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Key Clinical Message This case emphasizes the need for early recognition and accurate diagnosis of achalasia in young adults to avoid exacerbation of the condition and misdiagnosis as GERD. Patient outcomes and quality of life are greatly enhanced by suitable diagnostic techniques, appropriate therapy, interdisciplinary care, and comprehensive patient education along with frequent follow‐ups. Abstract Achalasia results from the degeneration of inhibitory ganglion cells within the esophageal myenteric plexus and the lower esophageal sphincter (LES), leading to a loss of inhibitory neurons and resulting in the absence of peristalsis with failure of LES relaxation. Its origins are multifactorial, potentially involving infections, autoimmune responses, and genetics, with equal incidence in males and females. The hallmark symptoms include progressive dysphagia for solids and liquids, along with regurgitation, heartburn, and non‐cardiac chest pain. A 22‐year‐old female patient initially diagnosed with gastroesophageal reflux disease (GERD) received proton pump inhibitors and antacid gel for persistent dysphagia and regurgitation. Subsequent tests including barium esophagogram and manometry indicated Type II Achalasia Cardia. The patient showed clinical improvement with relief of dysphagia, regurgitation, and heartburn symptoms after pneumatic balloon dilatation (PBD). She was advised to follow up after 6 months with upper gastrointestinal (UGI) endoscopy and manometry in the outpatient clinic for regular endoscopic surveillance as there is a risk of transformation to esophageal carcinoma. Diagnosing achalasia in young adults poses challenges due to its diverse presentation and resemblance to other esophageal disorders like GERD. Diagnosis relies on clinical symptoms and imaging studies such as barium esophagogram revealing a bird's beak appearance and esophageal manometry showing absent peristalsis. UGI endoscopy is needed to rule out malignancy. Treatment options include non‐surgical approaches like medication and Botox injections, as well as surgical methods such as pneumatic balloon dilation, laparoscopic Heller myotomy, and per‐oral endoscopic myotomy (POEM). The treatment options depend upon the patient's condition at presentation and their individual choices. This case report emphasizes that it is crucial to consider achalasia as a potential differential diagnosis in young adults with dysphagia, especially if conventional treatments for acid peptic disorder do not alleviate symptoms. Prompt diagnosis and appropriate management can lead to significant clinical improvement and better patient outcomes.

Summary: Leishmania is the causative agent of cutaneous and visceral diseases affecting millions of individuals worldwide. Pseudouridine (Ψ), the most abundant modification on rRNA, changes during the parasite life cycle. Alterations in the level of a specific Ψ in helix 69 (H69) affected ribosome function. To decipher the molecular mechanism of this phenotype, we determine the structure of ribosomes lacking the single Ψ and its parental strain at ∼2.4–3 Å resolution using cryo-EM. Our findings demonstrate the significance of a single Ψ on H69 to its structure and the importance for its interactions with helix 44 and specific tRNAs. Our study suggests that rRNA modification affects translation of mRNAs carrying codon bias due to selective accommodation of tRNAs by the ribosome. Based on the high-resolution structures, we propose a mechanism explaining how the ribosome selects specific tRNAs.

Abstract Trypanosomes are protozoan parasites that cycle between insect and mammalian hosts and are the causative agent of sleeping sickness. Here, we describe the changes of pseudouridine (Ψ) modification on rRNA in the two life stages of the parasite using four different genome-wide approaches. CRISPR-Cas9 knock-outs of all four snoRNAs guiding Ψ on helix 69 (H69) of the large rRNA subunit were lethal. A single knock-out of a snoRNA guiding Ψ530 on H69 altered the composition of the 80S monosome. These changes specifically affected the translation of only a subset of proteins. This study correlates a single site Ψ modification with changes in ribosomal protein stoichiometry, supported by a high-resolution cryo-EM structure. We propose that alteration in rRNA modifications could generate ribosomes preferentially translating state-beneficial proteins.

This paper examines the short-run and long-run relationship between energy consumption, export performance, and economic growth in a landlocked developing country, Nepal, from 1980 to 2018. We employ an Autoregressive distributed lag (ARDL) bounds testing approach to co-integration to investigate the relationship and role of energy consumption and exports on economic growth. The estimated results confirm the existence of a long-run relationship between economic growth and its regressors. The empirical estimation indicates the presence of a positive and statistically significant impact of exports on economic growth. Energy consumption and economic growth are positively associated; however, the coefficient is not statistically significant. Using the Granger Causality approach, the causality test reveals that there is unidirectional causality from energy consumption to economic growth, economic growth to export, and energy consumption to export.

ABSTRACT In the parasite Trypanosoma brucei, the causative agent of human African sleeping sickness, all mRNAs are trans-spliced to generate a common 5′ exon derived from the spliced leader (SL) RNA. Perturbations of protein translocation across the endoplasmic reticulum (ER) induce the spliced leader RNA silencing (SLS) pathway. SLS activation is mediated by a serine-threonine kinase, PK3, which translocates from the cytosolic face of the ER to the nucleus, where it phosphorylates the TATA-binding protein TRF4, leading to the shutoff of SL RNA transcription, followed by induction of programmed cell death. Here, we demonstrate that SLS is also induced by depletion of the essential ER-resident chaperones BiP and calreticulin, ER oxidoreductin 1 (ERO1), and the Golgi complex-localized quiescin sulfhydryl oxidase (QSOX). Most strikingly, silencing of Rhomboid-like 1 (TIMRHOM1), involved in mitochondrial protein import, also induces SLS. The PK3 kinase, which integrates SLS signals, is modified by phosphorylation on multiple sites. To determine which of the phosphorylation events activate PK3, several individual mutations or their combination were generated. These mutations failed to completely eliminate the phosphorylation or translocation of the kinase to the nucleus. The structures of PK3 kinase and its ATP binding domain were therefore modeled. A conserved phenylalanine at position 771 was proposed to interact with ATP, and the PK3F771L mutation completely eliminated phosphorylation under SLS, suggesting that the activation involves most if not all of the phosphorylation sites. The study suggests that the SLS occurs broadly in response to failures in protein sorting, folding, or modification across multiple compartments. IMPORTANCE In this study, we found that SLS is induced by depletion of the essential ER-resident chaperones BiP and calreticulin, ER oxidoreductin 1 (ERO1), and the Golgi complex-localized quiescin sulfhydryl oxidase (QSOX). Most strikingly, silencing of Rhomboid-like 1 (TIMRHOM1), involved in mitochondrial protein import, also induces SLS. We also report on the autophosphorylation of PK3 during SLS induction. This study has implications for our understanding of how trypanosomes keep the homeostasis between the ER and the mitochondria and suggests that PK3 may participate in the connection between these two organelles. The pathway, when induced, leads to the suicide of these parasites, and its induction offers a potential novel drug target against these parasites.

Summary: The parasite Trypanosoma brucei is the causative agent of sleeping sickness and cycles between insect and mammalian hosts. The parasite appears to lack conventional transcriptional regulation of protein coding genes, and mRNAs are processed from polycistronic transcripts by the concerted action of trans-splicing and polyadenylation. Regulation of mRNA function is mediated mainly by RNA binding proteins affecting mRNA stability and translation. In this study, we describe the identification of 62 non-coding (nc) RNAs that are developmentally regulated and/or respond to stress. We characterized two novel anti-sense RNA regulators (TBsRNA-33 and 37) that originate from the rRNA loci, associate with ribosomes and polyribosomes, and interact in vivo with distinct mRNA species to regulate translation. Thus, this study suggests for the first-time anti-sense RNA regulators as an additional layer for controlling gene expression in these parasites.