92-XX BIOLOGY AND OTHER NATURAL SCIENCES
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Synapses are connections between different nerve cells that form an essential link in neural signal transmission. It is generally distinguished between electrical and chemical synapses, where chemical synapses are more common in the human brain and are also the type we deal with in this work.
In chemical synapses, small container-like objects called vesicles fill with neurotransmitter and expel them from the cell during synaptic transmission. This process is vital for communication between neurons. However, to the best of our knowledge no mathematical models that take different filling states of the vesicles into account have been developed before this thesis was written.
In this thesis we propose a novel mathematical model for modeling synaptic transmission at chemical synapses which includes the description of vesicles of different filling states. The model consists of a transport equation (for the vesicle growth process) plus three ordinary differential equations (ODEs) and focuses on the presynapse and synaptic cleft.
The well-posedness is proved in detail for this partial differential equation (PDE) system. We also propose a few different variations and related models. In particular, an ODE system is derived and a delay differential equation (DDE) system is formulated. We then use nonlinear optimization methods for data fitting to test some of the models on data made available to us by the Animal Physiology group at TU Kaiserslautern.
Bei Frauen ist Brustkrebs mit einem Viertel aller Krebserkrankungen die am häufigsten diagnostizierte Krebsart, während die Inzidenz bei Männern wesentlich geringer ist. Nur 10-15% aller Brustkrebserkrankungen können auf familiär prädisponierende Faktoren wie BRCA1 und BRCA2 zurückgeführt werden. Eine genetische Prädisposition bei hereditärem männlichem Brustkrebs wird für BRCA2 bestätigt. Funktionelle Analysen geben Grund zur Annahme, dass BRCA2 eine duale Rolle besitzt. Neben der Caretaker-Funktion für genomische Stabilität, ist auch eine Gatekeeper-Funktion bei der Transkriptionsregulation beschrieben. Die Basis dieser Arbeit beruht auf der Beobachtung, dass männliche BRCA2-Mutationsträger von 3 verschiedenen Familien mit hereditärem Brustkrebs auffällige chromosomale Veränderungen der Region 9p23-24 aufweisen. Vorarbeiten ließen einen kausalen Zusammenhang zwischen BRCA2-Mutation und 9p-Veränderung möglich erscheinen. Das Ziel der Arbeit bestand darin, durch molekularbiologische Methoden die Bruchpunkte in 9p23-24 bei BRCA2-Mutationsträgern unabhängiger Familien zu identifizieren und damit einen weiteren Hinweis auf die Entstehung dieser Instabilität zu geben. In dieser Arbeit konnten mittels FISH, PFGE und bioinformatischer Techniken sowohl Inversionen als auch Duplikationen festgestellt werden. Eine überlappende Inversion zeigte sich hierbei deutlich bei allen untersuchten Mutationsträgern. Mit einer FISH-Analyse konnte bei den Mutationsträgern der Familien 1 bis 3 eine Inversion im Bereich der STS-Marker D9S267 und D9S775 detektiert werden. Ferner konnte durch Interphasen-FISH eine Duplikation im Bruchpunktbereich um den STS-Marker D9S268 identifiziert werden. Southern-Analysen konnten Bruchpunkte in den Mutationsträgern der Familien 1 und 2 mittels der Enzyme EcoRI und SacI bestätigen. In dieser Arbeit konnte weiterhin gezeigt werden, dass sich die Inversionsbruchpunkte der Mutationsträger 3.3, 3.4 und 3.5 von Familie 1 in der unmittelbaren Nähe von low-copy repeats befinden, deren Größe 5kb-8kb beträgt. Die identifizierte Inversion überspannt im Wesentlichen die Gene TYRP1 und mPDZ. Bei dem durch die Inversion direkt betroffenen Gen handelt es sich um das mPDZ-Gen. Das Protein besitzt 13 PDZ-Domänen, deren Interaktionspartner beschrieben sind. Die Genexpression beider Gene konnte in lymphoblastoiden Zellen nachgewiesen werden. Die Erkenntnisse erlauben die Schlussfolgerung, dass Repeat-Sequenzen in der Umgebung der Bruchpunkte bei der Entstehung von Rearrangements auch in diesen BRCA2-Mutationsträgern eine große Rolle spielen.
