Evidence of human occupation in Mexico around the Last Glacial Maximum.

The initial colonization of the Americas remains a highly debated topic1, and the exact timing of the first arrivals is unknown. The earliest archaeological record of Mexico-which holds a key geographical position in the Americas-is poorly known and understudied. Historically, the region has remained on the periphery of research focused on the first American populations2. However, recent investigations provide reliable evidence of a human presence in the northwest region of Mexico3,4, the Chiapas Highlands5, Central Mexico6 and the Caribbean coast7-9 during the Late Pleistocene and Early Holocene epochs. Here we present results of recent excavations at Chiquihuite Cave-a high-altitude site in central-northern Mexico-that corroborate previous findings in the Americas10-17of cultural evidence that dates to the Last Glacial Maximum (26,500-19,000 years ago)18, and which push back dates for human dispersal to the region possibly as early as 33,000-31,000 years ago. The site yielded about 1,900 stone artefacts within a 3-m-deep stratified sequence, revealing a previously unknown lithic industry that underwent only minor changes over millennia. More than 50 radiocarbon and luminescence dates provide chronological control, and genetic, palaeoenvironmental and chemical data document the changing environments in which the occupants lived. Our results provide new evidence for the antiquity of humans in the Americas, illustrate the cultural diversity of the earliest dispersal groups (which predate those of the Clovis culture) and open new directions of research.

Multiplexed gene editing in citrus by using a multi-intron containing Cas9 gene.

Several expression systems have been developed in clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) framework allowing for gene editing of disease-associated genes across diverse citrus varieties. In this study, we present a new approach employing a multi-intron containing Cas9 gene plus multiple gRNAs separated with tRNA sequences to target the phytoene desaturase gene in both 'Carrizo' citrange and 'Duncan' grapefruit. Notably, using this unified vector significantly boosted editing efficiency in both citrus varieties, showcasing mutations in all three designated targets. The implementation of this multiplex gene editing system with a multi-intron-containing Cas9 plus a gRNA-tRNA array demonstrates a promising avenue for efficient citrus genome editing, equipping us with potent tools in the ongoing battle against several diseases such as canker and huanglongbing.

Development and qualification of 3 L scale-down model for large scale vaccine process on Vero cell culture using microcarriers.

Scale-down models (SDM) are pivotal tools for process understanding and improvement to accelerate the development of vaccines from laboratory research to global commercialization. In this study, a 3 L SDM representing a 50 L scale Vero cell culture process of a live-attenuated virus vaccine using microcarriers was developed and qualified based on the constant impeller power per volume principle. Both multivariate data analysis (MVDA) and the traditional univariate data analysis showed comparable and equivalent cell growth, metabolic activity, and product quality results across scales. Computational fluid dynamics simulation further confirmed similar hydrodynamic stress between the two scales.

Growth of Smart Microgels in a Flow Reactor Scrutinized by In-Line SAXS.

In this work, a continuous flow setup for in situ investigation of microgel growth with small-angle X-ray scattering (SAXS) is established. Poly(N-n-propylacrylamide) (PNNPAM) and poly(N-isopropylacrylamide) (PNIPAM) microgels are synthesized in H2O at different residence times inside a continuous flow reactor. The microgels are investigated by in situ SAXS and ex situ photon correlation spectroscopy. The size of the microgels was found to be reproducible in independent experiments with run times of up to 7 h. Already the scattering curves of the microgels with a time of residence of 15 min show a well-defined form factor. Further analysis of the scattering profiles confirms the spherical shape of the microgels. At a residence time of 2 min, the scattering intensity is significantly lower corresponding to a smaller particle size. The experimental conditions remain constant over time, which is crucial for long-time experiments. The PNNPAM system is found to be more suitable for the flow reactor experiment with in-line SAXS as it shows less polymer deposition in the tubing and forms particles with lower polydispersity. The presented reactor is characterized by a compact design and offers a plug-and-play setup close to the sample environment. This work paves the way for investigations of microgel growth at e.g. synchrotron X-ray beamlines.

Tuning Xanthan Viscosity by Directed Random Coil-to-Helix Transition.

