Challenges to food safety for children and adolescents in Brazil.

Malnutrition increases the chance of cognitive delay, recurrent infections, micro and macronutrient deficiencies, stigmatization. According to the Brazilian Society of Pediatrics (Sociedade Brasileira de Pediatria), more than half (58%) of Brazilian families with children and adolescents reported changes in eating habits in the same period. For 31%, there was an increase in consumption of processed foods such as chocolate, filled cookies, instant noodles, and canned foods. Therefore, despite food security being a human right contemplated in article 25 of the Universal Declaration of Human Rights and reiterated by article 6 of the Brazilian Federal Constitution in 2010, the country still has a long way to go. With the advent of the COVID-19 pandemic, there was a deepening of poverty, misery, and hunger in the country, which directly reflected on the income of families and placed children/adolescents in a situation of extreme vulnerability.

Reflections on early childhood education in the COVID-19 pandemic.

The COVID-19 pandemic is a complex and multifaceted event, and it is even argued that it should be seen as a syndemic and not a pandemic . Its impacts will still be felt over the years and, perhaps, are irreparable in some aspects. It is essential to mobilize Governments, civil society and non-governmental organizations to outline measures to combat school dropout and social inclusion.

Cemetery, tombstones, tears and hidden silences: Suicide in children and adolescents.

Recent studies have reported a deterioration in children's mental health since the onset of the COVID-19 pandemic, with an increase in anxiety and mood disorders leading to significant suicidal ideation and suicide rates. Suicide is complex, and individual tragedies and circumstances can diverge. Evidence suggests that the mental health and well-being of some children and youth were substantially affected because of and during the pandemic. Those with pre-existing mental health problems that experienced the most negative impacts compared to pre-pandemic data.

Victims of sexual exploitation and violence in Brazil.

At least 8.9% of Brazilian women have already suffered some type of sexual violence in their lives. Every hour, Brazil has 2.2 cases of sexual violence against children and adolescents. Of the approximately 35,000 cases of violence against children and adolescents in 2021, in around 12,000 ethnic groups were not identified, 10,064 were white, 9634 were brown, 2505 black, 141 yellow, and 61 indigenous. If compared to age groups, boys from zero to 6 years reach 30%, but when the age is 12 to 18, women reach 91% of the victims. The whistleblowers are almost always anonymous, unlike in the case of violence against women, which are usually the victims themselves who complain or when they are third parties, they are usually identified. According to official data, around 96% of sexual violence takes place at home. The data are frightening and prove that sexual violence is the result of a scenario of gender inequality because it affects the lives of girls and women in a much more profound way.

Stolen innocence: Dishonor and taint in times of war.

As soon as they are taken prisoner, children and adolescents in times of war are inserted into a spiral of cruelty that progresses to rape or other countless forms of physical and psychological torture using sex as a weapon. Were these children and adolescents war sex slaves? Oral sex and other sexual barbarities are part of spaces of abuse and humiliation. The damage to the personality structure of these children and adolescents is severe. The psychological consequences are numerous. Over the years, a vicious circle has been observed around this brutality.

Deaths announced in Brazil - A dark sweetness: COVID-19 among children and adolescents.

While the Ministry of Health of Brazil postpones the inclusion of children aged 5-12 years in the National Immunization Plan against COVID-19, current evidence highlights that the number of hospitalizations and deaths caused by COVID-19 in the pediatric population, of in general, including the group of children aged 5-11 years, it is not within acceptable levels. Unfortunately, child mortality and fatality rates in Brazil are among the highest in the world. In 2020, there were 1203 deaths from Severe Acute Respiratory Syndrome (SRAG). In 2021, there were 2293. Also 65 deaths were reported from Pediatric Multisystem Inflammatory Syndrome (P-SIM); an aggressive manifestation of the virus in children.

High maternal mortality rates: Racial, geographic, and socioeconomic disparities in Brazil.

What are the harsh consequences of racism and our country's slavery past in the life of every black woman today? How does the current federal government reinforce the reproduction of structural sexism and racism during a pandemic? Hunger, domestic violence, femicide, informal work, unemployment, and political under-representation are issues that are urgently presented by the need for an anti-racist social transformation. Black women remain vulnerable to social inequalities. And in the pandemic, these inequalities are not only related to its management (contamination, death, and vaccination), but also its economic and social consequences.

Children are in need of humanitarian aid in Afghanistan.

Almost 60% of Afghans forced to flee their homes in 2021 because of the Taliban advance are children. They are starving. It is estimated that approximately one million will suffer from severe, life-threatening malnutrition by the end of 2021. Many have been separated from their families by the chaos that has ensued in Afghanistan after Taliban took power, and hundreds of them were driven out of the country unaccompanied. How must these children have been when they suddenly found themselves without their relatives during the chaotic crisis, or when they boarded an evacuation flight? It is vital to identify them quickly. Too many children witnessed scenes that no child should see. Children and teenagers are dealing with anxiety and fear and desperately need help and mental health care. This is the sad reality facing Afghan children, regardless of ongoing political developments and changes in government.