Messtechnische Bestimmung der Outputfaktoren für die roboter-gestützte Hochpräzisionsbestrahlung
(2021)
Als ein Teilbereich der Strahlentherapie fokussiert sich die Radiochirurgie auf klar abgrenzbare und nicht allzu große Tumore. Durch eine Eskalation der eingestrahlten Dosis in wenigen Fraktionen wird eine bessere Tumorkontrolle angestrebt. Allerdings wird hierbei das therapeutische Fenster weiter verkleinert. Um dieses schmale Fenster optimal zu nutzen, muss der Dosisgradient hin zum Normalgewebe extrem steil sein. Des Weiteren müssen sehr kleine Feldgrößen wählbar sein um eine sehr gute Dosiskonformität zu erzielen. Die Unschärfen der Einzelschritte der Therapiekette sollten minimal sein. Um diese Anforderungen an die geometrische, dosimetrische und letztlich an die Genauigkeit des Gesamtsystems zu erfüllen, sind dedizierte Geräte notwendig. Als dediziertes Gerät für die Radiochirurgie nutzt das Cyberknife© VSI (Fa. Accuray, Sunnyvale, CA, USA) die Kombination vieler kleiner Felder von 60 mm bis zu 5 mm Durchmesser unter verschiedenen Einstrahlrichtungen um die Dosis selbst bei irregulär geformten Tumoren hochkonformal, unter maximaler Schonung des umgebenden Gewebes, anzupassen. Durch die nichtisozentrische Feldanordnung wird dies noch einmal verbessert. Voraussetzung neben der geometrischen Präzision ist die exakte dosimetrische Berechnung der einzelnen, kleinen Felder aus denen letztlich die Gesamtdosis resultiert. Doch gerade die Kleinfelddosimetrie ist hochempfindlich und daher oftmals mit Fehlern behaftet. Neben der Positioniergenauigkeit, ist die Auswahl der geeigneten Detektoren in Bezug auf Größe und Material, für die Messung der kleinen Felder, besonders wichtig. Insbesondere die korrekte Bestimmung der Wasser-Energiedosis auf dem Zentrahlstrahl, aufgrund des fehlenden lateralen Sekundärelektronengleichgewichts, bleibt auch bei der Verwendung geeigneter Detektoren fehleranfällig. Als Outputfakor bzw. auch totaler Streufaktor, wird das Verhältnis der Dosis auf dem Zentrahlstrahl eines beliebigen Feldes zu einem Referenzfeld bezeichnet. Um eine Gesamtungenauigkeit in der Dosisberechnung von 5 % einzuhalten, ist es notwendig eben diese Outputfaktoren mit einer Unsicherheit von < 3 % zu bestimmen. Ziel der Arbeit ist es anhand verschiedener, für diesen Messzweck geeigneten, Detektoren die Outputfaktoren für die fixen Rundkollimatoren sowie für die Iriskollimatoren des Cyberknife© VSI Systems (Fa. Accuray, Sunnyvale, CA, USA) zu bestimmen. Das Augenmerk gilt hierbei den Feldgrößen kleiner als 25 mm. Ab dieser Feldgröße herrscht aufgrund der Photonengrenzenergie von 6 MeV kein laterales Sekundärelektronengleichgewicht, da die Reichweite der Elektronen größer als die betrachtete Feldgröße ist. Somit lassen sich die Outputfaktoren bzw. totale Streufaktoren nicht direkt mit den zur Verfügung stehenden Messmitteln messen, sondern müssen mit detektorspezifischen Korrekturfaktoren bestimmt werden. Die gemessenen Outputfaktoren werden ausgewertet und mit den Ergebnissen in der Literatur diskutiert. Aus den Ergebnissen der verschiedenen Detektoren soll ein gemittelter Wert abgeleitet und für die Dosisberechnungsalgorithmen als Basisdaten übernommen werden und zu einer Erhöhung der Gesamtgenauigkeit führen.