Xanthan gum is a polysaccharide that is widely used as a thickening agent in numerous food, cosmetic, and technical applications. Therefore, the knowledge of the molecular interplay that builds up and stabilizes water-binding networks is crucial for the optimization of xanthan thickening performance. Using atomic force microscopy, rheometry, and inductively coupled plasma optical emission spectroscopy, we show a clear correlation between xanthan thickening properties and the ability to form characteristic secondary structures as well as the valence and amount of cations coordinated at the polysaccharide side chain. Based on these findings and the Debye-Hückel theory, we derive an ion-interaction model in which divalent cations mediate bridging of adjacent single polymer strands due to chelate-like coordination building stable secondary structures. We furthermore demonstrate in a cation exchange assay that xanthan secondary structures can be modified in a directed and reversible manner, which, in turn, alters its thickening properties.

ppGpp, the General Stress Response Alarmone, Is Required for the Expression of the α-Hemolysin Toxin in the Uropathogenic Escherichia coli Isolate, J96.

ppGpp is an intracellular sensor that, in response to different types of stress, coordinates the rearrangement of the gene expression pattern of bacteria to promote adaptation and survival to new environmental conditions. First described to modulate metabolic adaptive responses, ppGpp modulates the expression of genes belonging to very diverse functional categories. In Escherichia coli, ppGpp regulates the expression of cellular factors that are important during urinary tract infections. Here, we characterize the role of this alarmone in the regulation of the hlyCABDII operon of the UPEC isolate J96, encoding the toxin α-hemolysin that induces cytotoxicity during infection of bladder epithelial cells. ppGpp is required for the expression of the α-hemolysin encoded in hlyCABDII by stimulating its transcriptional expression. Prototrophy suppressor mutations in a ppGpp-deficient strain restore the α-hemolysin expression from this operon to wild-type levels, confirming the requirement of ppGpp for its expression. ppGpp stimulates hlyCABDII expression independently of RpoS, RfaH, Zur, and H-NS. The expression of hlyCABDII is promoted at 37 °C and at low osmolarity. ppGpp is required for the thermoregulation but not for the osmoregulation of the hlyCABDII operon. Studies in both commensal and UPEC isolates demonstrate that no UPEC specific factor is strictly required for the ppGpp-mediated regulation described. Our data further support the role of ppGpp participating in the coordinated regulation of the expression of bacterial factors required during infection.

Stent treatment or surgical closure for perforated duodenal ulcers: a prospective randomized study.

BACKGROUND: Perforated peptic ulcer is a life-threatening condition. Traditional treatment is surgery. Esophageal perforations and anastomotic leakages can be treated with endoscopically placed covered stents and drainage. We have treated selected patients with a perforated duodenal ulcer with a partially covered stent. The aim of this study was to compare surgery with stent treatment for perforated duodenal ulcers in a multicenter randomized controlled trial. METHODS: All patients presenting at the ER with abdominal pain, clinical signs of an upper G-I perforation, and free air on CT were approached for inclusion and randomized between surgical closure and stent treatment. Age, ASA score, operation time, complications, and hospital stay were recorded. Laparoscopy was performed in all patients to establish diagnosis. Surgical closure was performed using open or laparoscopic techniques. For stent treatment, a per-operative gastroscopy was performed and a partially covered stent was placed through the scope. Abdominal lavage was performed in all patients, and a drain was placed. All patients received antibiotics and intravenous PPI. Stents were endoscopically removed after 2-3 weeks. Complications were recorded and classified according to Clavien-Dindo (C-D). RESULTS: 43 patients were included, 28 had a verified perforated duodenal ulcer, 15 were randomized to surgery, and 13 to stent. Median age was 77.5 years (23-91) with no difference between groups. ASA score was unevenly distributed between the groups (p = 0.069). Operation time was significantly shorter in the stent group, 68 min (48-107) versus 92 min (68-154) (p = 0.001). Stents were removed after a median of 21 days (11-37 days) without complications. Six patients in the surgical group had a complication and seven patients in the stent group (C-D 2-5) (n.s.). CONCLUSIONS: Stent treatment together with laparoscopic lavage and drainage offers a safe alternative to traditional surgical closure in perforated duodenal ulcer. A larger sample size would be necessary to show non-inferiority regarding stent treatment.

Landscape of genomic alterations in cervical carcinomas.

Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

Host species influence on flea (Siphonaptera) infection parameters of terrestrial micromammals in a temperate forest of Mexico.

Studies of abundance and distribution of organisms are fundamental to ecology. The identity of host species is known to be one of the major factors influencing ectoparasitic flea abundance, but explanations are still needed regarding how host taxa influence abundance parameters of different flea species. This study was carried out at La Malinche National Park (LMNP), Tlaxcala, Mexico, where previously 11 flea species had been recorded on 8 host species. Our aims were to list micromammal flea species, to determine flea infection parameters [flea prevalence (FP) and flea mean abundance (FMA)] and to analyse the influence of host species on these parameters. A total of 16 species of fleas were identified from 1178 fleas collected from 14 species of 1274 micromammals captured with Sherman® traps from March 2014 to December 2015 in 18 sites at LMNP. Some host species influence FP and FMA, in particular, Microtus mexicanus and Peromyscus melanotis showed particularly higher infection values than other host species. Plusaetis aztecus and Plusaetis sibynus were identified as the most abundant flea species.

Perineal groove in female infants: A case series and literature review.

BACKGROUND: Perineal groove is a rare congenital malformation that is unknown to many clinicians and is often misdiagnosed. Although it may be self-resolving during childhood, this nonepithelized mucous membrane can pose the risk of local irritation and infection, particularly urinary tract infection. METHODS: A retrospective study of female infants diagnosed with a perineal groove was performed, demographic characteristics and clinical features were analyzed, and a photographic review was conducted. RESULTS: Five patients with perineal groove were observed in our clinic in 2015-16. The mean age was 14 months. None had symptoms, and no treatment was required. During follow-up of 1 year, all remained asymptomatic. CONCLUSIONS: Our retrospective review suggests that perineal groove may be an underdiagnosed condition. Most cases resolve spontaneously, but confusion in diagnosis may lead to misdiagnosis or misinterpretation of sexual abuse and unnecessary treatments.

Modification of tRNA(Lys) UUU by elongator is essential for efficient translation of stress mRNAs.

The Elongator complex, including the histone acetyl transferase Sin3/Elp3, was isolated as an RNA polymerase II-interacting complex, and cells deficient in Elongator subunits display transcriptional defects. However, it has also been shown that Elongator mediates the modification of some tRNAs, modulating translation efficiency. We show here that the fission yeast Sin3/Elp3 is important for oxidative stress survival. The stress transcriptional program, governed by the Sty1-Atf1-Pcr1 pathway, is affected in mutant cells, but not severely. On the contrary, cells lacking Sin3/Elp3 cannot modify the uridine wobble nucleoside of certain tRNAs, and other tRNA modifying activities such as Ctu1-Ctu2 are also essential for normal tolerance to H2O2. In particular, a plasmid over-expressing the tRNA(Lys) UUU complements the stress-related phenotypes of Sin3/Elp3 mutant cells. We have determined that the main H2O2-dependent genes, including those coding for the transcription factors Atf1 and Pcr1, are highly expressed mRNAs containing a biased number of lysine-coding codons AAA versus AAG. Thus, their mRNAs are poorly translated after stress in cells lacking Sin3/Elp3 or Ctu2, whereas a mutated atf1 transcript with AAA-to-AAG lysine codons is efficiently translated in all strain backgrounds. Our study demonstrates that the lack of a functional Elongator complex results in stress phenotypes due to its contribution to tRNA modification and subsequent translation inefficiency of certain stress-induced, highly expressed mRNAs. These results suggest that the transcriptional defects of these strain backgrounds may be a secondary consequence of the deficient expression of a transcription factor, Atf1-Pcr1, and other components of the transcriptional machinery.

[Hispanic American kidney patients in the age of online social networks: content analysis of postings, 2010 - 2012]. / Enfermos renales hispanoamericanos en la época de las redes sociales virtuales: análisis de contenido de sus publicaciones, 2010 - 2012.