"When night falls": Violence against women and its repercussions on children and adolescents.

Violence against women is a profound global injustice. It is a major obstacle to fulfilling the human rights of women and their children. Confined to their aggressors, women exposed to this violence have even greater difficulty in accessing support networks and care services. Furthermore, the economic impact of the pandemic, which disproportionately affected women, created additional barriers. In reality, however, femicide is forgotten, underestimated, and poorly prosecuted throughout the world. In this context, more than 100 children witnessed a murder or were at home when it took place. This form of indirect violence is vicarious, in which children are left out, anonymous, and invisible. The trauma generated potentiates mentalization difficulties, emotional dependence, and instability in future relationships, caused by pain and psychological suffering.

Pandemic of hunger: The severe nutritional deficiency that kills Yanomami ethnic children.

Chronic malnutrition is the painful reality that Yanomami children face in Brazil's largest Indigenous Land and is pointed out by specialists as one of the results of the federal government's "anti-indigenous policy". The lack, or scarcity, of medical care, together with the lack of environmental inspection, pushes the Yanomami into a desperate scenario. It is estimated that 20,000 illegal miners operate in the territory. Mining activity contaminates rivers with mercury and has caused deformities and illnesses in women and children. They live on the largest indigenous reserve in Brazil. There are nine million hectares within the Amazon Forest. Malaria has persistently advanced in Yanomami land: there are more than 16,000 cases this year alone. Several children are dying.

Echoes of Global Silence: Is there protection and safety for Venezuelan children and adolescents?

As the crisis in Venezuela deepens, an increasing number of children urgently needs shelter, protection, and access to basic services, including food, medicine, clean water, and sanitation. Children and young people in transit are particularly at risk of criminal activity or being separated from their families. The consequences of the humanitarian crisis for children could be devastating for the country's future. The child labor problem was fueled by a mass migration of more than five million Venezuelans that turned many children into livelihoods for their families. The pandemic has aggravated risk factors for child labor. The work ranges from working in dumps to agricultural fields, adding that children in rural areas are more likely to depend on public assistance and are at greater risk of being recruited by gangs. Some Venezuelan women and girls are traveling for hours or days to cross the Colombian border and earn money as sex workers. The complex and multifaceted reality of international migration reveals enormous challenges that directly affect the lives of children and adolescents, especially the most vulnerable, and demand urgent responses from the constituted powers and civil society in the face of countless human rights violations those people experience.

Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations.

Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations.

A human microprotein that interacts with the mRNA decapping complex.

Proteomic detection of non-annotated microproteins indicates the translation of hundreds of small open reading frames (smORFs) in human cells, but whether these microproteins are functional or not is unknown. Here, we report the discovery and characterization of a 7-kDa human microprotein we named non-annotated P-body dissociating polypeptide (NoBody). NoBody interacts with mRNA decapping proteins, which remove the 5' cap from mRNAs to promote 5'-to-3' decay. Decapping proteins participate in mRNA turnover and nonsense-mediated decay (NMD). NoBody localizes to mRNA-decay-associated RNA-protein granules called P-bodies. Modulation of NoBody levels reveals that its abundance is anticorrelated with cellular P-body numbers and alters the steady-state levels of a cellular NMD substrate. These results implicate NoBody as a novel component of the mRNA decapping complex and demonstrate potential functionality of a newly discovered microprotein.

Comparative Membrane Proteomics Reveals a Nonannotated E. coli Heat Shock Protein.

Recent advances in proteomics and genomics have enabled discovery of thousands of previously nonannotated small open reading frames (smORFs) in genomes across evolutionary space. Furthermore, quantitative mass spectrometry has recently been applied to analysis of regulated smORF expression. However, bottom-up proteomics has remained relatively insensitive to membrane proteins, suggesting they may have been underdetected in previous studies. In this report, we add biochemical membrane protein enrichment to our previously developed label-free quantitative proteomics protocol, revealing a never-before-identified heat shock protein in Escherichia coli K12. This putative smORF-encoded heat shock protein, GndA, is likely to be ∼36-55 amino acids in length and contains a predicted transmembrane helix. We validate heat shock-regulated expression of the gndA smORF and demonstrate that a GndA-GFP fusion protein cofractionates with the cell membrane. Quantitative membrane proteomics therefore has the ability to reveal nonannotated small proteins that may play roles in bacterial stress responses.

Spatial localisation of Discoidin Domain Receptor 2 (DDR2) signalling is dependent on its collagen binding and kinase activity.

Discoidin Domain Receptor 2 (DDR2) is a collagen-binding receptor tyrosine kinase that initiates delayed and sustained tyrosine phosphorylation signalling. To understand the molecular basis of this unique phosphorylation profile, here we utilise fluorescence microscopy to map the spatiotemporal localisation of DDR2 and tyrosine phosphorylated proteins upon stimulation with collagen. We show that cellular phosphorylated proteins are localised to the interface where DDR2 is in contact with collagen and not in the early endosomes or lysosomes. We find that DDR2 localisation is independent of integrin activation and the key DDR2 signalling effector SHC1. Structure-function analysis reveals that DDR2 mutants defective for collagen binding or kinase activity are unable to localise to the cell surface, demonstrating for the first time that both collagen binding and kinase functions are required for spatial localisation of DDR2. This study provides new insights into the underlying structural features that control DDR2 activation in space and time.