Im Verlauf dieser Dissertation konnte gezeigt werden, dass eine erhöhte Expression des tonoplastidären Dicarboxylat Transporters zu einem erhöhten Gehalt an Malat bei gleichzeitig vermindertem Citratgehalt in den Überexpressions-Pflanzen führt. Somit konnte, ähnlich wie in den k.o.-Pflanzen, ein reziprokes Verhalten von Citrat und Malat aufgezeigt werden.
Elektrophysiologische Analysen an Oozyten von X. laevis in Zusammenhang mit Aufnahmeversuchen an Proteoliposomen zeigten weiterhin, dass der Transport von Citrat ebenfalls durch den TDT katalysiert wird. Anhand eines negativen Einwärts-Strom an Oozyten konnte gezeigt werden, dass dieser Citrat-Transport elektrogen ist. Weiterhin konnte gezeigt werden, dass Citrat2-H die transportierte Form von Citrat darstellt. Dieses wird vermutlich zusammen mit drei Protonen transportiert.
Die Dianionen Malat und Succinat, sowie höchstwahrscheinlich auch Fumarat, werden ebenfalls über den TDT transportiert. Unter Standardbedingungen werden diese in die Vakuole importiert. Im Gegenzug wird Citrat aus der Vakuole exportiert. Die trans-stimulierende Wechselwirkung von Malat, Succinat und Fumarat auf den Citrat Transport und vice versa bestärkt den in dieser Arbeit postulierten Antiport der jeweiligen Carboxylate über den Tonoplasten. Dieser ist jedoch nicht obligat, was an dem verringerten Transport von Citrat ohne Gegensubstrat über die Membran gezeigt werden konnte.
Unter Trockenstress und osmotischen Stress konnte ebenfalls gezeigt werden, dass die erhöhte Expression des TDT maßgeblich an der Akkumulation von Malat und der Mobilisierung von Citrat unter den genannten Stressbedingungen beteiligt ist.
Letztlich konnte mittels Säurestressexperimenten nachgewiesen werden, dass die Malatakkumulation, bei gleichzeitigem Citrat Abbau nicht zwingend miteinander gekoppelt sind, unter Säurestress müssen daher weitere regulatorische Effekte auf den Malat-Import bzw. den Citrat-Export vorherrschen.
Synaptic transmission is controlled by re-uptake systems that reduce transmitter concentrations in the synaptic cleft and recycle the transmitter into presynaptic terminals. The re-uptake systems are thought to ensure cytosolic concentrations in the terminals that are sufficient for reloading empty synaptic vesicles (SVs). Genetic deletion of glycine transporter 2 (GlyT2) results in severely disrupted inhibitory neurotransmission and ultimately to death. Here we investigated the role of GlyT2 at inhibitory glycinergic synapses in the mammalian auditory brainstem. These synapses are tuned for resilience, reliability, and precision, even during sustained high-frequency stimulation when endocytosis and refilling of SVs probably contribute substantially to efficient replenishment of the readily releasable pool (RRP). Such robust synapses are formed between MNTB and LSO neurons (medial nucleus of the trapezoid body, lateral superior olive). By means of patch-clamp recordings, we assessed the synaptic performance in controls, in GlyT2 knockout mice (KOs), and upon acute pharmacological GlyT2 blockade. Via computational modeling, we calculated the reoccupation rate of empty release sites and RRP replenishment kinetics during 60-s challenge and 60-s recovery periods. Control MNTB-LSO inputs maintained high fidelity neurotransmission at 50 Hz for 60 s and recovered very efficiently from synaptic depression. During 'marathon-experiments' (30,600 stimuli in 20 min), RRP replenishment accumulated to 1,260-fold. In contrast, KO inputs featured severe impairments. For example, the input number was reduced to ~1 (vs. ~4 in controls), implying massive functional degeneration of the MNTB-LSO microcircuit and a role of GlyT2 during synapse maturation. Surprisingly, neurotransmission did not collapse completely in KOs as inputs still replenished their small RRP 80-fold upon 50 Hz | 60 s challenge. However, they totally failed to do so for extended periods. Upon acute pharmacological GlyT2 inactivation, synaptic performance remained robust, in stark contrast to KOs. RRP replenishment was 865-fold in marathon-experiments, only ~1/3 lower than in controls. Collectively, our empirical and modeling results demonstrate that GlyT2 re-uptake activity is not the dominant factor in the SV recycling pathway that imparts indefatigability to MNTB-LSO synapses. We postulate that additional glycine sources, possibly the antiporter Asc-1, contribute to RRP replenishment at these high-fidelity brainstem synapses.
