the wild type, suggesting that knockout of AtIPT9 gene triggered the differentiation of extra MMC-like cells. CONCLUSIONS: Our results indicate that AtIPT9 might be involved in the proper differentiation of a single MMC during ovule development. The expression of a BbrizIPT9, localized in male and female sporocytes, and lower in apomicts than in sexuals, and effect of IPT9 knockout in Arabidopsis, suggest involvement of IPT9 in early ovule development.

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Brachiaria, a genus from the Poaceae family, is largely cultivated as forage in Brazil. Among the most cultivated varieties of Brachiaria spp., B. brizantha cv. Marandu (syn. Urochloa brizantha) is of great agronomical importance due to the large areas cultivated with this species. This cultivar is apomictic and tetraploid. Sexual diploid genotype is available for this species. The difference in levels of ploidy among sexual and apomictic plants contributes to hindering Brachiaria breeding programs. The induction of haploids and double haploids is of great interest for the generation of new genotypes with potential use in intraspecific crosses. A key factor for the success of this technique is identifying adequate microspore developmental stages for efficient embryogenesis induction. Knowledge of the morphological changes during microsporogenesis and microgametogenesis and sporophytic tissues composing the anther is critical for identifying the stages in which microspores present a higher potential for embryogenic callus and somatic embryo through in vitro culture. In this work, morphological markers were associated with anther and pollen grain developmental stages, through histological analysis. Anther development was divided into 11 stages using morphological and cytological characteristics, from anther with archesporial cells to anther dehiscence. The morphological characteristics of each stage are presented. In addition, the response of stage 8 anthers to in vitro culture indicates microspores initiating somatic embryogenic pathway.

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OBJECTIVE: This study compared the modulatory effect of two intravenous magnesium sulfate (MgSO4) regimens on the systemic inflammatory response in pregnant women diagnosed with imminent eclampsia. STUDY DESIGN: In a single-blind cross-sectional study, 33 women were allocated according to the Zuspan (n = 16) and Sibai (n = 17) MgSO4 regimens, and treated for 24 h. Blood samples were collected pre-administration of the loading dose, at 24 h of the maintenance dose of MgSO4, and at 48 h, when patients were without treatment. Plasma was used to determine interleukin (IL)-1 beta (IL-1ß), IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), heat shock protein (Hsp70), and heme oxygenase-1 (HO-1) by ELISA. RESULTS: The treatment with the Zuspan's regimen didn't change plasma concentrations of TNF-α, IL-10, and Hsp70 in the three-time points studied. However, it decreased IL-1ß at 24 h and 48 h and IL-6 at 48 h, and increased HO-1 concentration at 48 h. On the other hand, compared to the pre-treatment period, Sibai's regimen induced a significant decrease in TNF-α, IL-1ß, IL-6, and Hsp70, while increased HO-1 levels both at 24 h and 48 h and, IL-10 concentration at 48 h. CONCLUSIONS: Sibai's regimen determined an early and efficient immunoregulatory effect on systemic inflammatory response in preeclampsia, suggesting that the maintenance dose of two grams of MgSO4 was better than one gram in the treatment of imminent eclampsia.

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MAIN CONCLUSION: In Brachiaria brizantha BbrizSERK1, BbrizSERK2 and BbrizSERK3 were identified. SERK expression marks somatic embryogenesis, sexual MMC, and sexual and apomictic PMC. BbrizSERK3 might have a regulatory role in reproductive development. Somatic embryogenesis receptor-like kinase (SERK) consists of plasma membrane receptor genes that have been characterized in various species, associated with several aspects of plant development, including reproduction. SERK genes are involved in anther development and in early embryo development in sexual and asexual seed formation. To comprehend the complexity of the SERK genes and their function in Brachiaria reproduction, we performed a homology-based search in a genomic database of a sexual B. brizantha and identified sequences of three SERK genes, BbrizSERK1, BbrizSERK2, and BbrizSERK3. RNASeq data showed equivalent abundance of BbrizSERK1 and BbrizSERK2 transcripts in ovaries at early megasporogenesis of sexuals and apomicts, while BbrizSERK3 transcripts were more abundant in ovaries of sexuals than in apomicts. BbrizSERK3 results in three coding sequences due to alternative splicing, among them Variant 1 results in a protein with all the predicted domains of a SERK. BbrizSERK transcripts were detected in male reproductive tissues of both sexual and apomictic plants, suggesting a role in controlling anther development. BbrizSERK transcripts were detected early in ovule development, in the integuments, and in the megaspore mother cell of the sexual plant, but not in the cells that give rise to apomictic embryo sacs, suggesting a role in female reproductive development of sexuals. This paper provides evidences that SERK genes plays a role in the onset and establishment of somatic embryogenesis and in the reproductive development of B. brizantha and suggests a distinct role of BbrizSERK in apomixis initiation.