OBJECTIVE: Describe the use of online social networks by people with chronic kidney disease, their caregivers, and family members, living in Hispanic American countries, and identify the most frequent topics and subtopics in their postings. METHODS: A qualitative study was conducted of postings by chronic kidney patients, their caregivers, and family members, living in Hispanic America, on five social networks: Blogger, Facebook, Twitter, WordPress, and YouTube, from 2010 to 2012. The internal search engines of each network were used with medical and lay terms in Spanish: chronic kidney disease, renal failure, peritoneal dialysis, hemodialysis, renal transplant, renal patient, nephropathy, and kidney patients association. An analysis was carried out of the thematic content of 1 846 postings on Facebook, Blogger, and WordPress. RESULTS: A total of 162 social network accounts were identified (97 individuals and 65 groups); the majority was in Mexico (46), with others in Argentina, Chile, Colombia, and Peru (44 accounts). The most frequent topics were exchange of information (46.0%), descriptions of experiences as patients (17.9%), support (15.6%), descriptions of experiences with health services (8.5%), interaction with peers (3.5%), and promotion of behavior change (3.4%). CONCLUSIONS: Chronic kidney patients living in Hispanic America use online social networks to inform and to be informed, describe their experiences with the disease and health services, and as a support mechanism. This produces knowledge that is different from and complementary to knowledge conveyed by health professionals. There is a pressing need to promote studies of the opportunities that these technologies offer in the Americas, a region characterized by enormous social inequality.

Granulomatosis With Polyangiitis (GPA): Isolated Nasal Bridge Involvement.

Granulomatosis with polyangiitis (GPA) is a rare autoimmune vasculitis primarily affecting small blood vessels and presenting with systemic manifestations, including those in the kidneys and respiratory tracts. Diagnosis involves clinical assessment and specific serological tests. This paper presents the case of a 68-year-old morbidly obese woman with chronic sinusitis, hypertension, and hyperlipidemia who developed a saddle nose deformity. Despite the absence of typical respiratory and renal symptoms, her laboratory results showed positive antineutrophil cytoplasmic antibodies (ANCA) and antinuclear antibodies (ANA), with a nasal septal biopsy confirming GPA. She was treated with methotrexate and folic acid. This case underscores the variability of GPA presentations and the critical importance of early diagnosis and treatment to prevent irreversible damage.

A Bayesian approach for evaluating equivalence over multiple groups, and comparison with frequentist tost.

Manufacturing and testing of pharmaceutical products frequently occur in multiple facilities within a company's network. It is of interest to demonstrate equivalence among the alternative testing/manufacturing facilities to ensure product consistency and quality regardless of the facility where it was manufactured/tested. In the Frequentist framework, equivalence testing is well established when comparing two labs or manufacturing facilities; however, when considering more than two labs or production sites, the Frequentist approach may not always offer appropriate or interpretable estimates for demonstrating equivalence among all of them simultaneously. This paper demonstrates the utility of Bayesian methods to the equivalence assessment of multiple groups means, with a comparison against traditional Frequentist methods. We conclude that a Bayesian strategy is very useful for addressing the problem of multi-group equivalence. While it is not our intention to argue that Bayesian methods should always replace Frequentist ones, we show that among the advantages of a Bayesian analysis is that it provides a more nuanced understanding of the degree of similarity among sites than the hypothesis testing underpinning the Frequentist approach.

Effectiveness of an e-Health Quasi-Randomized Controlled Universal Prevention Program for Eating Disorders in Spanish Adolescents.

Eating disorders (EDs) and sub-threshold conditions are prevalent in the adolescent population. Unfortunately, most preventive interventions have been targeted at emerging adults and the effectiveness of online prevention programs has yet to be determined in adolescents. This study sought to examine the short-term effectiveness of a universal e-Health psychoeducational prevention program for EDs compared to a control (non-intervention) group in Spanish adolescents. Using a quasi-randomized trial design, a total of 161 [% girls: 45.96; Mage(SD) = 12.43 (0.43)] adolescents from 5 participating schools were allocated to two intervention arms: (1) psychoeducational intervention (n = 79) and (2) wait-list control (n = 82). The intervention was delivered over 3 months through 3 modules that were accessible 24/7 and 3 school sessions guided by the students´ tutors focusing on nutrition, promoting a healthy lifestyle, mitigating body concerns, and social pressures. Participants completed an online assessment battery including the Eating Attitudes Test (EAT-26) and measures of self-esteem, family disruption, compliance with the Mediterranean diet, and lifestyle. Correlational analysis showed small to moderate relationships between self-esteem and family function (rho = 0.413, p = 0.001), BMI (body mass index) and the EAT-26 dieting subscale (rho = 0.417, p = 0.001), physical activity and the bulimia subscale (rho = - 0.237, p = 0.003), and self-esteem and the dieting subscale (rho = - 0.223, p = 0.004). At the post-intervention assessment, the intervention group showed a statistically significant reduction in ED risk (EAT-26) (d = - 0.323, p = 0.040) and the oral control subscale (d = 0.327, p = 0.038). The e-health intervention including tutor-led digital components was effective for reducing ED risk in children. Results must be interpreted with caution due to the low statistical power and the limited sample size. Large scale randomized controlled trials with longer follow-ups will be needed to bolster the evidence.