Grape powdery mildew, Erysiphe necator, is one of the most significant plant pathogens, which affects grape growing regions world-wide. Because of its short generation time and the production of large amounts of conidia throughout the season, E. necator is classified as a moderate to high risk pathogen with respect to the development of fungicide resistance. The number of fungicidal mode of actions available to control powdery mildew is limited and for some of them resistances are already known. Aryl-phenyl-ketones (APKs), represented by metrafenone and pyriofenone, and succinate-dehydrogenase inhibitors (SDHIs), composed of numerous active ingredients, are two important fungicide classes used for the control of E. necator. Over the period 2014 to 2016, the emergence and development of metrafenone and SDHI resistant E. necator isolates in Europe was followed and evaluated. The distribution of resistant isolates was thereby strongly dependent on the European region. Whereas the north-western part is still predominantly sensitive, samples from east European countries showed higher resistance frequencies.
Classical sensitivity tests with obligate biotrophs can be challenging regarding sampling, transport and especially the maintenance of the living strains. Whenever possible, molecular genetic methods are preferred for a more efficient monitoring. Such methods require the knowledge of the resistance mechanisms. The exact molecular target and the resistance mechanism of metrafenone is still unknown. Whole genome sequencing of metrafenone sensitive and resistant wheat powdery mildew isolates, as well as adapted laboratory mutants of Aspergillus nidulans, where performed with the aim to identify proteins potentially linked to the mode of action or which contribute to metrafenone resistance. Based on comparative SNP analysis, four proteins potentially associated with metrafenone resistance were identified, but validation studies could not confirm their role in metrafenone resistance. In contrast to APKs, the mode of action of SDHIs is well understood. Sequencing of the sdh-genes of less sensitive E. necator isolates identified four different target-site mutations, the B-H242R, B-I244V, C-G169D and C-G169S, in sdhB and sdhC, respectively. Based on this information it was possible to develop molecular genetic monitoring methods for the mutations B-H242R and C-G169D. In 2016, the B-H242R was thereby identified as by far the most frequent mutation. Depending on the analysed SDH compound and the sdh-genotype, different sensitivities were observed and revealed a complex cross-resistance pattern.
Growth competition assays without selection pressure, with mixtures of sensitive and resistant E. necator isolates, were performed to determine potential fitness costs associated with fungicide resistance. With the experimental setups used, a clear fitness disadvantage associated with metrafenone resistance was not identified, although a strong variability of fitness was observed among the tested resistant E. necator isolates. For isolates with a reduced sensitivity towards SDHIs, associated fitness costs were dependent on the sdh-genotype analysed. Competition tests with the B-H242R genotypes gave evidence that there are no fitness costs associated with this mutation. In contrast, the C-G169D genotypes were less competitive, indicating a restricted fitness compared to the tested sensitive partners. Competition assays of field isolates, which exhibited several resistances towards different fungicide classes, indicated that there are no fitness costs associated with a multiple resistant phenotype in E. necator. Overall, these results clearly indicate the importance to analyse a representative number of isolates with sensitive and resistant phenotypes.