Comparative Proteomics Enables Identification of Nonannotated Cold Shock Proteins in E. coli.

Recent advances in mass spectrometry-based proteomics have revealed translation of previously nonannotated microproteins from thousands of small open reading frames (smORFs) in prokaryotic and eukaryotic genomes. Facile methods to determine cellular functions of these newly discovered microproteins are now needed. Here, we couple semiquantitative comparative proteomics with whole-genome database searching to identify two nonannotated, homologous cold shock-regulated microproteins in Escherichia coli K12 substr. MG1655, as well as two additional constitutively expressed microproteins. We apply molecular genetic approaches to confirm expression of these cold shock proteins (YmcF and YnfQ) at reduced temperatures and identify the noncanonical ATT start codons that initiate their translation. These proteins are conserved in related Gram-negative bacteria and are predicted to be structured, which, in combination with their cold shock upregulation, suggests that they are likely to have biological roles in the cell. These results reveal that previously unknown factors are involved in the response of E. coli to lowered temperatures and suggest that further nonannotated, stress-regulated E. coli microproteins may remain to be found. More broadly, comparative proteomics may enable discovery of regulated, and therefore potentially functional, products of smORF translation across many different organisms and conditions.

A Molecular Staple: D-Loops in the I Domain of Bacteriophage P22 Coat Protein Make Important Intercapsomer Contacts Required for Procapsid Assembly.

UNLABELLED: Bacteriophage P22, a double-stranded DNA (dsDNA) virus, has a nonconserved 124-amino-acid accessory domain inserted into its coat protein, which has the canonical HK97 protein fold. This I domain is involved in virus capsid size determination and stability, as well as protein folding. The nuclear magnetic resonance (NMR) solution structure of the I domain revealed the presence of a D-loop, which was hypothesized to make important intersubunit contacts between coat proteins in adjacent capsomers. Here we show that amino acid substitutions of residues near the tip of the D-loop result in aberrant assembly products, including tubes and broken particles, highlighting the significance of the D-loops in proper procapsid assembly. Using disulfide cross-linking, we showed that the tips of the D-loops are positioned directly across from each other both in the procapsid and the mature virion, suggesting their importance in both states. Our results indicate that D-loop interactions act as "molecular staples" at the icosahedral 2-fold symmetry axis and significantly contribute to stabilizing the P22 capsid for DNA packaging. IMPORTANCE: Many dsDNA viruses have morphogenic pathways utilizing an intermediate capsid, known as a procapsid. These procapsids are assembled from a coat protein having the HK97 fold in a reaction driven by scaffolding proteins or delta domains. Maturation of the capsid occurs during DNA packaging. Bacteriophage HK97 uniquely stabilizes its capsid during maturation by intercapsomer cross-linking, but most virus capsids are stabilized by alternate means. Here we show that the I domain that is inserted into the coat protein of bacteriophage P22 is important in the process of proper procapsid assembly. Specifically, the I domain allows for stabilizing interactions across the capsid 2-fold axis of symmetry via a D-loop. When amino acid residues at the tip of the D-loop are mutated, aberrant assembly products, including tubes, are formed instead of procapsids, consequently phage production is affected, indicating the importance of stabilizing interactions during the assembly and maturation reactions.

ADP-dependent conformational changes distinguish Mycobacterium tuberculosis SecA2 from SecA1.

In bacteria, most secreted proteins are exported through the SecYEG translocon by the SecA ATPase motor via the general secretion or "Sec" pathway. The identification of an additional SecA protein, particularly in Gram-positive pathogens, has raised important questions about the role of SecA2 in both protein export and establishment of virulence. We previously showed in Mycobacterium tuberculosis, the causative agent of tuberculosis, the accessory SecA2 protein possesses ATPase activity that is required for bacterial survival in host macrophages, highlighting its importance in virulence. Here, we show that SecA2 binds ADP with much higher affinity than SecA1 and releases the nucleotide more slowly. Nucleotide binding also regulates movement of the precursor-binding domain in SecA2, unlike in SecA1 or conventional SecA proteins. This conformational change involving closure of the clamp in SecA2 may provide a mechanism for the cell to direct protein export through the conventional SecA1 pathway under normal growth conditions while preventing ordinary precursor proteins from interacting with the specialized SecA2 ATPase.

A method to investigate protein association with intact sealed mycobacterial membrane vesicles.

In mycobacteria, probing the association of cytoplasmic proteins with the membrane itself, as well as with integral or peripheral membrane proteins, is limited by the difficulty in extracting intact sealed membrane vesicles due to the complex cell wall structure. Here we tested the association of Mycobacterium tuberculosis SecA1 and SecA2 proteins with intact membrane vesicles by a flotation assay using iodixanol density gradients. These protocols have wide applications for studying the association of other mycobacterial cytoplasmic proteins with the membrane and membrane-associated proteins.