Species distribution and antifungal susceptibility of bloodstream fungal isolates in paediatric patients in Mexico: a nationwide surveillance study.

OBJECTIVES: To establish the species distribution and in vitro susceptibilities of 358 bloodstream fungal isolates from paediatric patients in Mexico. METHODS: Isolates were collected during a 2 year surveillance programme in 14 medical centres in 10 Mexican states. A molecular approach was used to determine the Candida parapsilosis species complex. In vitro susceptibility to amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin and micafungin was determined according to CLSI procedures. Species-specific clinical breakpoints for fluconazole, voriconazole and echinocandins were applied. RESULTS: Candida spp. accounted for 98.33% of fungaemias, including 127 Candida albicans isolates, 127 C. parapsilosis complex isolates (121 C. parapsilosis sensu stricto, 4 Candida orthopsilosis and 2 Candida metapsilosis strains) and 72 Candida tropicalis isolates. C. albicans and C. parapsilosis complex were the species predominant in neonates (48 cases each; 41.02%). C. parapsilosis complex was also the predominant species in patients 1 month to <2 years of age (P = 0.007). In contrast, C. albicans was the most frequent species in patients aged 2 to <12 years (P = 0.003). Antifungal resistance was rare among the subset of isolates. Candida glabrata showed the highest resistance rate to amphotericin B (1/9 isolates), fluconazole (1/9 isolates) and itraconazole (2/9 isolates). CONCLUSIONS: The species distribution differed with the age of the patients, with C. albicans and C. parapsilosis complex being the most commonly isolated species. C. glabrata showed the highest resistance rate to amphotericin B, fluconazole and itraconazole. This is the first study of fungaemia episodes in Mexican children.

Cooling rate effects on the microstructure, solid content, and rheological properties of organogels of amides derived from stearic and (R)-12-hydroxystearic acid in vegetable oil.

Using safflower oil as the liquid phase, we investigated the organogelation properties of stearic acid (SA), (R)-12-hydroxystearic acid (HSA), and different primary and secondary amides synthesized from SA and HSA. The objective was to establish the relationship between the gelator's molecular structure, solid content, and gels' microstructure that determines the rheological properties of organogels developed at two cooling rates, 1 and 20 °C/min. The results showed that the presence of a 12-OH group in the gelator molecule makes its crystallization kinetics cooling rate dependent and modifies its crystallization behavior. Thus, SA crystallizes as large platelets, while HSA crystallizes as fibers forming gels with higher solid content, particularly at 20 °C/min. The addition to HSA of a primary or a secondary amide bonded with an alkyl group resulted in gelator molecules that crystallized as fibrillar spherulites at both cooling rates. Independent of the cooling rate, gels of HSA and its amide derivatives showed thixotropic behavior. The rheological properties of the amide's organogels depend on a balance between hydrogen-bonding sites and the alkyl chain length bonded to the amide group. However, it might also be associated with the effect that the gelators' molecular weight has on crystal growth and its consequence on fiber interpenetration among vicinal spherulites. These results were compared with those obtained with candelilla wax (CW), a well-known edible gelling additive used by the food industry. CW organogels had higher elasticity than HSA gels but lower than the gels formed by amides. Additionally, CW gels showed similar or even higher thixotropic behavior than HSA and the amide's gels. These remarkable rheological properties resulted from the microstructural organization of CW organogels. We concluded that microstructure has a more important role determining the organogels' rheology than the solid content. The fitting models developed to describe the organogels rheological behavior support this argument.