Phycobilisomes (PBS) are the major light-harvesting complexes for the majority of cyanobacteria
and allow these organisms to absorb in the so-called green gap. They consist of smaller units called
phycobiliproteins (PBPs), which are composed of an α- and a β-subunit with covalently bound
linear tetrapyrroles (phycobilins). The latter are attached to the apo-PBPs by phycobiliprotein
lyases. Interestingly, cyanobacteria of the genus Prochlorococcus lack complete PBS and instead
use prochlorophyte chlorophyll-binding proteins (Pcbs), which effectively utilize the energy of the
blue light region. The low-light-adapted (LL) strain Prochlorococcus marinus SS120 has a single
PBP, phycoerythrin-III (PE-III). It has been postulated that PE-III is chromophorylated with the
phycobilins phycourobilin (PUB) and phycoerythrobilin (PEB) in a 3:1 ratio. Thereby, the function
of PE-III remains unclear so far, so that light-gathering function and also photoreceptor function
are discussed.
The main goal of this work was to characterize the assembly of PE-III and thus the function of the
six putative phycobiliprotein lyases of P. marinus SS120. Previous work found that the individual
lyases could not be produced in soluble form, so we switched to a dual pDuet™ plasmid system in
E. coli, which was successfully established. Investigation of the binding of PEB to Apo-PE
revealed that the CpeS lyase specifically chromophorylated Cys82 with 3Z-PEB. Unfortunately,
additional chromophorylation could not be observed using the pDuet system. Therefore, in a
second part of the work, the entire PE gene cluster from P. marinus SS120 was to be introduced
into E. coli and expressed. Although the gene cluster was successfully transcribed within E. coli,
no translation was observed, possibly due to incompatible translation initiation between
Prochlorococcus and E. coli. The introduction of a mini PE cluster (CpeAB) into the
cyanobacterium Synechococcus sp. PCC 7002 was also successfully performed, in which case
production of CpeB but not CpeA from Prochlorococcus was detected. Recombinant CpeB was
also detected together with intrinsic PBP in Synechococcussp. 7002, indicating structural similarity
and incorporation into PBS in Synechococcus sp. 7002. Overall, the obtained results suggest that a
cyanobacterial host is a good option for the studies on the assembly of PE-III from P. marinus and,
based on this, future work could aim at generating an artificial operon using synthetic biology to
achieve efficient translation of all genes.
Increasing costs due to the rising attrition of drug candidates in late developmental phases alongside post-marketing withdrawal of drugs challenge the pharmaceutical industry to further improve their current preclinical safety assessment strategies. One of the most common reasons for the termination of drug candidates is drug induced hepatotoxicity, which more often than not remains undetected in early developmental stages, thus emphasizing the necessity for improved and more predictive preclinical test systems. One reason for the very limited value of currently applied in vitro test systems for the detection of potential hepatotoxic liabilities is the lack of organotypic and tissue-specific physiology of hepatocytes cultured in ordinary monolayer culture formats.
The thesis at hand primarily deals with the evaluation of both two- and three-dimensional cell culture approaches with respect to their relative ability to predict the hepatotoxic potential of drug candidates in early developmental phases. First, different hepatic cell models, which are routinely used in pharmaceutical industry (primary human hepatocytes as well as the three cell lines HepG2, HepaRG and Upcyte hepatocytes), were investigated in conventional 2D monolayer culture with respect to their ability to detect hepatotoxic effects in simple cytotoxicity studies. Moreover, it could be shown that the global protein expression levels of all cell lines substantially differ from that of primary human hepatocytes, with the least pronounced difference in HepaRG cells.