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Brachiaria brizantha is a forage grass well adapted to tropical areas and cultivated in millions of hectares in Brazil. The apomictic mode of reproduction in this species, in addition to differences in ploidy between sexual and apomictic plants, impairs crossbreeding. The development of a methodology to transform apomictic cultivars will provide an option to introduce agronomic important traits to B. brizantha cv. Marandu. In addition, it will open the possibility to study in vivo the function of candidate genes involved in the apomictic reproduction. The objective of this work was to evaluate peeled seeds, isolated embryo from mature seeds, embryogenic calluses and embryogenic cell suspensions, as target explant for genetic transformation via biolistics. Plasmids bearing the marker genes gus and hptII under the control of the rice actin 1 promoter (pAct1-Os) or the maize ubiquitin 1 promoter (pUbi1Zm) were used. All the target-explants used were suitable for transient gene expression after bombardment, showing gus expression and resistance to hygromycin. Using embryogenic calluses and cell suspensions as target tissues, transgenic plants were regenerated and transgenes detected.

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"Mascadera" is a chronic emaciating neuropathy affecting goats; it produces significant economic losses in many regions and its cause is unknown. Here, the histological lesions found in 15 animals naturally affected by the disease are described. Complete necropsy was performed and tissue samples were collected for histopathological study. Severe atrophy of the masseter and buccinator muscles and tongue was observed, as well as vacuolar degeneration of neurons in the nuclei of the trigeminal, facial, and glossopharyngeal nerves. No relevant lesions were observed in other tissues. These findings and the clinical signs are consistent with those observed by other authors in animals spontaneously and experimentally intoxicated with Prosopis juliflora. The disease may be due to consumption of a similar species present in our country that is still unknown. Further research on the etiology and pathogenesis of this disease is needed to establish appropriate prevention guidelines.

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Preeclampsia is a pregnancy disorder characterized by imbalance between pro- and anti-inflammatory cytokines associated with high plasma levels of uric acid and Interleukin-1 beta (IL-1ß). The inflammasome is a protein complex that mediates innate immune responses via caspase-1 activation promoting secretion of IL-1ß and IL-18 in their active forms, and also release of the high-mobility group box 1 protein (HMGB1). As the placenta seems to play an important role in the pathogenesis of PE, the present study investigated the expression of genes and proteins related to the inflammasome in placentas from pregnant women with severe preeclampsia. Placental tissue was collected from 20 normotensive pregnant women and 20 preeclamptic women, and inflammasome components, NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3), caspase-1, IL-1ß and IL-18, as well as tumor necrosis factor-alpha (TNF-α) and HMGB1 were evaluated by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and also quantified by reverse transcription-qPCR (RT-qPCR). Compared with normotensive pregnant women, placenta from women with PE showed a significant increase in NLRP3, caspase-1, IL-1ß, TNF-α and HMGB1 mRNA. Immunohistochemical staining of NLRP3, caspase-1, IL-1ß and TNF-α in placental villi, as well as the levels of caspase-1, IL-1ß, TNF-α and HMGB1 in placental homogenate were significantly higher in the preeclamptic group than in the normotensive group. However, mRNA expression of IL-18 and its protein concentrations were lower in placentas from preeclamptic women. The results suggest that placentas from pregnant women with preeclampsia show higher expression of NLRP3 inflammasome, which may be involved in the exaggerated inflammatory state in preeclampsia.

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