O3-Annealing Effect on the Etching Resilience of a TiO2/Al2O3 filter Prepared by Atomic Layer Deposition.

This research investigates the improvements of ozone (O3) annealing on the optical and etching characteristics of TiO2/Al2O3 multilayer band-pass filters designed for potential optoelectronic applications. The band-pass filters were fabricated using atomic layer deposition (ALD), and their performance was systematically analyzed after the addition of O3 annealing at moderate temperatures (up to 300 °C). Results reveal that O3 annealing improves the optical transmittance of the multilayers by approximately 40% without significant spectral changes (∼6 nm). The observed enhancement in the transmittance is attributed to the improved stoichiometry of TiO2. By filling in the oxygen vacancies created during the fabrication process, it reduces its extinction coefficient. Furthermore, the O3 annealing enhances the stability of TiO2 against wet etching, improving the uniformity of etched surfaces. Etching on the ozone-annealed multilayer was up to 8 times more homogeneous, as observed in the roughness. The relatively short duration of the O3 annealing process, approximately 1.6 h, makes it a cost-effective alternative compared to using ozone in the ALD process, which can last several hours for thick optical coatings.

Immunization with messenger RNA vaccines against COVID-19 in adolescents with a history of multisystem inflammatory syndrome: a case series. / Inmunización con vacunas ARN mensajero contra la COVID-19 en pacientes adolescentes con antecedente de síndrome inflamatorio multisistémico: serie de casos.

In most cases, children with SARS-CoV-2 have a mild infection. However, very rarely, some children may develop a severe disease called multisystem inflammatory syndrome in children temporally associated with COVID-19 (MIS-C). Given its recent emergence, some aspects of its pathophysiology are still unknown. The possibility of recurrence in case of reinfection or SARS-CoV-2 vaccination are new questions we are facing. Here we report a case series of 4 adolescent patients who developed MIS-C and, months later, received the SARS-CoV-2 vaccine with messenger RNA (mRNA) platforms without disease recurrence or cardiac adverse events.

Los niños cursan mayormente la infección por el virus SARS-CoV-2 en forma leve. Sin embargo, de forma muy infrecuente algunos pueden desarrollar una patología con marcada gravedad denominada síndrome inflamatorio multisistémico en niños relacionado temporalmente con COVID-19 (SIM-C). Dado su reciente surgimiento, aún hay aspectos de su fisiopatología que se desconocen. La posibilidad de recidiva en caso de reinfección o ante la vacunación contra SARS-CoV-2 son nuevos interrogantes a los que nos enfrentamos. Reportamos una serie de casos de 4 pacientes adolescentes que cursaron SIM-C y meses después han sido vacunados contra SARS-CoV-2 con plataformas ARN mensajero (ARNm) sin presentar recurrencia de la enfermedad ni efectos adversos cardiológicos.

Nonlinear manifolds underlie neural population activity during behaviour.

There is rich variety in the activity of single neurons recorded during behaviour. Yet, these diverse single neuron responses can be well described by relatively few patterns of neural co-modulation. The study of such low-dimensional structure of neural population activity has provided important insights into how the brain generates behaviour. Virtually all of these studies have used linear dimensionality reduction techniques to estimate these population-wide co-modulation patterns, constraining them to a flat "neural manifold". Here, we hypothesised that since neurons have nonlinear responses and make thousands of distributed and recurrent connections that likely amplify such nonlinearities, neural manifolds should be intrinsically nonlinear. Combining neural population recordings from monkey motor cortex, mouse motor cortex, mouse striatum, and human motor cortex, we show that: 1) neural manifolds are intrinsically nonlinear; 2) the degree of their nonlinearity varies across architecturally distinct brain regions; and 3) manifold nonlinearity becomes more evident during complex tasks that require more varied activity patterns. Simulations using recurrent neural network models confirmed the proposed relationship between circuit connectivity and manifold nonlinearity, including the differences across architecturally distinct regions. Thus, neural manifolds underlying the generation of behaviour are inherently nonlinear, and properly accounting for such nonlinearities will be critical as neuroscientists move towards studying numerous brain regions involved in increasingly complex and naturalistic behaviours.