The introduction of a third dimension through the cultivation of spheroids enables hepatocytes to recapitulate their typical native polarity and furthermore dramatically increases the contact surface of adjacent cells. These differences in cellular architecture have a positive influence on hepatocyte longevity and the expression of drug metabolizing enzymes and transporters, which could be proven via immunofluorescent (IF) staining for at least 14 days in PHH and at least 28 days in HepaRG spheroids, respectively. Additionally, the IF staining of three different phase III transporters (MDR1, MRP2 and BSEP) indicated a bile canalicular network in spheroids of both cell models. A dose-dependent inducibility of important cytochrome P450 isoenzymes in HepaRG spheroids could be shown on the protein level via IF for at least 14 days. CYP inducibility of HepaRG cells cultured in 2D and 3D was compared on the mRNA level for up to 14 days and inducibility was generally lower in 3D compared to 2D under the conditions of this study. In a comparative cytotoxicity study, both PHH and HepaRG spheroids as well as HepaRG monolayers have been treated with five hepatotoxic drugs for up to 14 days and viability was measured at three time points (days 3, 7 and 14). A clear time- and dose-dependent onset of the drug-induced hepatotoxic effects was observable in all conditions tested, indicated by a shift of the respective EC50 value towards lower doses by increasing exposure. The observed effects were most pronounced in PHH spheroids, thus indicating those as the most sensitive cell model in this study. Moreover, HepaRG cells were more sensitive in spheroid culture compared to monolayers, which suggests a potential application of spheroids as long-term test system for the detection of hepatotoxicities with slow onset. Finally, the basal protein expression levels of three antigens (CYP1A2, CYP3A4 and NAT 1/2) were analyzed via Western Blotting in HepaRG cells cultured in three different cell culture formats (2D, 3D and QV) in order to estimate the impact of the cell culture conditions on protein expression levels. In the QV system enables a pump-driven flow of cell culture media, which introduces both mechanical stimuli through shear and molecular stimuli through dynamic circulation to the monolayer. Those stimuli resulted in a clearly positive effect on the expression levels of the selected antigens by an increased expression level in comparison to both 2D and 3D. In contrast, HepaRG spheroids showed time-dependent differences with the overall highest levels at day 7.
The studies presented in this thesis delivered valuable information on the increased physiological relevance in dependence on the cell culture format: three-dimensionality as well as the circulation of media lead to a more differentiated phenotype in hepatic cell models. Those cell culture formats are applicable in preclinical drug development in order to obtain more relevant information at early developmental stages and thus help to create a more efficient drug development process. Nonetheless, further studies are necessary to thoroughly characterize, validate and standardize such novel cell culture approaches prior to their routine application in industry.
Pervasive human impacts rapidly change freshwater biodiversity. Frequently recorded exceedances of regulatory acceptable thresholds by pesticide concentrations suggest that pesticide pollution is a relevant contributor to broad-scale trends in freshwater biodiversity. A more precise pre-release Ecological Risk Assessment (ERA) might increase its protectiveness, consequently reducing the likelihood of unacceptable effects on the environment. European ERA currently neglects possible differences in sensitivity between exposed ecosystems. If the taxonomic composition of assemblages would differ systematically among certain types of ecosystems, so might their sensitivity toward pesticides. In that case, a single regulatory threshold would be over- or underprotective.
In this thesis, we evaluate (1) whether the assemblage composition of macroinvertebrates, diatoms, fishes, and aquatic macrophytes differs systematically between the types of a European river typology system, and (2) whether these taxonomical differences engender differences in sensitivity toward pesticides. While a selection of ecoregions is available for Europe, only a single typology system that classifies individual river segments is available at this spatial scale - the Broad River Types (BRT).
In the first two papers of this thesis, we compiled and prepared large databases of macroinvertebrate (paper one), diatom, fish, and aquatic macrophyte (paper two) occurrences throughout Europe to evaluate whether assemblages are more similar within than among BRT types. Additionally, we compared its performance to that of different ecoregion systems. We employed multiple tests to evaluate the performances, two of which were also designed in the studies. All typology systems failed to reach common quality thresholds for the evaluated metrics for most taxa. Nonetheless, performance differed markedly between typology systems and taxa, with the BRT often performing worst. We showed that currently available, European freshwater typology systems are not well suited to capture differences in biotic communities and suggest several possible amelioration.
In the third study, we evaluated whether ecologically meaningful differences in sensitivity exist between BRT types. To this end, we predicted the sensitivity of macroinvertebrate assemblages across Europe toward Atrazine, copper, and Imidacloprid using a hierarchical species sensitivity distribution model. The predicted assemblage sensitives differed only marginally between BRT types. The largest difference between
median river type sensitivities was a factor of 2.6, which is far below the assessment factor suggested for such models (6), as well as the factor of variation commonly observed between toxicity tests of the same species-compound pair (7.5 for copper). Our results don’t support the notion that a type-specific ERA might improve the accuracy of thresholds. However, in addition to the taxonomic composition the bioavailability of chemicals, the interaction with other stressors, and the sensitivity of a given species might differ between river types.
Northwest Africa is predicted to undergo a climatic shift from a temperate to an arid climate resulting in increased aridity, water salinity, and river intermittency. These changes have the potential to impact freshwater communities, ecosystem functioning, and related ecosystem services. However, there is still limited data on the impact of climate change and salinity on river ecosystems and the people depending on it, particularly in understudied regions such as Northwest Africa. In this dissertation, I focus on the Draa River basin in southern Morocco to assess the primary factors shaping and altering macroinvertebrate communities. A particular focus is placed on the impacts of salt on the ecosystem and the consequences for human well-being. We conducted a meta-analysis covering 195 sites in Northwest Africa to examine the responses of insect communities and their trait profiles to climate change and anthropogenically induced stressors. To exclude large-scale geographic patterns such as variations in climate conditions we conducted a confluence-based study focusing on tributaries and their joint downstream sections near three confluences in the Draa River basin. Additionally, we investigated the water and biological quality of 17 further sites, aiming to explore the relationship between human well-being and the ecosystem. Our approach involved conducting water measurements, biological monitoring, and household surveys to create water, biological, and human satisfaction indices. Our findings revealed that insect family richness in arid sites of Northwest Africa was, on average, 37 % lower than in temperate sites. Among the strongest factors contributing to reduced richness and low biological quality were low flow and high water salinity. Based on the results of the confluence study only around five taxa comprised over 90 % of specimens per site, with a higher proportion of salt-tolerant generalist species in saline sites. Resistance and resilience traits such as small body size, aerial dispersal, and air breathing were found to promote survival in arid and saline sites. However, low γ-diversity in the basin caused minimal differences in macroinvertebrate community composition suggesting that the community was generally adapted to the arid climate. We observed positive associations between river water quality and biological quality indices. However, no significant associations were found between these indices and human satisfaction. Human satisfaction was particularly low in the Middle Draa, where 89 % of respondents reported emotional distress due to water salinity and scarcity. Inhabitants in areas characterized by higher levels of water salinity and scarcity generally rated drinking and irrigation water quality lower. Considering that large parts of Northwest Africa will become arid by the end of the century, we can expect a loss of macroinvertebrate diversity affecting the entire ecosystem, which might potentially affect human well-being negatively. To protect the integrity of the ecosystem in the face of ongoing climate change, it is crucial to limit anthropogenic stressors such as secondary salinization and the pressures on water resources. Protecting both more and less saline rivers, preserving natural water flow, and maintaining connectivity between habitats will allow to maintain the Draa River biodiversity, ensure ecosystem functioning, and benefit inhabitants through ecosystem services. Future policies and action plans should consider the interdependence between ecosystems and human inhabitants to enhance overall well-being.